Accepted Manuscript

Preeclampsia: Novel Insights from Global RNA Profiling of Trophoblast

Subpopulations

Mr. Matthew Gormley, BS, Ms. Katherine Ona, BS, Miko Kapidzic, MD, Tamara
Garrido-Gomez, PhD, Tamara Zdravkovic, PhD;, Susan J. Fisher, PhD

PII: S0002-9378(17)30441-6
DOI: 10.1016/j.ajog.2017.03.017
Reference: YMOB 11588

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 19 January 2017

Revised Date: 15 March 2017
Accepted Date: 17 March 2017

Please cite this article as: Gormley M, Ona K, Kapidzic M, Garrido-Gomez T, Zdravkovic T, Fisher SJ,
Preeclampsia: Novel Insights from Global RNA Profiling of Trophoblast Subpopulations, American
Journal of Obstetrics and Gynecology (2017), doi: 10.1016/j.ajog.2017.03.017.

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Preeclampsia: Novel Insights from Global RNA Profiling

of Trophoblast Subpopulations

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Mr. Matthew GORMLEY, BS; Ms. Katherine ONA, BS; Miko KAPIDZIC, MD;
Tamara GARRIDO-Gomez, PhD; Tamara ZDRAVKOVIC, PhD; and Susan J.

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FISHER, PhD

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Center for Reproductive Sciences, Department of Obstetrics, Gynecology, and

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Reproductive Sciences, The Eli & Edythe Broad Center for Regeneration
Medicine and Stem Cell Research and the Department of Anatomy, University of
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California San Francisco, San Francisco, CA (USA)
(Mr. Gormley, Ms. Ona and Drs. Kapidzic, Garrido-Gomez, Zdravkovic, and
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Fisher).
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This study was funded by 1 R37HD076253 to S.F.

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The authors report no conflicts of interest.

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Corresponding author: S.J. Fisher, PhD. 35 Medical Center Way, Box 0665, San
Francisco, CA (USA), telephone (415) 476-5297, fax (415) 476-1635,
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email susan.fisher@.ucsf.edu
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Word Count 7395

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CONDENSATION AND SHORT VERSION OF TITLE

Brief Summary

Global profiling of trophoblast subpopulations isolated by laser microdissection

from the placentas of severe preeclampsia cases revealed novel aspects of RNA

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dysregulation in this syndrome.

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Short Title

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RNA Misexpression in Severe Preeclampsia

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ABSTRACT

BACKGROUND: The maternal signs of preeclampsia, including the new onset of

high blood pressure, can occur secondary to faulty placentation. We theorized

that transcriptomic analyses of trophoblast subpopulations in situ would lend new

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insights into the role of these cells in preeclampsia pathogenesis.

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OBJECTIVE: Our goal was to enrich syncytiotrophoblasts, invasive

cytotrophoblasts or endovascular cytotrophoblasts from the placentas of severe

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preeclampsia cases. Total RNA was subjected to global transcriptional profiling

to identify RNAs that were misexpressed as compared to controls.

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STUDY DESIGN: This was a cross-sectional analysis of placentas from women
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diagnosed with severe preeclampsia. Gestational age-matched controls were

placentas from women who had a preterm birth with no signs of infection. Laser
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microdissection enabled enrichment of syncytiotrophoblasts, invasive

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cytotrophoblasts or endovascular cytotrophoblasts. Following RNA isolation, a

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microarray approach was used for global transcriptional profiling.

Immunolocalization identified changes in mRNA expression that carried over to

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the protein level. Differential expression of non-protein-coding RNAs was

confirmed by in situ hybridization. A two-way ANOVA of non-coding RNA

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expression identified particular classes that distinguished trophoblasts in cases

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vs. controls. Cajal body foci were visualized by COILIN immunolocalization.

RESULTS: Comparison of the trophoblast subtype data within each group

(severe preeclampsia or noninfected preterm birth) identified many highly

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differentially expressed genes. They included molecules known to be expressed

by each subpopulation, evidence that the method worked. Genes that were

differentially expressed between the two groups, in a cell-type specific manner,

encoded a combination of molecules that previous studies associated with

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severe preeclampsia and those that were not known to be dysregulated in this

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pregnancy complication. Gene ontology analysis of the syncytiotrophoblast data

highlighted the dysregulation of immune functions, morphogenesis, and transport

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as well as responses to VEGF and progesterone. The invasive cytotrophoblast

data provided evidence of alterations in cellular movement, which is consistent

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with the shallow invasion often associated with severe preeclampsia. Other
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dysregulated pathways included immune, lipid, oxygen and transforming growth

factor-beta responses. The data for endovascular cytotrophoblasts showed

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disordered metabolism, signaling and vascular development. Additionally, the

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transcriptional data revealed the differential expression in severe preeclampsia of

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two classes of non-coding RNAs: lncRNAs and snoRNAs. The long non-coding

RNA, UROTHELIAL CANCER ASSOCIATED 1, was the most highly up

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regulated in this class. In situ hybridization confirmed severe preeclampsia-

associated expression in syncytiotrophoblasts. The snoRNAs, which chemically

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modify RNA structure, also correlated with severe preeclampsia. Thus, we

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enumerated Cajal body foci, sites of snoRNA activity, in primary cytotrophoblasts

isolated from control and severe preeclampsia placentas. In severe

preeclampsia, cytotrophoblasts had approximately double the number of these

foci as the control samples.

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CONCLUSION: A laser microdissection approach enabled the identification of

novel mRNAs and non-coding RNAs that were misexpressed by various

trophoblast subpopulations in severe preeclampsia. The results suggested new

avenues of investigation, in particular, the roles of PRG2, Kell blood group

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determinants and UROTHELIAL CANCER ASSOCIATED 1 in

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syncytiotrophoblast pathologies. Additionally, many of the newly identified

dysregulated molecules might have clinical utility as biomarkers of severe

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preeclampsia.

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KEYWORDS: cytotrophoblasts, laser microdissection, mRNA, non-protein-
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coding RNA, placenta, potential biomarkers, severe preeclampsia,

syncytiotrophoblast, transcriptomics
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INTRODUCTION

In many ways the placenta steers the course of pregnancy 1. Preeclampsia (PE)

is one of the great obstetrical syndromes, which also include intrauterine growth

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restriction, preterm labor, preterm premature rupture of membranes, late

spontaneous abortion, and placental abruption2. They share the common feature

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of being associated with defects in deep placentationthe depth to which

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cytotrophoblasts invade the uterus is relatively shallow as compared to normal

pregnancies. This is oftentimes accompanied by aberrations in physiologic

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transformation of the spiral arteries2, 3. How this common denominator diverges
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into the disparate signs of each condition is not understood. PE, which affects 3-

7% of pregnancies in developed countries, is diagnosed according to the

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maternal signs, which include the new onset of high blood pressure, and variably,

proteinuria4. Severe (and early-onset) PE (sPE) entails exacerbation of the

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hypertension or new findings such as thrombocytopenia, impaired liver function5,

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. PE is also a major cause of premature birth and low birth weight7. Beyond
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pregnancy, development of a pregnancy complication that is associated with

faulty placentation, such as PE, positively correlates with an elevated relative risk
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of maternal cardiovascular disease years later 8.

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The association between PE and abnormal placentation has been the impetus

for studies aimed at understanding the origins and dimensions of the latter

defects. At a morphological level, abnormalities in formation of the placental bed

are thought to be particularly important. Cytotrophoblast (CTB) invasion of the

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uterine wall is variably shallow rather than deep. More consistently, CTB

remodeling of uterine spiral arteries is incomplete, which has the net effect of

reducing maternal blood flow to the placenta9. At a molecular level, CTB

differentiation along the pathway that leads to uterine invasion is abnormal as

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demonstrated by deficits in the elaborate switching of stage specific antigens that

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normally enable invasion, vascular mimicry and their cohabitation of the decidua

with the unusual maternal immune cells that reside in this location10. In addition

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to morphological and targeted molecular analyses, investigators are also

applying global transcriptional profiling approaches to better understand the

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placental defects that are associated with PE. To date, these studies have
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focused on chorionic villi (e.g., 11, 12), the maternal-fetal interface (e.g.,13) or

purified CTBs as they differentiate along the invasive pathway in vitro (e.g., 14).
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These studies have the advantage of being unbiased, therefore, enabling the de
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novo discovery of misregulated genes.

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However, the global transcriptional profiling approaches applied to date all have
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certain disadvantages. In tissue-based analyses, signals from the cell type(s) of

interest are diluted by the many other cell types that contribute to the gene
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expression signature of the sample. Cultured CTBs, while a more homogenous

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cell type, may not wholly recapitulate differentiation along the invasive pathway in

the absence of maternal cells and the signals they provide. To circumvent these

problems we applied a laser microdissection approach to placentas from sPE

pregnancies. This enabled the enrichment and transcriptional profiling of specific

TB subpopulationssyncytiotrophoblasts (STBs), invasive CTBs (iCTBs) and

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endovascular CTBs (eCTBs). The results revealed novel aspects of gene

expression in each of the cell types we examined, which could be useful sPE

biomarkers if they appear in maternal blood. The data also suggested new

theories about the pathogenesis of sPE, particularly in terms of the placental

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manifestations.

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Materials and Methods

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Study Design
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This was a case-control study with the goal of identifying changes in TB gene

expression in sPE as compared to nPTB. The American College of Obstetrics

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and Gynecology (ACOG) criteria were used to identify PE patients 5, 15. These

include: 1) the new onset of hypertension measured on two occasions of least 4

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h apartblood pressure 140 mm Hg (systolic) or 90 mm Hg (diastolic) in a

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woman who was normotensive before 20 wks of pregnancy; 2) the appearance

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of proteinuriaexcretion of 300 mg in a 24-h period or protein/creatinine ratio

greater than or equal to 0.3 mg/dL or dipstick reading of 1+, which is used only if
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other quantitative methods are not available. sPE was also diagnosed using
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ACOG criteria 5, 15, based on additional signs and symptoms: systolic blood

pressure 160 mm Hg and/or diastolic pressure 110 mm Hg on two occasions

at least four hours apart while the patient is on bed rest; proteinuria of 5 g in a

24-h period or 3+ on urine dipstick; hemolysis (peripheral blood smear and/or

LDH 480); elevated liver function (SGOT 64 or SGPT 80);

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thrombocytopenia (platelets 100,000); oliguria ( 500 cc in 24 h); creatinine

1.1 mg/dL or a doubling of the serum creatinine concentration with no known

renal dysfunction/disease; cerebral or visual disturbances and/or convulsions

with no prior history of seizure disorders.

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As controls, samples were obtained from women who delivered due to nPTL,

diagnosed according to the criteria recommended by Herron and colleagues 16,

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including regular uterine contractions after 20 wks or before 37 wks of gestation,

which are 5 to 8 min apart, and accompanied by one or more of the following:

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(1) progressive changes in the cervix; (2) cervical dilation 2 cm and/or (3)
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cervical effacement 80 percent. Patients with evidence of inflammation were

excluded on the basis of the following criteria: maternal fever > 100.4F, uterine
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tenderness, fetal tachycardia (fetal heart rate > 160 beats per min) and/or
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(placental) histological criteria compatible with inflammation 17 18, 19. Women with
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pre-existing medical conditions such as thyroid insufficiency, chronic

hypertension or diabetes were excluded from the case and the control groups.
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Other exclusion criteria included premature rupture of membranes and/or fetal

anomaly. The UCSF Institutional Review Board (Committee on Human

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Research) approved this study. Written informed consent was obtained from all
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donors.

A laser microdissection approach was used to isolate STBs, iCTBs and eCTBs.

Total RNA was purified from each sample type and subjected to microarray

analyses, which enabled the identification of misexpressed transcripts. An

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immunolocalization approach was used to identify sPE-associated alterations in

mRNA abundance that carried over to the protein level. A two-ANOVA identified

changes in the expression of non-protein-coding RNAs that tracked with sPE. An

in situ hybridization approach was used to verify the latter data.

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Immunolocalization of coilin enabled enumeration of Cajal body foci, sites of

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snoRNA activity.

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Human Tissue Collection

Samples were collected within 1 h of birth, washed in phosphate-buffered saline

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(PBS), transferred to ice-cold cytowash medium (DME/H-21 Medium, 1%
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glutamine plus, 1% penicillin/streptomycin, 0.1% gentamycin) supplemented with

2.5% FBS, and transferred on ice to the laboratory for immediate processing.
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The clinical characteristics of the sPE and noninfected preterm birth (nPTB)
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pregnancies are summarized in Tables 1A (microarray experiments) and 1B

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(immunolocalization and in situ experiments). Additionally, we verified at gross

and histological levels that spiral artery invasion was deficient in sPE and normal
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in nPTL biopsies.
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Laser microdissection and RNA isolation

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We used laser microdissection to enrich for STBs, iCTBs and eCTBs from

placentas of pregnancies complicated by sPE or nPTB (n=4/group). Briefly, the

chorionic villi with the attached portions of the basal plate from three regions of

the placenta were washed repeatedly in cold PBS to remove blood. Unfixed

specimens (1 x 1 x 0.5 cm) were placed in cryomolds containing optimal cutting

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temperature medium (OCT), frozen over a dry ice/ethanol slurry, and stored at -

80oC. The blocks were sectioned at 20 m by using a Leica CM3050 cryostat.

The sections were mounted on UV-treated polyethylene naphthalate-membrane

slides (ThermoFisher Scientific), and stored under dry ice prior to laser

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microdissection later that day. Immediately before the procedure, sections were

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immersed in cold PBS until the OCT dissolved (~1 min), dipped in 0.1% toluidine

blue for 30 s, washed in cold PBS, dehydrated (30 s/treatment) in a graded

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ethanol series (75% x 2, 95%, 100%), then rapidly dried with compressed

nitrogen. All solutions were made with nuclease-free water. STBs, iCTBs and

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eCTBs were laser dissected (Leica LMD 7000) and collected directly into RLT
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Plus (cell lysis) Buffer (Qiagen RNeasy Plus Micro kit).
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Total RNA was isolated according to the manufacturers protocol and

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concentrations were measured photometrically (NanoDrop 2000c). RNA integrity

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was determined via microfluidic phoresis (Agilent Bioanalyzer 2100) in which a

fluorescent dye is introduced into RNA, detected and translated into gel-like
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images (bands) and electropherograms (peaks). The samples were stored at -

80C prior to analysis.

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Microarray analyses

Global RNA profiling was accomplished by using the GeneChip HuGene 2.0 ST

array (Affymetrix). Sample processing and hybridization were done according to

protocols that were devised by the UCSF Gladstone (NHLBI) Genomics Core

Facility. Gene level expression data quality was confirmed, normalized (RMA)
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and summarized (Affymetrix Expression Console Software). Significant

differential expression was determined using the limma package with ANOVA in

R to identify genes with an absolute linear fold change 2 and an adjusted p <

0.05 20, 21. The data were deposited in GEO (accession number GSE93839).

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Gene set enrichment analysis

To identify biological processes that were significantly overrepresented (sPE vs.

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nPTB) in the various TB subtypes we used gene set enrichment analysis

(preranked; GSEA software)22. The data were summarized in the form of a Trellis

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plot that was generated in OriginPro (OriginLabs). The same approach was used
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to identify chromosomal locations that were enriched in genes that were

differentially expressed in sPE.

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Immunolocalization
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Three to 4 samples from each pregnancy group, sPE or nPTL, other than those

used for the microarray analyses, were analyzed. The antibodies we employed
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are listed in Supplemental Table 1 along with the sources and working

concentrations.
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We published the methods we used23. Briefly, biopsies of the basal plate were

fixed in 3% paraformaldehyde for 1 h, washed three times in PBS, infiltrated with

5 to 15% sucrose followed by OCT and frozen in liquid nitrogen. Sections (~10

m) were cut on a Leica cryostat and mounted on glass slides. They were
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rehydrated in PBS for 20 min and nonspecific reactivity was blocked by

incubation in 3% bovine serum albumin (BSA)/0.1% Tween 20 (Fisher Scientific)

at room temperature for 30 min. The sections were incubated at 37C for 1 h with

primary antibodies. Then they were washed three times with PBS before they

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were incubated for 30 min at 37C with species-spec ific secondary antibodies

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(conjugated to a fluorescent reporter) and diluted in PBS. Finally, they were

washed three times in PBS. Vectashield mounting medium with 4',6-diamidino-2-

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phenylindole (DAPI; Vector Laboratories, USA) was used to visualize nuclei.

Controls included omission of the primary antibody or secondary antibody. The

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tissue sections were examined and images captured by using a Leica DM5000 B
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microscope.
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Isolation of villous and extravillous cytotrophoblasts CTBs were purified by using

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published methods24, 25. Briefly, chorionic villi were subjected to a series of

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sequential enzymatic digestion steps that sluffed the outer STB layer and

removed the underlying CTBs, which were isolated by centrifugation on a Percoll

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density gradient. Only cell preparations that were >90% pure as determined by

cytokeratin staining were used in experiments.

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ANOVA

We used OriginPro (OriginLAb) software to perform a two-way ANOVA that

identified non-protein-coding RNA classes that were significantly differentially

expressed (sPE vs. nPTB).

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In situ hybridization

Expression of the non-coding RNA UROTHELIAL CANCER ASSOCIATED 1

(UCA1), the most highly up regulated non-protein-coding RNA in STBs, was

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confirmed in 4 sets of sPE/nPTB samples by using an in situ hybridization

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approach according to the manufacturers instructions (Stellaris RNA FISH; LGC

Biosearch).

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Enumeration of Cajal body foci

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We found sPE-associated misregulation of snoRNAs. Since Cajal bodies are
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sites of their activity, we visualized these subnuclear foci by immunolocalization

of COILIN, a structural component of Cajal bodies. The method we used was

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described above. A serial set of images (Z-stacks) that enabled a three-

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dimensional reconstruction were collected by confocal microscopy (Leica SP5)

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and 100 cells/sample were analyzed by using Volocity Software (Perkin Elmer),

which enabled automated counting of the number of Cajal body foci/nucleus. The
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results were summarized in a box and whiskers plot, showing the median and

range.
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Results

Laser microdissection of trophoblast subtypes

We used a laser microdissection approach to analyze the gene expression

patterns of trophoblast subpopulations in sPE. We focused on STBs, iCTBs

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within the superficial decidua and eCTBs. The location of these cellsat the

surface of chorionic villi, the uterus and arterial walls, respectivelyfacilitated

their isolation. Since cells at the periphery of the microdissected area are

vaporized, we used a laser path that obliterated the underlying cells and enriched

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for the TB subtype of interest. Photomicrographs of the process are shown in

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Figure 1. The dotted lines indicate the areas that were targeted for removal by

laser microdissection of toluidine blue-stained, unfixed frozen sections (A and C).

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The regions that were removed are shown in the adjacent images (B and D).

Microdissection of STBs (Figure 1A and B), iCTBs and eCTBs (Figure 1C and D)

is illustrated.
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Global transcriptional profiling of trophoblast subtypes (sPE vs. nPTB)
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As a proof of concept that the approach worked, we asked whether we observed

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the expected differences in the transcriptomes of the TB subpopulations within

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each dataset. The results for the sPE and nPTB samples are shown in

Supplemental Figures 1 and 2, respectively. As a group, these datasets

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contained many highly differentially expressed genes, the expected result given

the large phenotypic differences among these TB populations. We also observed

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the upregulation of mRNAs that encoded proteins, which are known to be

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differentially expressed by each subpopulation. Examples in the STB samples

(Supplemental Figures 1A and 2A) included genes involved in steroid hormone

synthesis (HSDB1 and -B2), hCG subunits, pregnancy specific proteins, the

transferrin receptor and endogenous retroviruses (ERVW1), which have been

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implicated in cell fusion 26, a process that is required to produce the

multinucleated TB sheet that covers the surface of chorionic villi.

iCTBs and eCTBs that were isolated from the nPTB samples (Supplemental

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Figure 2B and C, respectively) had the most similar transcriptional profiles, which

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is consistent with the fact that these two cell types lie on a continuum of

differentiation along the invasive/extravillous pathway. In contrast, there were

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much greater differences between these two CTB populations in sPE

(Supplemental Figure 1B and C, respectively), which is in accord with the

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concept that this pregnancy complication is associated with defects in this
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differentiation pathway.
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In the iCTB vs. eCTB comparison, we also observed patterns of modulation that
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were expected, such as the down regulation of cadherin 1 (E-cadherin), which

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we previously reported 25, and JAM2, which is consistent with the loss of apical-

basal polarity that is coincident with CTB invasion. We also observed the
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opposite pattern of regulation (higher expression in eCTB than iCTB) for

molecules that we previously showed were upregulated during vascular invasion,

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e.g., VCAM 27. Together, these results suggested that laser microdissection had
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enriched the TB subpopulations of interest.

Next, we compared the gene expression profiles of particular TB subtypes in sPE

and nPTB. Supplemental Figures 3, 4 and 5 summarize the global transcriptional

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profiling data for STBs, iCTBs and eCTBs, respectively. The results are shown

as a heatmapa graphical representation of the results in which RNA

expression levels are depicted as colors. Previously, we showed that the

placenta and placental bed were essentially normal in nPTB17. Subsequently, this

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study design, comparing gene expression in sPE vs. nPTB, enabled us to

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pinpoint changes in placental gene expression that are specific to the former

syndrome13, 14 rather than attributable to alterations that occur with advancing

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gestational age28.

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Gene Ontology analyses revealed the many biological processes that sPE
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impacted in each TB subtype profiled. With regard to STBs, several aspects of

immune functions emerged. This result was in line with the two-stage theory of
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PE in which the first stage, faulty placentation, leads to the second stage, an
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inflammatory response 29. Morphogenesis was also affected, which is consistent

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with sPE-associated pathologies of the syncytium, including Tenney-Parker

changes and other STB lesions 17. In addition, transport was altered, which was
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in keeping with the fact that the newborns in the sPE group had significantly

lower birth weights than those in the nPTB category. That transcription was
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altered went along with our RNA profling results, which showed the differential
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expression of numerous genes and non-protein-coding RNAs (Supplemental

Figures 3-5). The results of this analysis also bolstered the evidence that VEGF
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, progesterone actions 32 and disordered protein serine threonine kinase
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signaling (e.g., downstream of VEGF 33) are involved in sPE pathogenesis as

related to STBs.

With regard to CTBs, we found that the effects of sPE were specific to each

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subtype we profiled. In terms of the iCTB population, there was again evidence

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that immune-related functions were impacted. Of particular interest were the

effects on cellular movement as CTB invasion is shallow in sPE2. The

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identification of pathways related to lipid, oxygen and TGF-beta responses was

consistent with the roles of dyslipidemia 34, oxidative stress 35, 36 and activin

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signaling 37, respectively, in sPE pathogenesis. Effects at the level of the cell
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cycle and DNA metabolism could be related to iCTB apoptosis in sPE 38. Finally,

the pathways that were specific to eCTBs included metabolism of small

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molecules. Regulation of vascular development was in keeping with the fact that
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these cells fail to assume a vascular phenotype in sPE 27. Finally, intracellular
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signaling was also perturbed.

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As to specific genes, the most highly up regulated mRNA in the STB data set

(Supplemental Figure 3) encoded PROTEOGLYCAN 2 (PRG2). This protein,

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which is also known as (eosinophil) MAJOR BASIC PROTEIN-1, is toxic to

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mammalian cells as well as to bacteria and helminths39. Other mRNAs that were

up regulated in STBs from sPE placentas included FOS, FOSB and JUNB. FOS

and JUN family members dimerize to form the activating protein-1 transcription

factor complex, a regulator of TB differentiation 40. Expression of FSTL3 was also

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elevated. The protein that this mRNA encodes, FOLLISTATIN-LIKE 3, inhibits

the actions of activin, a stimulator of FSH production and antagonist of BMP

signaling41. It was reported as up regulated in chorionic villus samples of women

who went on to develop PE42. In accord with this result, elevated FSTL-3 at mid-

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gestation was associated with an increased risk of developing this pregnancy

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complication43. The up regulated group also included MTSS1L (or ABBA), a

signal transduction molecule that links the plasma membrane to the actin

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cytoskeleton44. RDH13 was also in this category. This mitochondrial short-chain

retinol dehydrogenase/reductase is hypothesized to protect cells from oxidative

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stress45. The mRNA encoding KEL was also up regulated. This blood group
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antigen is third in importance behind the ABO and Rh systems in terms of

transfusion reactions due to the immunogenicity of some of the KELL

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glycoprotein antigens26. Finally, we also detected elevated levels of mRNAs

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encoding molecules that have varying degrees of utility as biomarkers of PE:

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INHBA, FLT1 and ENG 46, 47. This finding suggested that the more highly

differentially expressed genes in this dataset might be interesting to explore in

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this context.
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The down regulated genes included ABCB1 and ABCG2, which are expressed
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on the apical surface of syncytiotrophoblasts. Both proteins play an important

role in effluxing drugs and environmental chemicals48. Expression of SCN7A, an

atypical channel that in neurons senses Na levels in body fluids49, was also

reduced. The down regulated category included the mRNA encoding

NEUROSERPIN (SERPINl1). This molecule, which has been best studied in the
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context of the nervous system, plays an important role in neuroprotection. It has

also been found in amyloid plaques of Alzheimers patients, suggesting that,

similar to PRG2, it can form aggregates that are toxic to cells50. Likewise,

expression of FRZB, a secreted WNT inhibitor, was also down regulated as was

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CPS1, which catalyzes the first and rate-limiting step of the urea cycle51. One

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consequence could be a decrease in nitric oxide production52. IDO1, which

metabolizes tryptophan to kynurenine, and KMO, which metabolizes the latter

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molecule53, were both down regulated, which could compromise maternal

immunosuppression54. GSTA3, another down regulated mRNA, encodes a

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protein that is involved in the synthesis of testosterone and progesterone55. In
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other settings, it also functions as an anti-oxidant56. Finally, ERVFRD-1

(SYNCYTIN-2) was down regulated at the mRNA level, which confirmed

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previously published results57.

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Supplemental Figure 4 is a heatmap of the global transcriptional profiling results

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for iCTBs in sPE vs nPTL. This was the only dataset that contained n 4

samples because one of the sPE iCTB RNA preparations did not meet our RNA
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quality inclusion criteria. The mRNA encoding METALLOTHIONEIN 1G was at

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the top of the up regulated list. Proteins in this family are involved in numerous
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cellular processes, including zinc ion homeostasis, detoxification of heavy

metals, and protection against oxidative stress58. CXCL8 was also up regulated.

This chemokine, which is induced by pro-inflammatory cytokines such as TNF

and IL-1, recruits neutrophils and granulocytes to sites of inflammation59. F8A1,

which is nested within the largest intron of factor VIII, is transcribed in the
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opposite direction of the parent gene60. Although its function is unknown, it is

interesting to speculate about an involvement in coagulation. HMOX1 up

regulation was consistent with its role in the vasculature and induction by hypoxia
61
. Deletion of a single copy of this gene in mice produces a PE-like syndrome 62.

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HCAR2, the receptor for niacin, a powerful lipid modulator63, was also among the

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up regulated mRNAs as was the receptor protein-tyrosine kinase ephrin B2,

which we previously showed was up regulated as CTBs entered the uterine wall

SC
64
.

U
Overall, the list of genes that were DE in iCTBs was notable for the strongly
AN
down regulated mRNAs it contained, the highest fold of any dataset in this study.

This is in accord with the concept that CTB differentiation along the invasive
M

pathway is partially blocked in sPE10. The most down regulated mRNA encoded
D

a chemokine, CXCL9. Many of the DE genes encoded mRNAs that are specific
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to the placenta or enriched in this organ. They included GH2, several PSGs as

well as CGA, CYP19A1, INSL4, LGALS13 (placental protein 13) and LGALS14
EP

(placental protein 13 like). Other strongly down regulated mRNAs included

PDK4, which plays an important role in regulating energy homeostasis during

C

extreme nutritional conditions65. Whether or not this is evidence of a loss of

AC

compensatory mechanisms remains to be determined. The mRNA encoding

SVEP1, which is a ligand for integrin 9/166, was also in this group. Genetic

variants of this molecule are associated with an increased risk of coronary artery

disease and high blood pressure67; a presumed loss of function mutation is

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associated with poor outcomes in septic shock patients68. F5 mRNA was also

down regulated, which could be relevant to the fact that polymorphisms in this

gene impart an increased risk of sPE69. Finally, decreased expression of the

mRNA encoding the Notch ligand JAG1 was in accord with our previous

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description of a sPE-associated down regulation of this molecule in iCTBs 70.

RI
Many of the mRNAs in this category were placenta-specific or placenta-enriched.

SC
They included LGAL13 and -14, which are part of a primate-specific cluster of

galectin genes. Additionally, LGAL13, -14 and -16 are placenta-specific.

U
Evidence suggests that they contribute to immune tolerance of hemiallogeneic
AN
TBs by inducing apoptosis of T lymphocytes 71. LGAL13 and -14 were previously

reported to be down regulated in sPE 72. Their expression is controlled by

M

transcription factors that regulate TB differentiation and differential DNA

D

methylation, mechanisms that go awry in sPE72.

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Supplemental Figure 5 is a heatmap of the gene expression patterns (sPE vs.

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nPTL) of an enriched population of eCTBs that were microdissected from the

endovascular compartment of spiral arteries. REN, which encodes RENIN, had

C

the highest fold up regulation in sPE. Thus, the eCTB subpopulation might play a
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role in the dysregulation of the renin-angiotensin system that is observed in PE73.

This category of DE genes also included CHI3L1 (a glycosidase that is an

important modulator of the tumor microenvironment) 74, VTRNA2-1 (which plays

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important roles in apoptosis) 75, HMOX1, and KDR (VEGFR-2), which we

previously showed was down regulated as CTBs differentiate along the invasive

pathway 30. Its up regulation in the context of sPE is consistent with deficits in

eCTB differentiation. An mRNA that encoded a PROLINE-RICH PROTEIN,

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PRB1. In other settings, structurally related proteins have anti-bacterial activity76.

RI
The down regulated genes included CGA and PSG1, as well as SHOOM3, which

SC
is essential for normal kidney development in mice 77. We also found decreased

expression of an mRNA that encodes ELOVL2, which is involved in the extension

U
of long chain fatty acids. In addition, the cell surface heparan sulfate
AN
proteoglycan, GLYPICAN 3, was also expressed at lower levels. In

hepatocellular carcinoma cells, this oncofetal antigen binds to FRIZZLED thereby

M

promoting WNT signaling, which stimulates growth78. Our data suggest that the
D

opposite might be true in PE. The very low density lipid receptor (VLDLE) was
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also in this category. In keeping with the faulty CTB invasion that is a hallmark of

PE, ADGRG2, which encodes a G protein-coupled receptor with a role in

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adhesion and migration, was also down regulated79. The mRNA encoding

ADAMDEC1, which protects the intestines from inflammation, was similarly down
C

regulated80. Likewise, the expression of the atypical chemokine receptor ACKR2,

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which limits branching morphogenesis in the mammary gland81, was lower along

with another component of the renin-angiotensin system, ANGIOTENSIN I

CONVERTING ENZYME 2. Finally, we also observed down regulation of JAG1.

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Gene set enrichment showed that a portion of the sPE-associated transcripts that

were differentially expressed in the STB and the iCTB datasets were encoded by

particular regions of the genome. STB genes were overrepresented in two

areaschromosomes 1p and 19q. Chromosome 6q contributed to the iCTB

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gene signature. Thus, our data suggested that these chromosomal locations

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could be drivers of the placental phenotype in sPE.

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Differential mRNA expression carried over to the protein level

In these experiments, we used an immunolocalization approach, which enabled

U
simultaneous evaluation of the cell types that expressed a molecule and its
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potential functional relevance in terms of translating into expression differences

at the protein level. Trophoblast identity was confirmed by co-staining with an

M

antibody that was specific for cytokeratin (CK). These results are shown in Figure
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4. The individual anti-CK immunolocalization patterns are included in an

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expanded version of this Figure (Supplemental Figure 6).

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With regard to the syncytium, widespread immunostaining for PRG2 (up

regulated at the mRNA level) was detected in sPE. The signal was primarily in
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cytokeratin- (CK) positive STBs that form the surface of floating villi (Figure 4A).
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nPTB samples had much lower immunoreactivity. In keeping with the fact that

this protein is toxic to cells39, caspase-3 immunoreactivity, which was evaluated

in serial sections, tended to be in areas that had a strong PRG2 signal (Figure

4B). This finding suggested that the enhanced expression of this amyloidogenic

protein was associated with apoptosis. KEL (blood group antigen) expression
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was also confirmed as highly up regulated in sPE (Figure 4C). Immunoreactivity

was detected in the syncytium and the villous cores whereas in nPTB staining

was limited to the latter compartment. Likewise, anti-RDH13, which gave a strong

syncytiotrophoblast signal in sPE, did not stain or reacted weakly with floating villi

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from the nPTB cases (Supplemental Figure 7A). FSTL3 was primarily

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expressed in the stroma of the control samples with a punctate pattern of

immunoreactivity. In tissue sections of sPE placentas, a strong signal was

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detected in this compartment and in association with the syncytium

(Supplemental Figure 7B). Conversely, as expected from the global

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transcriptional profiling results, immunolocalization of GSTA3 in the nPTB
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samples showed strong antibody reactivity, primarily in the syncytial layer, which

was nearly absent in sPE chorionic villi (Supplemental Figure 7C). Likewise, the
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SERPINl1 signal was also reduced in the latter samples as compared to the
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nPTB cases (Supplemental Figure 7D).

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We used the same approach to confirm the expression patterns of the genes that
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were differentially expressed by the other TB subpopulations in sPE. With regard

to iCTBs within the superficial portion of the uterine wall, CXCL8 was more
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broadly expressed and gave a stronger signal in sPE vs. nPTB (Supplemental
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Figure 7E). The opposite pattern was observed for GH2 and PLAC1, i.e.,

stronger immunostaining of invasive CTBs in nPTB vs. sPE (Figure 4D and E).

With regard to the endovascular compartment, RENIN was the most highly up

regulated mRNA. Immunolocalization of its protein product showed that

endovascular CTBs reacted strongly with anti-RENIN in samples from sPE

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pregnancies whereas these cells gave a much weaker signal in nPTB (Figure

4F). In addition, widespread strong immunostaining of CK-positive perivascular

CTBs and CK-negative decidual cells was also detected. The latter pattern was

much less prominent in the nPTB samples. FABP4 expression also increased

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(Supplemental Figure 7F) and SHROOM3 decreased (Supplemental Figure

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7G).

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Trophoblast misexpression of non-protein-coding RNAs in severe

preeclampsia

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The global transcriptional profiling data (Supplemental Figures 3-5) revealed
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the differential expression of many non-coding RNAs: long non-coding RNAs

(lncRNAs), naturally occurring anti-sense transcripts (NATs), small nucleolar

M

RNAs (snoRNAs, which chemically modify RNA structure), pseudogenes, and

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microRNAs. The number of unique transcripts from each RNA class that were
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profiled is shown in Figure 5A (left hand panel). The right hand panel is a

summary of the number of RNAs in each class that were differentially expressed
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in sPE as compared to nPTB. A two-way ANOVA showed that lncRNAs and

snoRNAs were significantly differentially expressed in the case vs. control

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samples (Figure 5B).

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Next we sought independent means of confirming these results. In STBs, the

lncRNA UROTHELIAL CANCER ASSOCIATED 1 was the most highly

differentially expressed non-coding RNA in STBs (elevated 6-fold in sPE vs.

nPTB; Supplemental Figure 3). In situ hybridization confirmed this result

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(Figure 5C). As an additional control, samples of invasive bladder cancer (n = 3)

also gave a strong signal (data not shown). Interestingly, this lncRNA, which is

up regulated by hypoxia, plays pleiotropic roles including inhibition of apoptosis

82
.

PT
RI
Lastly, we asked whether there was complimentary evidence of snoRNA

dysregulation in sPE. In this regard, we analyzed Cajal bodies, subnuclear

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organelles and sites of snoRNA activity83, in primary CTBs isolated from normal

second trimester or term placentas and in the equivalent cells purified from the

U
placentas of women who experienced nPTB or sPE. The strategy was to
AN
visualize Cajal body foci by immunolocalizing COILIN, which serves as a scaffold

for these structures, and consequently, is required for their function84; CTB
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identity was confirmed by immunolocalizing CK. The images are shown in Figure
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6A. The upper panels are representative confocal micrographs and the lower
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panels are representative images of Volocity analyses of Z-stacks. The results

are quantified in Figure 6B. The number of Cajal body foci decreased as
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gestation advanced from second trimester to term. The nPTB samples had

numbers that were equivalent to CTBs at term. In contrast, CTBs isolated from
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sPE placentas had nearly double the number of Cajal body foci as the normal
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second trimester cells and ~6-fold more than either the term or the nPTB CTBs.

Thus, these results were consistent with dysregulation at the level of snoRNAs.

Discussion

Principal Findings of the Study

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This study revealed the sPE-associated differential expression of many novel

mRNAs by individual TB subtypes that lie at the maternal-fetal interface.

Because of the cells location we think that that the proteins they encode could

play interesting and previously unappreciated roles in the pathogenesis of this

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condition. Since, the datasets also contained molecules that are proposed sPE

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biomarkers, we theorize that some of the differentially expressed molecules that

we identified might also have utility in this regard. Finally, the results of this study

SC
suggested that a subset of non-protein-coding RNAs, lncRNAs and snoRNAs

that play an important role in modifying RNA structure, were also misexpressed

in sPE.
U
AN
As to approach, we used a laser microdissection approach to isolate specific TB
M

subpopulations from the placentas of pregnancies that were complicated by sPE.

D

For comparison purposes, we used the equivalent cells that were microdissected
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from the placentas of nPTB cases. Previous studies that employed laser

microdissection and placental samples were aimed at protein analyses85-88 or

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particular mRNA targets89. To our knowledge, this is the first time that such an

approach has been used with the goal of global transcriptional profiling. We
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reasoned that enriching for TBs would amplify signals from these cells that are
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diluted by the other cell types that are present in biopsies of placenta or the

maternal-fetal interface.

Meaning of the Findings for the Understanding of Preeclampsia

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29

The results of this study enabled us to propose new theories that advance our

understanding of the disease mechanisms underlying sPE that could be

investigated in a research context. We think that the differentially expressed

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mRNAs and the biological processes that they govern hold important new clues

about the causes and consequences of TB dysfunction in sPE. As to the non-

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coding RNAs, our data point to the involvement of at least two classes, lncRNAs

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and snoRNAs.

U
Research Implications
AN
The results of this study highlight particular RNAs whose functions will be

interesting to study in a research context. PRG2, which encodes MAJOR BASIC

M

PROTEIN-1, was the most highly up regulated mRNA in STBs of sPE placentas.
D

A previous reanalysis of placental gene expression data in early onset PE90 also
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identified this mRNA as up regulated. In contrast, down regulated levels in

maternal serum during the first trimester have been proposed as a biomarker of
EP

adverse pregnancy outcomes91. PRG2 forms extracellular aggregates that

damage cells92. It is possible that a portion of the placental pathologies that are
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associated with sPE are attributable to enhanced expression, secretion and

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aggregation of this protein. In this regard, STBs in regions of high PRG2

expression also immunostained for CASPASE 3 (Figure 4A and B), which plays

a central role in apoptosis. Thus, this protein may have autocrine effects at sites

of its production in the placenta. Whether PRG2 aggregates dislodge from the
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placental surface, travel through the circulation, and damage maternal cells

remains to be determined. Additionally, the proform of PRG2 covalently

complexes with PREGNANCY ASSOCIATED PLASMA PROTEIN A and

ANGIOTENSINOGEN, which compromises the activities of the latter proteins93.

PT
RI
Our data strongly implicated FOS, FOSB and JUNB, and the AP1 complexes that

the FOS/JUN dimers form, as playing an important role in mediating STB

SC
responses to sPE. They are immediate early genes with expression undetectable

in most cells under baseline conditions and rapid up regulation in response to

U
growth factor stimulation, DNA damage or stress 94. They also play important
AN
roles in development. For example, deletion of JUN results in mid-gestational

embryonic lethality due to hematopoietic stem cell apoptosis as well as heart and
M

liver abnormalities 95. JUNB null animals die before mid-gestation due to
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placental abnormalities 96. The numerous functions of AP1 transcription factor

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complexes are consistent with the concept that they play an important role in the

broad STB dysfunction that is associated with sPE.

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To our knowledge, the KELL blood group system has not been implicated in the
C

pathogenesis of preeclampsia. We were interested to find that this antigen was

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up regulated by STBs in sPE (Supplemental Figure 3), which we confirmed by

immunolocalization (Figure 4C). The KELL glycoprotein is expressed at cell

surfaces disulfide-bonded to another protein, XK97. This blood group system is

highly polymorphic, consisting of 35 antigens, and its immunogenicity is second

only to the ABO and RhD systems. Additionally, KELL expression differs by race.
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The K2 genotype is expressed by 88-99% of most populations with K1

accounting for the rest of the individuals98. Anti-K1 alloantibodies can cause

hemolytic anemia, and variably, hydrops in utero99. The mechanisms include

suppressing fetal erythropoiesis in the marrow as well as hemolysis100. As to

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function, the K2 gene encodes a zinc endoproteinase that cleaves big

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endothelin-1 and -3; K1, which has a point mutation that deletes an N-

glycosylation site and likely changes its tertiary structure, is inactive26, 101.

SC
Whether and/or how this might be relevant to the role of endothelin in the

pathogenesis of PE102 remains to be determined as does the potential of certain

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combinations of mismatched KELL antigens to evoke a maternal immune
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response.
M

The invasive CTB transcriptomic dataset was notable for the strong down
D

regulation of gene expression in sPE as compared to nPTB. This finding was

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consistent with our previous work showing that this pregnancy complication is

associated with a block in the differentiation program that leads to invasion30, 103.
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As shown in Figure 3, many of the differentially expressed genes mapped to

specific regions of chromosome 6q. This finding suggested the possible

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importance of future studies, focusing on this chromosomal location. Potential

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mechanisms of regulation, including promotor polymorphisms and epigenetic

marks, could be of particular interest.

With regard to the endovascular compartment, RENIN was the most highly up

regulated gene. A great deal of work over many decades has gone into
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investigating the role of the circulating renin-angiotensin system (RAS) in PE73.

The RAS, which plays a major role in regulating blood pressure104, is

dysregulated in hypertension. PE patients have lower plasma renin105, 106 and

higher sensitivity to angiotensin II107, 108, which predates the appearance of the

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signs of this pregnancy complication109. Additionally, PE-associated

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dysregulation of placental and decidual RAS has been reported, including

elevated levels of angiotensinogen, renin, and angiotensin converting enzyme110.

SC
Our mRNA expression data and verification of this result at the protein level via

immunolocalization were in accord with higher decidual expression of RENIN in

U
sPE and extended its site of production to endovascular CTBs. Whether this is
AN
the proform of the molecule, which is inactive, or the cleaved active form remains

to be determined.
M
D

Finally, we found that the expression of non-coding RNAs was dysregulated in

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sPE (Figure 5A). Our findings are in line with reports from other groups that

miRNAs are misexpressed in this condition111-114. However, as with the

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differentially expressed mRNAs, we identified novel sPE-associated non-coding

RNAs likely due to our study design, which targeted TB subpopulations. They
C

included UCA1, which promotes cancer progression via its roles in regulating
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proliferation, apoptosis and metabolism82. We speculate that its up regulation by

STBs in sPE may be an attempt to promote cell survival by inhibiting apoptosis.

Additionally, we found that the differentially expressed snoRNAs separated all

the TB cell types we profiled in sPE from their counterparts in nPTB (Figure 5B).

They are encoded in the introns of genes and processed out following pre-mRNA
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splicing. snoRNAs undergo exonucleolytic trimming, which stops at their 3 and 5

ends. Their functions include modifying the structure of non-coding RNAs such

as ribosomal and snRNAs115.

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Dysregulated snoRNA expression led us to search for corroborating evidence.

RI
Thus, we asked whether sPE had an impact on Cajal bodies of CTBs where

snoRNAs function83. Specifically, Cajal bodies play an important role in site-

SC
specific modifications of snRNAs, 2-O-methylation and pseudouridylation.

Telomerase, a ribonucleoprotein complex with the latter modification, is also

U
enriched in Cajal bodies116. Accordingly, we immunolocalized the Cajal body
AN
marker, COILIN, in CTBs isolated from the placentas of several groups: normal

pregnancy (second and third trimester) as well as sPE and nPTB cases. We
M

found an increase in Cajal body foci that was specific to sPE. Whether this is
D

indicative of dysregulated functions of the splicesomal small nuclear and

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nucleolar riboproteins that are concentrated in these structures remains to be

determined. For example, the ongoing synthesis of splicesomal small nuclear

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riboproteins is required to maintain the integrity of Cajal bodies117, which can also

be perturbed by aberrations in proteolysis118.

C
AC

Clinical Implications

The results of this study also have implications in terms of their potential clinical

utility. The sPE vs. nPTB comparison for STBs revealed several molecules that

have been or are being used as PE biomarkers. They included INHBA, FLT1 and
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34

ENG. Because tests based on these and/or other molecules work best in subsets

of patients, they have not been broadly adopted. Their relatively low levels of

differential expression (2.2 to 2.5-fold) could explain why. Conversely,

investigating whether other more highly differentially expressed molecules in the

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STB and other datasets may have better predictive power as biomarkers could

RI
be interesting to explore in the future.

SC
Strengths and Limitations

U
The main strength of the study was the laser microdissection approach we used,
AN
which enabled us to focus on gene expression in an enriched population of TBs

that lie at the maternal-fetal interface. Limitations included the fact that we
M

focused on one narrowly defined subset of sPE patients. This was a practical

necessity given the labor-intensive nature of the laser dissection method that we
D

used. For the same reason we had only one control group, nPTB samples.
TE

Therefore, it will be important to determine how broadly applicable our findings

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are among PE patients as a whole. It will also be important to determine whether

the differentially expressed genes are specific to this pregnancy complication or

C

misregulated in other conditions, particularly disorders that are related to

AC

alterations in deep placentation. Finally, it will be important to determine the

extent to which DNA methylation and other epigenetic marks drive the sPE-
119
associated changes in TB RNA expression that we observed .
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Conclusions

In summary, we used a laser microdissection approach to isolate specific TB

subpopulations from biopsies of placentas from sPE and nPTB cases. Global

transcriptional profiling enabled the identification of a number of novel

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misregulated transcripts, several of which were shown to be differentially

RI
expressed at the protein level. We also found evidence of sPE-associated

disturbances in the production of non-coding RNAs. Thus, we think that this

SC
approach is a useful addition to the technologies that are currently being applied

to understand TB functions throughout normal pregnancy and in a variety of

pregnancy complications.
U
AN
M

Acknowledgements
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We are grateful to Dr. Mari-Paule Thiet and the UCSF Maternal-Fetal Medicine
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Division for making acquisition of the samples that went into this study possible.

We also thank the recruiters: Mss. Lisa Wilson, Lisa Gertridge, Allison OLeary,
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Stephanie Leong, Jean Perry and Rachel Freyre. We are indebted to the patient

participants. We are grateful to Dr. Michael McMaster for critical reading of the
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manuscript and help with preparation of the figures. This study was funded by
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1 R37HD076253 to S.F.
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Figure Legends

Figure 1

Photomicrographs depicting laser microdissection of trophoblast

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subpopulations

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Tissue sections of unfixed frozen specimens of a placenta obtained at the time of

delivery from a pregnancy that was complicated by severe preeclampsia (sPE)

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were stained with toluidine blue, which enabled visualization of the cellular

architecture. A, C The dotted lines indicate the areas that were targeted for

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removal by laser microdissection. B, D The regions that were removed are
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shown in the adjacent images. A, B Microdissection of syncytiotrophoblasts

(STBs), (C, D) invasive CTBs (iCTBs) and endovascular CTBs (eCTBs) is

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illustrated. FV, floating villus; AV, anchoring villus. Size bar = 100 m.
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Figure 2
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Trellis plot of the gene ontology of the differentially expressed mRNAs in

enriched samples of syncytiotrophoblasts, invasive cytotrophoblasts and

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endovascular cytotrophoblasts
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Shown are the biological processes that were affected by severe preeclampsia

(sPE) as compared to noninfected preterm birth (nPTB) (p < 0.05). The number

of differentially expressed genes are shown as tiles (red up regulated; blue down

regulated). sPE impacted immune cell functions, transport, metabolic pathways

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and vascular development. Responses to VEGF, TGF-beta, oxygen and lipids

were also altered. Syncytiotrophoblasts (STBs); invasive cytotrophoblasts

(iCTBs); endovascular cytotrophoblasts (eCTBs); normalized enrichment score

(NES).

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Figure 3

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Gene set enrichment of the RNAs that were misexpressed in severe

preeclampsia showed an overrepresentation in certain chromosomal

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locations
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Many of the mRNAs and non-coding RNAs that were differentially expressed in

the syncytiotrophoblast (STB) and invasive cytotrophoblast (iCTB) datasets were

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encoded in specific regions of the genome, suggesting their importance to

placental dysfunction in this pregnancy complication. eCTBs, endovascular

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cytotrophoblasts. * p < 0.05.

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Figure 4
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Confirmation of the microarray results at the protein level

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Tissue sections of placentas or the basal plate from pregnancies that were
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complicated by severe preeclampsia (sPE) or noninfected preterm birth (nPTB)

were analyzed. Chorionic villi or biopsies of the basal plate were immunostained

with an antibody that recognized the antigen of interest (green). Cytokeratin (CK)

expression (red) enabled the identification of syncytiotrophoblasts (STBs),

invasive cytotrophoblasts (iCTBs) and endovascular cytotrophoblasts (eCTBs).

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A, Widespread immunostaining for PRG2 was detected in sPE. The signal was

primarily in the CK-positive STB covering of floating villi. In contrast,

immunostaining of nPTB samples showed that PRG2 expression was primarily in

the stromal cores of the villi. B, Consistent with the fact that this protein is toxic to

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cells, PRG2 immunoreactivity frequently co-localized with staining for CASPASE-

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3, which was absent in the nPTB samples. C, KELL (blood group antigen)

expression by STBs was confirmed as highly up regulated in sPE.

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Immunoreactivity was also detected in association with the villous cores. In

nPTB, staining was limited to the latter compartment. D, GH2 expression was

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significantly down regulated among iCTBs in sPE as compared to nPTB
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samples. E, the same pattern was observed for PLAC1. F, eCTBs reacted

strongly with anti-RENIN in samples from sPE pregnancies whereas these cells
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rarely gave a signal in nPTB. In both cases, immunoreactivity was detected in

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association with CK-negative decidual cells. Arrows indicate the direction of CTB
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invasion. AV, anchoring villi; SA, spiral artery. Size bar = 100 m.
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Figure 5

Differential expression of non-coding RNAs by trophoblasts: severe

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preeclampsia vs. noninfected preterm birth

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A, (left pie chart) The number of unique transcripts from each RNA class that

was profiled is shown. (right pie chart) A summary of the number of RNAs in

each class that were differentially expressed in severe preeclampsia (sPE) as

compared to noninfected preterm birth (nPTB) is shown. B, A two-way ANOVA

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showed that lncRNAs and snoRNAs were differentially expressed in sPE as

compared to nPTB. C, In situ hybridization confirmed up regulation, in

syncytiotrophoblasts (STBs), of the long non-coding RNA UROTHELIAL

CANCER ASSOCIATED 1 (UCA1) in sPE vs. nPTB. P < 0.05.

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Figure 6

Increased numbers of Cajal body foci in cytotrophoblasts purified from

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placentas of severe preeclampsia cases

A, (upper panels) Cajal bodies, sites of snoRNA activity, were visualized by

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immunostaining for the scaffold protein COILIN; cytotrophoblast (CTB) identity
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was confirmed by cytokeratin (CK) expression. (lower panels) Representative

images from Volocity analysis of the confocal Z-stacks. CTBs were isolated from
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normal placentas (second [n=4] or third trimester [n=3]) or from placentas

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following delivery due to a pregnancy complication (noninfected preterm birth

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[nPTB, n=2]; severe preeclampsia [sPE, n=3]). B, Quantification of the results is

shown in A. The box and whisker plots illustrate the median (line), average
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(square) and the range (box). The number of Cajal body foci decreased as

gestation advanced from second trimester to term with nPTB having values that
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were similar to the term cells. CTBs isolated from sPE placentas had nearly
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double the number of Cajal body foci as the normal second trimester samples

and ~6-fold higher than term or nPTB CTBs. Size bar = 10 m.

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Table 1A. Maternal and neonatal characteristics (microarray studies)

Characteristic sPE (n=4) nPTB (n=4) P value

Maternal age, ya 28.3 ( 5.9) 31 ( 3) 0.50
Parity G1P0, G2P0,G2P1,G4P1 G1P0, G2P0, G2P1, G2P1
Gestational age at delivery, wka 27.7 ( 3.6) 31.6 ( 2) 0.19

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Systolic blood pressure, mmHga 174 ( 6) 113 ( 8) 0.05
Diastolic blood pressure, mmHga 106 ( 5) 73 ( 5) 0.002
BMI, kg/m2 a 30 ( 6.4) 24 ( 0.5) 0.11

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Proteinuria, mgb 2150 (696, 4875) 0 0.04
Birth weight, gb 775 (557, 1528) 1990 (1720, 2090) 0.11

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a
Data are shown as mean standard deviation, 2-tailed Student t-test
b
Data are shown as median (Q1, Q3), Mann-Whitney test

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Table 1B. Maternal and neonatal characteristics (immunolocalization and in situ
hybridization studies)
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Characteristic sPE (n=4) nPTB (n=4) P value
Maternal age, ya 34.8 ( 11.1) 33.7 ( 2.5) 0.88
Parity G1P0, G5P0,G2P1,G2P1 G1P0, G2P0, G2P1, G2P1
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Gestational age at delivery, wka 31.2 ( 2.3) 32.3 ( 1.8) 0.64

Systolic blood pressure, mmHga 169 ( 9) 119 ( 3) 0.02
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Diastolic blood pressure, mmHga 108 ( 3) 75 (8) 0.01

BMI, kg/m2 a 32.2 ( 6.7) 25.3 ( 3.3) 0.16
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Proteinuria, mgb 949.5 (520, 2082) 0 0.02

Birth weight, gb 1035 (848, 1233) 2117.5 (2015, 2366) 0.03
a
Data are shown as mean standard deviation, 2-tailed Student t-test
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b
Data are shown as median (Q1, Q3), Mann-Whitney test
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Supplemental Table 1. Antibodies

Supplemental Figures

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Supplemental Figure 1

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Global transcriptional profiling of trophoblasts in severe preeclampsia (sPE):

syncytiotrophoblasts (A, STBs) vs. invasive cytotrophoblasts (B, iCTBs) vs.

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endovascular CTBs (C, eCTBs)

The cells were enriched by laser microdissection. Then total RNA was purified and gene

U
expression analyzed by using an Affymetrix microarray platform. The data were
AN
centered and scaled gene-wise before plotting. The differentially expressed genes

are depicted as a heat map (red, higher expression; blue, lower expression). The
M

fold changes are shown on the right (). n = 4 sPE samples.

D
TE

Supplemental Figure 2

Global transcriptional profiling of trophoblasts in noninfected preterm birth

EP

(nPTB): (A, STBs) vs. invasive cytotrophoblasts (B, iCTBs) vs. endovascular

CTBs (C, eCTBs)

C

The cells were enriched by laser microdissection. Then total RNA was purified and gene
AC

expression analyzed by using an Affymetrix microarray platform. The data were

centered and scaled gene-wise before plotting. The differentially expressed genes

are depicted as a heat map (red, higher expression; blue, lower expression). The

fold changes are shown on the right (). n = 4 nPTB samples.

 ACCEPTED MANUSCRIPT
Supplementary 2

Supplemental Figure 3

Global transcriptional profiling of syncytiotrophoblasts (STBs): severe

preeclampsia (sPE) vs. noninfected preterm birth (nPTB)

PT
The cells were enriched by laser microdissection. Then total RNA was purified and gene

RI
expression analyzed by using an Affymetrix microarray platform. The data were

centered and scaled gene-wise before plotting. The differentially expressed genes

SC
are depicted as a heat map (red, higher expression; blue, lower expression). The

fold changes are shown on the right (). n = 4 sPE samples and n = 4 nPTB samples.

U
AN
Supplemental Figure 4

Global transcriptional profiling of invasive cytotrophoblasts (iCTBs): severe

M

preeclampsia (sPE) vs. noninfected preterm birth (nPTB)

D

The cells were isolated by laser microdissection. Then RNA was prepared and gene
TE

expression analyzed by using an Affymetrix microarray platform. The data were

centered and scaled gene-wise before plotting. The differentially expressed genes
EP

are depicted as a heat map (red, higher expression; blue, lower expression). The

fold changes are shown on the right (). n = 3 sPE samples and n = 4 nPTB samples.
C
AC

Supplemental Figure 5

Global transcriptional profiling of endovascular cytotrophoblasts (eCTBs): severe

preeclampsia (sPE) vs. noninfected preterm birth (nPTB)

The cells were isolated by laser microdissection. Then RNA was prepared and gene
 ACCEPTED MANUSCRIPT
Supplementary 3

expression analyzed by using an Affymetrix microarray platform. The data were

centered and scaled gene-wise before plotting. The differentially expressed genes

are depicted as a heat map (red, higher expression; blue, lower expression). The

fold changes are shown on the right (). n = 4 sPE samples and n = 4 nPTB samples.

PT
RI
Supplemental Figure 6

Differential mRNA expression carried over to the protein level

SC
An expanded version of Figure 5 is shown that includes the individual anti-cytokeratin

(CK) immunostaining patterns.

U
AN
Supplemental Figure 7

Differential mRNA expression carried over to the protein level (continued)

M

Tissue sections of placentas from pregnancies that were complicated by severe

D

preeclampsia (sPE) or noninfected preterm birth (nPTB) were analyzed. Chorionic villi
TE

or biopsies of the basal plate were immunostained with an antibody that recognized the

antigen of interest (green). Cytokeratin (CK) expression (red) enabled the identification
EP

of syncytiotrophoblasts (STBs), invasive cytotrophoblasts (iCTBs) and endovascular

cytotrophoblasts (eCTBs). A, Widespread immunostaining for RDH13 was detected in

C

sPE. The signal was primarily in the CK-positive syncytiotrophoblast (STB) covering of
AC

floating villi. In contrast, little immunoreactivity was detected in the nPTB samples. B, In

sPE, FSTL3 expression was associated with the syncytium and villous cores. In nPTB,

immunostaining was limited to the latter compartments. C, In sPE, syncytial GSTA3

expression was reduced as compared to the strong signal that was detected in nPTB
 ACCEPTED MANUSCRIPT
Supplementary 4

samples. D, A similar pattern of SERPINl1 immunostaining was observed except that

stronger stromal expression was detected in both sample groups. E, In sPE, CXCL8

expression was higher among invasive cytotrophoblasts (iCTBs). F, In sPE, a stronger

FABP4 signal was detected in association with endovascular CTBs (eCTBs) than was

PT
observed in comparable regions of the nPTB samples. G, In contrast, anti-SHROOM3

RI
immunoreactivity had the opposite pattern. Arrows indicate the direct of CTB invasion.

SA, spiral artery; AV, anchoring villi. Size bar = 100 m.

U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Supplemental Table 1. Antibodies

Catalog number/ Concentration

Antigen Source
clone g/ml)
(
Coillin ab87913 Abcam 10
PRG2 NBP1-88573 Novus Biologicals 0.2

PT
active-CASP3 ab32042 Abcam 1
KEL PA5-28365 Thermo Fisher 4

RI
GH2 ab198007 Abcam 19
PLAC1 ab105395 Abcam 10

SC
RENIN ab137731 Abcam 10
RDH13 NBP1-92324 Novus Biologicals 2
FSTL3 F8056-200UL Sigma Aldrich 15.8

U
GSTA3 sc-100547 Santa Cruz Biotechnology 1
AN
SERPINI1 ab32901 Abcam 5
CXCL8 ab18672 Abcam 10
FABP4 ab23693 Abcam 4
M

SHROOM3 ab151009 Abcam 2

CK7 7D3 Damsky et al., 1992* 26
D

FITC-conjugated anti-
715-095-151 Jackson ImmunoResearch 15
mouse secondary
TE

FITC-conjugated anti-
711-095-152 Jackson ImmunoResearch 15
rabbit secondary
TRITC-conjugated anti-rat
712-025-153 Jackson ImmunoResearch 15
secondary
EP

_________________
*Damsky CH, Fitzgerald ML, Fisher SJ. Distribution patterns of extracellular matrix components and
C

adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the
invasive pathway, in vivo. J Clin Invest 1992; 210-22.
AC
A ACCEPTED MANUSCRIPT
sPE
STB iCTB eCTB Symbol Name D
PLAC4 placenta specific 4 33.0
BMP5 bone morphogenetic protein 5 30.1
FABP4 fatty acid binding protein 4, adipocyte 28.7
SPTLC3 serine palmitoyltransferase, long chain base subunit 3 27.2
LOC100129935 lectin, galactoside-binding, soluble, 14 pseudogene 24.8
EGFL6 EGF-like-domain, multiple 6 24.7
SNORD114-14 small nucleolar RNA, C/D box 114-14 20.3
HSD17B2 hydroxysteroid (17-beta) dehydrogenase 2 19.7
MEOX2 mesenchyme homeobox 2 19.1

PT
MIR1323 microRNA 1323 19.1
PAGE4 P antigen family, member 4 (prostate associated) 18.8
PSG8 pregnancy specific beta-1-glycoprotein 8 18.0
TFPI2 tissue factor pathway inhibitor 2 17.5

RI
CRH corticotropin releasing hormone 16.4
PSG11 pregnancy specific beta-1-glycoprotein 11 16.1
SNORD114-12 small nucleolar RNA, C/D box 114-12 16.0

SC
AREG amphiregulin 16.0
PABPC4L poly(A) binding protein, cytoplasmic 4-like 15.5
PEG10 paternally expressed 10 15.3
SNORD114-2 small nucleolar RNA, C/D box 114-2 15.2

U
HGF hepatocyte growth factor (hepapoietin A; scatter factor) 14.3
SNORD114-3 small nucleolar RNA, C/D box 114-3 13.9
PSG6
LOC100128988
SNORD114-5
AN
pregnancy specific beta-1-glycoprotein 6
uncharacterized LOC100128988
small nucleolar RNA, C/D box 114-5
13.8
13.7
13.1
SNORD114-1 small nucleolar RNA, C/D box 114-1 12.9
M
SNORD114-16 small nucleolar RNA, C/D box 114-16 12.8
SNORD114-7 small nucleolar RNA, C/D box 114-7 12.6
HBG1 hemoglobin, gamma A 12.5
D

PSG9 pregnancy specific beta-1-glycoprotein 9 12.5

ERVW-1 endogenous retrovirus group W, member 1 12.3
SNORD114-13 small nucleolar RNA, C/D box 114-13 12.3
TE

GLDN gliomedin 12.1

TRPV6 transient receptor potential cation channel, subfamily V, member 6 12.1
GNG11 guanine nucleotide binding protein (G protein), gamma 11 12.0
MIR498 microRNA 498 11.6
EP

SNORD114-20 small nucleolar RNA, C/D box 114-20 11.2

OLAH oleoyl-ACP hydrolase 10.9
CDO1 cysteine dioxygenase type 1 10.9
C

LOC284561 uncharacterized LOC284561 10.8

FAM184A family with sequence similarity 184, member A 10.8
AC

CD36 CD36 molecule (thrombospondin receptor) 10.6

LRP2 LDL receptor related protein 2 10.6
GABRE gamma-aminobutyric acid (GABA) A receptor, epsilon 10.5
APLNR apelin receptor 9.9
LOC55338 uncharacterized LOC55338 9.9
LINC00474 long intergenic non-protein coding RNA 474 9.8
SNORD114-19 small nucleolar RNA, C/D box 114-19 9.8
SNORD113-4 small nucleolar RNA, C/D box 113-4 9.8
SNORD113-2 small nucleolar RNA, C/D box 113-2 9.7
SNORD114-23 small nucleolar RNA, C/D box 114-23 9.7
TLR3 toll-like receptor 3 9.5
STS steroid sulfatase (microsomal), isozyme S 9.3
KRT23 keratin 23, type I 9.3
HSD3B1 hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 9.2
KISS1 KiSS-1 metastasis-suppressor 9.2
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
RPL31P11 ribosomal protein L31 pseudogene 11 9.0
DLK1 delta-like 1 homolog (Drosophila) 9.0
SIGLEC6 sialic acid binding Ig-like lectin 6 9.0
SNORD114-8 small nucleolar RNA, C/D box 114-8 8.8
PSG3 pregnancy specific beta-1-glycoprotein 3 8.7
EXPH5 exophilin 5 8.7
C21orf91-OT1 C21orf91 overlapping transcript 1 8.7
LGR5 leucine-rich repeat containing G protein-coupled receptor 5 8.6
GRB14 growth factor receptor bound protein 14 8.6

PT
P2RY1 purinergic receptor P2Y, G-protein coupled, 1 8.5
SNORD114-28 small nucleolar RNA, C/D box 114-28 8.4
SNORD113-9 small nucleolar RNA, C/D box 113-9 8.3
SNORD114-29 small nucleolar RNA, C/D box 114-29 8.2

RI
SNORD114-31 small nucleolar RNA, C/D box 114-31 8.2
PSG5 pregnancy specific beta-1-glycoprotein 5 8.1
MIR1305 microRNA 1305 8.0

SC
CGB8 chorionic gonadotropin, beta polypeptide 8 8.0
ADAMTS6 ADAM metallopeptidase with thrombospondin type 1 motif 6 7.9
MIR181B1 microRNA 181b-1 7.9
SLC19A3 solute carrier family 19 (thiamine transporter), member 3 7.8

U
LGALS16 lectin, galactoside-binding, soluble, 16 7.6
LOC728755 uncharacterized LOC728755 7.6
LGALS14
SNORD113-1
TBX5
AN
lectin, galactoside-binding, soluble, 14
small nucleolar RNA, C/D box 113-1
T-box 5
7.6
7.6
7.4
SNORD114-24 small nucleolar RNA, C/D box 114-24 7.4
M
SEMA6A sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6A
7.1
TCL6 T-cell leukemia/lymphoma 6 (non-protein coding) 7.1
LOC101927482 uncharacterized LOC101927482 7.1
D

CYP2J2 cytochrome P450, family 2, subfamily J, polypeptide 2 7.0

PLA2G2A phospholipase A2, group IIA (platelets, synovial fluid) 6.9
MAN1C1 mannosidase, alpha, class 1C, member 1 6.8
TE

PSG4 pregnancy specific beta-1-glycoprotein 4 6.8

SCN7A sodium channel, voltage gated, type VII alpha subunit 6.7
SNORD114-30 small nucleolar RNA, C/D box 114-30 6.7
SLC26A7 solute carrier family 26 (anion exchanger), member 7 6.7
EP

LOC100129345 uncharacterized LOC100129345 6.6

SNORD113-3 small nucleolar RNA, C/D box 113-3 6.6
KYNU kynureninase 6.6
C

CAPN6 calpain 6 6.6

ZNF554 zinc finger protein 554 6.5
AC

SNORD114-11 small nucleolar RNA, C/D box 114-11 6.5

SNORD114-15 small nucleolar RNA, C/D box 114-15 6.5
DAB2 Dab, mitogen-responsive phosphoprotein, homolog 2 (Drosophila) 6.5
SNORD113-5 small nucleolar RNA, C/D box 113-5 6.5
SNORD114-6 small nucleolar RNA, C/D box 114-6 6.4
TCF21 transcription factor 21 6.4
SNHG24 small nucleolar RNA host gene 24 6.4
PREX2 phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2 6.3
HIGD1B HIG1 hypoxia inducible domain family, member 1B 6.2
SNORD114-17 small nucleolar RNA, C/D box 114-17 6.2
SNORD114-21 small nucleolar RNA, C/D box 114-21 6.2
SLC43A2 solute carrier family 43 (amino acid system L transporter), member 2 6.2
NDNF neuron-derived neurotrophic factor 6.1
KRTAP26-1 keratin associated protein 26-1 6.0
BLID BH3-like motif containing, cell death inducer 6.0
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
CDH5 cadherin 5, type 2 (vascular endothelium) 6.0
PLEKHA6 pleckstrin homology domain containing, family A member 6 5.9
PCDH10 protocadherin 10 5.9
SLC19A2 solute carrier family 19 (thiamine transporter), member 2 5.8
AGTR1 angiotensin II receptor, type 1 5.8
CD34 CD34 molecule 5.6
FHDC1 FH2 domain containing 1 5.6
MAEL maelstrom spermatogenic transposon silencer 5.5
SNORD114-25 small nucleolar RNA, C/D box 114-25 5.5

PT
TREML2 triggering receptor expressed on myeloid cells-like 2 5.5
TBX3 T-box 3 5.4
SNORD113-7 small nucleolar RNA, C/D box 113-7 5.4
ERVV-1 endogenous retrovirus group V, member 1 5.3

RI
ZNF117 zinc finger protein 117 5.3
SNORD114-26 small nucleolar RNA, C/D box 114-26 5.3
C4orf36 chromosome 4 open reading frame 36 5.3

SC
MIR30A microRNA 30a 5.2
FAM162B family with sequence similarity 162, member B 5.2
IL22RA2 interleukin 22 receptor, alpha 2 5.2
TWIST1 twist family bHLH transcription factor 1 5.1

U
CSF3R colony stimulating factor 3 receptor 5.1
MIR548V microRNA 548v 5.1
RYBP
RBP7
LOC101929633
AN
RING1 and YY1 binding protein
retinol binding protein 7, cellular
uncharacterized LOC101929633
5.1
5.1
5.0
SNORD114-4 small nucleolar RNA, C/D box 114-4 5.0
M
EPHA3 EPH receptor A3 5.0
SH3BGRL2 SH3 domain binding glutamate-rich protein like 2 5.0
CCDC162P coiled-coil domain containing 162, pseudogene 4.9
D

ST8SIA6-AS1 ST8SIA6 antisense RNA 1 4.9

AHSP alpha hemoglobin stabilizing protein 4.9
LOC644919 uncharacterized LOC644919 4.9
TE

ENDOU endonuclease, polyU-specific 4.9

LOC100288570 glycosylphosphatidylinositol anchor attachment protein 1 homolog (yeast) pseudogene4.9
TACC2 transforming, acidic coiled-coil containing protein 2 4.9
GUCY1B3 guanylate cyclase 1, soluble, beta 3 4.8
EP

COLEC12 collectin sub-family member 12 4.8

ARHGAP42 Rho GTPase activating protein 42 4.8
CMYA5 cardiomyopathy associated 5 4.8
C

MED12L mediator complex subunit 12 like 4.8

CHODL-AS1 CHODL antisense RNA 1 4.7
AC

CASC9 cancer susceptibility candidate 9 (non-protein coding) 4.7

ANGPTL1 angiopoietin like 1 4.7
MFSD2A major facilitator superfamily domain containing 2A 4.7
MIR329-1 microRNA 329-1 4.7
ST8SIA6 ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 6 4.6
TMEM133 transmembrane protein 133 4.6
LOC284825 uncharacterized LOC284825 4.6
SNORD114-10 small nucleolar RNA, C/D box 114-10 4.6
RDH13 retinol dehydrogenase 13 (all-trans/9-cis) 4.6
RPS6KA5 ribosomal protein S6 kinase, 90kDa, polypeptide 5 4.6
MIR503HG MIR503 host gene 4.6
ZNF91 zinc finger protein 91 4.6
STEAP4 STEAP family member 4 4.5
FOXO4 forkhead box O4 4.5
HES1 hes family bHLH transcription factor 1 4.5
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
PHACTR2 phosphatase and actin regulator 2 4.5
LINC00113 long intergenic non-protein coding RNA 113 4.5
SLIT2 slit guidance ligand 2 4.4
SMAD6 SMAD family member 6 4.4
MIR181A1HG MIR181A1 host gene 4.4
TBX20 T-box 20 4.4
GPR171 G protein-coupled receptor 171 4.4
CYSLTR2 cysteinyl leukotriene receptor 2 4.3
EMP2 epithelial membrane protein 2 4.3

PT
LINC00622 long intergenic non-protein coding RNA 622 4.3
SMAGP small cell adhesion glycoprotein 4.3
FCGR2B Fc fragment of IgG, low affinity IIb, receptor (CD32) 4.3
ZNF750 zinc finger protein 750 4.3

RI
RSPO3 R-spondin 3 4.3
ZNF732 zinc finger protein 732 4.2
CYTL1 cytokine like 1 4.2

SC
ERV3-1 endogenous retrovirus group 3, member 1 4.2
OPHN1 oligophrenin 1 4.2
ALAS2 5-aminolevulinate synthase 2 4.2
CDS1 CDP-diacylglycerol synthase 1 4.2

U
ADGRL2 adhesion G protein-coupled receptor L2 4.1
COX4I2 cytochrome c oxidase subunit IV isoform 2 (lung) 4.1
CGB
FAM13A
LINC01415
AN
chorionic gonadotropin, beta polypeptide
family with sequence similarity 13, member A
long intergenic non-protein coding RNA 1415
4.1
4.1
4.1
C4orf32 chromosome 4 open reading frame 32 4.1
M
EXOC6 exocyst complex component 6 4.1
HPGDS hematopoietic prostaglandin D synthase 4.1
SNORD4B small nucleolar RNA, C/D box 4B 4.1
D

KIT v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog 4.1

GRIP1 glutamate receptor interacting protein 1 4.0
IGSF5 immunoglobulin superfamily, member 5 4.0
TE

CCDC68 coiled-coil domain containing 68 4.0

SEMA3B sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin)
4.03B
CNN3 calponin 3, acidic 4.0
TMEM88 transmembrane protein 88 3.9
EP

METTL21C methyltransferase like 21C 3.9

TOP2A topoisomerase (DNA) II alpha 3.9
ZFAT zinc finger and AT hook domain containing 3.9
C

SNORD114-22 small nucleolar RNA, C/D box 114-22 3.9

MIR126 microRNA 126 3.9
AC

ATP10D ATPase, class V, type 10D 3.9

LINC01118 long intergenic non-protein coding RNA 1118 3.8
MIR30C2 microRNA 30c-2 3.8
CXorf57 chromosome X open reading frame 57 3.8
MEST mesoderm specific transcript 3.8
TUSC3 tumor suppressor candidate 3 3.8
PPP1R14C protein phosphatase 1, regulatory (inhibitor) subunit 14C 3.8
LNPEP leucyl/cystinyl aminopeptidase 3.8
ADHFE1 alcohol dehydrogenase, iron containing 1 3.8
PCDH11X protocadherin 11 X-linked 3.8
WFDC1 WAP four-disulfide core domain 1 3.8
TTPA tocopherol (alpha) transfer protein 3.7
TYMS thymidylate synthetase 3.7
KEL Kell blood group, metallo-endopeptidase 3.7
FIRRE firre intergenic repeating RNA element 3.7
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
OR9A2 olfactory receptor, family 9, subfamily A, member 2 3.7
LOC220729 succinate dehydrogenase complex, subunit A, flavoprotein (Fp) pseudogene 3.7
LINC00472 long intergenic non-protein coding RNA 472 3.7
GGH gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl hydrolase) 3.6
SNORD114-9 small nucleolar RNA, C/D box 114-9 3.6
TFRC transferrin receptor 3.6
HOOK1 hook microtubule-tethering protein 1 3.6
PIP prolactin-induced protein 3.6
PCDH11Y protocadherin 11 Y-linked 3.6

PT
SMN1 survival of motor neuron 1, telomeric 3.6
MTMR10 myotubularin related protein 10 3.6
LOC101927359 uncharacterized LOC101927359 3.6
FAM156B family with sequence similarity 156, member B 3.6

RI
RHOBTB3 Rho-related BTB domain containing 3 3.5
GSTA3 glutathione S-transferase alpha 3 3.5
PCOLCE2 procollagen C-endopeptidase enhancer 2 3.5

SC
CSNK1A1P1 casein kinase 1, alpha 1 pseudogene 1 3.5
DSCR4 Down syndrome critical region 4 3.5
DEPDC1 DEP domain containing 1 3.5
RAPGEF5 Rap guanine nucleotide exchange factor 5 3.5

U
MIR520E microRNA 520e 3.5
DACH1 dachshund family transcription factor 1 3.4
BCL2
STARD4
SH3TC2
AN
B-cell CLL/lymphoma 2
StAR-related lipid transfer domain containing 4
SH3 domain and tetratricopeptide repeats 2
3.4
3.4
3.4
ZSCAN4 zinc finger and SCAN domain containing 4 3.4
M
PDE3B phosphodiesterase 3B, cGMP-inhibited 3.4
PART1 prostate androgen-regulated transcript 1 (non-protein coding) 3.4
PTPRD protein tyrosine phosphatase, receptor type, D 3.4
D

SDC1 syndecan 1 3.4

CCDC102B coiled-coil domain containing 102B 3.4
GREM2 gremlin 2, DAN family BMP antagonist 3.3
TE

HSPA4L heat shock 70kDa protein 4-like 3.3

AMD1 adenosylmethionine decarboxylase 1 3.3
MIR376B microRNA 376b 3.3
LINC01483 long intergenic non-protein coding RNA 1483 3.3
EP

GULP1 GULP, engulfment adaptor PTB domain containing 1 3.3

PAQR7 progestin and adipoQ receptor family member VII 3.3
CLIP4 CAP-GLY domain containing linker protein family, member 4 3.3
C

RANBP3L RAN binding protein 3-like 3.3

LOC255187 uncharacterized LOC255187 3.3
AC

CARD17 caspase recruitment domain family, member 17 3.3

CYYR1 cysteine/tyrosine-rich 1 3.2
CA8 carbonic anhydrase VIII 3.2
ETV5 ets variant 5 3.2
SULT1C4 sulfotransferase family 1C member 4 3.2
PLCB1 phospholipase C, beta 1 (phosphoinositide-specific) 3.2
FAM135A family with sequence similarity 135, member A 3.2
PIP5K1B phosphatidylinositol-4-phosphate 5-kinase, type I, beta 3.2
MEG8 maternally expressed 8 (non-protein coding) 3.2
SLC13A4 solute carrier family 13 (sodium/sulfate symporter), member 4 3.2
LINC01336 long intergenic non-protein coding RNA 1336 3.2
BET1 Bet1 golgi vesicular membrane trafficking protein 3.2
SLC16A10 solute carrier family 16 (aromatic amino acid transporter), member 10 3.2
TTC7B tetratricopeptide repeat domain 7B 3.2
HS6ST2 heparan sulfate 6-O-sulfotransferase 2 3.2
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
GUCY1A2 guanylate cyclase 1, soluble, alpha 2 3.2
RIMKLB ribosomal modification protein rimK-like family member B 3.2
KIAA1919 KIAA1919 3.2
PLAGL1 pleiomorphic adenoma gene-like 1 3.1
CFL1P1 cofilin 1 (non-muscle) pseudogene 1 3.1
NEB nebulin 3.1
HMMR hyaluronan-mediated motility receptor (RHAMM) 3.1
LOC101929461 uncharacterized LOC101929461 3.1
FGF10 fibroblast growth factor 10 3.1

PT
PLEKHG1 pleckstrin homology domain containing, family G (with RhoGef domain) member 1 3.1
PRSS12 protease, serine, 12 (neurotrypsin, motopsin) 3.1
DCP2 decapping mRNA 2 3.1
MAP7D2 MAP7 domain containing 2 3.1

RI
ZNF833P zinc finger protein 833, pseudogene 3.1
LINC01605 long intergenic non-protein coding RNA 1605 3.1
CLRN1 clarin 1 3.1

SC
FLJ34503 uncharacterized FLJ34503 3.1
ZNF354B zinc finger protein 354B 3.1
SERINC5 serine incorporator 5 3.1
NHSL1 NHS-like 1 3.1

U
LOC100288911 uncharacterized LOC100288911 3.1
ARL15 ADP-ribosylation factor like GTPase 15 3.0
PRKCZ
SLC7A5
LRRC36
AN
protein kinase C, zeta
solute carrier family 7 (amino acid transporter light chain, L system), member 5
leucine rich repeat containing 36
3.0
3.0
3.0
STAT5B signal transducer and activator of transcription 5B 3.0
M
TGFB3 transforming growth factor beta 3 3.0
KDM7A lysine (K)-specific demethylase 7A 3.0
IL1RAPL2 interleukin 1 receptor accessory protein-like 2 3.0
D

BTBD16 BTB (POZ) domain containing 16 3.0

PTEN phosphatase and tensin homolog 3.0
TTBK2 tau tubulin kinase 2 3.0
TE

HBA2 hemoglobin, alpha 2 2.9

CALM1 calmodulin 1 (phosphorylase kinase, delta) 2.9
MBTD1 mbt domain containing 1 2.9
PLEKHH1 pleckstrin homology domain containing, family H (with MyTH4 domain) member 1 2.9
EP

HAPLN1 hyaluronan and proteoglycan link protein 1 2.9

NOSTRIN nitric oxide synthase trafficking 2.9
COLEC10 collectin sub-family member 10 (C-type lectin) 2.9
C

LOC101928324 uncharacterized LOC101928324 2.9

KBTBD8 kelch repeat and BTB (POZ) domain containing 8 2.9
AC

TCHH trichohyalin 2.9

HSPB8 heat shock 22kDa protein 8 2.9
AKR1B15 aldo-keto reductase family 1, member B15 2.9
MEG3 maternally expressed 3 (non-protein coding) 2.9
IDO2 indoleamine 2,3-dioxygenase 2 2.9
ARHGAP26 Rho GTPase activating protein 26 2.9
CAP2 CAP, adenylate cyclase-associated protein, 2 (yeast) 2.9
MIR345 microRNA 345 2.9
TMEM2 transmembrane protein 2 2.8
STX3 syntaxin 3 2.8
ARHGEF37 Rho guanine nucleotide exchange factor 37 2.8
BEX2 brain expressed X-linked 2 2.8
SDHAP2 succinate dehydrogenase complex subunit A, flavoprotein pseudogene 2 2.8
KATNBL1 katanin p80 subunit B-like 1 2.8
HELLS helicase, lymphoid-specific 2.8
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
SPDYE8P speedy/RINGO cell cycle regulator family member E8, pseudogene 2.8
ZFP2 ZFP2 zinc finger protein 2.8
RARB retinoic acid receptor, beta 2.8
DLG5 discs, large homolog 5 (Drosophila) 2.8
SCARNA2 small Cajal body-specific RNA 2 2.8
CRISPLD1 cysteine-rich secretory protein LCCL domain containing 1 2.8
MIR100 microRNA 100 2.8
SNORA2C small nucleolar RNA, H/ACA box 2C 2.8
TMEM247 transmembrane protein 247 2.8

PT
SPG20-AS1 SPG20 antisense RNA 1 2.8
SNORA13 small nucleolar RNA, H/ACA box 13 2.8
EGFEM1P EGF-like and EMI domain containing 1, pseudogene 2.8
ATXN7 ataxin 7 2.8

RI
LONP2 lon peptidase 2, peroxisomal 2.8
SNORD113-8 small nucleolar RNA, C/D box 113-8 2.8
CLIP1 CAP-GLY domain containing linker protein 1 2.8

SC
ADRB1 adrenoceptor beta 1 2.7
SLC44A1 solute carrier family 44 (choline transporter), member 1 2.7
CADM1 cell adhesion molecule 1 2.7
FIGN fidgetin 2.7

U
RAB38 RAB38, member RAS oncogene family 2.7
ACADL acyl-CoA dehydrogenase, long chain 2.7
SLC13A3
LINC00939
RPS6KA6
AN
solute carrier family 13 (sodium-dependent dicarboxylate transporter), member 3
long intergenic non-protein coding RNA 939
ribosomal protein S6 kinase, 90kDa, polypeptide 6
2.7
2.7
2.7
SNORA2A small nucleolar RNA, H/ACA box 2A 2.7
M
TPPP3 tubulin polymerization-promoting protein family member 3 2.7
FLT4 fms-related tyrosine kinase 4 2.7
STRA6 stimulated by retinoic acid 6 2.7
D

FAM124B family with sequence similarity 124 member B 2.7

SLC22A11 solute carrier family 22 (organic anion/urate transporter), member 11 2.7
SCML2 sex comb on midleg-like 2 (Drosophila) 2.7
TE

SPIRE2 spire-type actin nucleation factor 2 2.7

MORN3 MORN repeat containing 3 2.7
MVB12B multivesicular body subunit 12B 2.7
BRWD1 bromodomain and WD repeat domain containing 1 2.7
EP

ACER3 alkaline ceramidase 3 2.7

LOC401585 uncharacterized LOC401585 2.6
HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 2.6
C

LOC102724153 uncharacterized LOC102724153 2.6

OR6W1P olfactory receptor, family 6, subfamily W, member 1 pseudogene 2.6
AC

SORBS2 sorbin and SH3 domain containing 2 2.6

NFE2L3 nuclear factor, erythroid 2-like 3 2.6
FXYD3 FXYD domain containing ion transport regulator 3 2.6
OR52N4 olfactory receptor, family 52, subfamily N, member 4 (gene/pseudogene) 2.6
HBM hemoglobin, mu 2.6
LMO7 LIM domain 7 2.6
PDZD2 PDZ domain containing 2 2.6
ABCA5 ATP binding cassette subfamily A member 5 2.6
FRRS1 ferric-chelate reductase 1 2.6
FAM3B family with sequence similarity 3, member B 2.6
SLC5A6 solute carrier family 5 (sodium/multivitamin and iodide cotransporter), member 6 2.6
LOC645513 uncharacterized LOC645513 2.6
NOS3 nitric oxide synthase 3 (endothelial cell) 2.6
POU2F3 POU class 2 homeobox 3 2.6
ADAMTS18 ADAM metallopeptidase with thrombospondin type 1 motif 18 2.6
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
ETFDH electron-transferring-flavoprotein dehydrogenase 2.6
SOX7 SRY box 7 2.6
RICTOR RPTOR independent companion of MTOR, complex 2 2.6
SOX5 SRY box 5 2.6
MIR17HG miR-17-92 cluster host gene 2.6
TAS2R39 taste receptor, type 2, member 39 2.6
CKMT1B creatine kinase, mitochondrial 1B 2.6
CCNB1 cyclin B1 2.6
RBMS3-AS3 RBMS3 antisense RNA 3 2.5

PT
XKRX X-linked Kx blood group related, X-linked 2.5
DYSF dysferlin 2.5
CHODL chondrolectin 2.5
RPIA ribose 5-phosphate isomerase A 2.5

RI
ACSS1 acyl-CoA synthetase short-chain family member 1 2.5
C10orf25 chromosome 10 open reading frame 25 2.5
MIR518A1 microRNA 518a-1 2.5

SC
AGPAT5 1-acylglycerol-3-phosphate O-acyltransferase 5 2.5
CEP85 centrosomal protein 85kDa 2.5
AMMECR1 Alport syndrome, mental retardation, midface hypoplasia and elliptocytosis chromosomal
2.5 region
SLC16A12 solute carrier family 16, member 12 2.5

U
CLIC5 chloride intracellular channel 5 2.5
MTUS1 microtubule associated tumor suppressor 1 2.5
TPRXL
LCOR
PLXNA2
AN
tetra-peptide repeat homeobox-like
ligand dependent nuclear receptor corepressor
plexin A2
2.5
2.5
2.5
RGPD3 RANBP2-like and GRIP domain containing 3 2.5
M
PAG1 phosphoprotein membrane anchor with glycosphingolipid microdomains 1 2.5
SH3D21 SH3 domain containing 21 2.5
PAXBP1 PAX3 and PAX7 binding protein 1 2.5
D

SCNN1B sodium channel, non voltage gated 1 beta subunit 2.5

ISM1 isthmin 1, angiogenesis inhibitor 2.5
CECR2 cat eye syndrome chromosome region, candidate 2 2.5
TE

CNOT6L CCR4-NOT transcription complex subunit 6-like 2.4

STK17A serine/threonine kinase 17a 2.4
SCAPER S-phase cyclin A-associated protein in the ER 2.4
LINC01004 long intergenic non-protein coding RNA 1004 2.4
EP

NEK7 NIMA-related kinase 7 2.4

PSMD6-AS2 PSMD6 antisense RNA 2 2.4
MIR573 microRNA 573 2.4
C

LOC101927973 uncharacterized LOC101927973 2.4

MIR302D microRNA 302d 2.4
AC

GLDC glycine dehydrogenase (decarboxylating) 2.4

ANKRD20A2 ankyrin repeat domain 20 family, member A2 2.4
FAM133B family with sequence similarity 133, member B 2.4
AUNIP aurora kinase A and ninein interacting protein 2.4
OCLN occludin 2.4
RBM5-AS1 RBM5 antisense RNA 1 2.4
LGALSL lectin, galactoside-binding-like 2.4
RTTN rotatin 2.4
FURIN furin (paired basic amino acid cleaving enzyme) 2.4
DVL3 dishevelled segment polarity protein 3 2.4
RALGAPA2 Ral GTPase activating protein, alpha subunit 2 (catalytic) 2.4
TRIM40 tripartite motif containing 40 2.4
DTL denticleless E3 ubiquitin protein ligase homolog (Drosophila) 2.4
CADM3 cell adhesion molecule 3 2.4
DDX59 DEAD (Asp-Glu-Ala-Asp) box polypeptide 59 2.4
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
ZSCAN12P1 zinc finger and SCAN domain containing 12 pseudogene 1 2.4
CCNA2 cyclin A2 2.4
DOCK9-AS1 DOCK9 antisense RNA 1 2.4
HYMAI hydatidiform mole associated and imprinted (non-protein coding) 2.4
TBC1D32 TBC1 domain family, member 32 2.4
RMI2 RecQ mediated genome instability 2 2.4
CSGALNACT1 chondroitin sulfate N-acetylgalactosaminyltransferase 1 2.4
THAP9 THAP domain containing 9 2.4
NREP neuronal regeneration related protein 2.3

PT
SDHAP1 succinate dehydrogenase complex subunit A, flavoprotein pseudogene 1 2.3
HEXIM1 hexamethylene bis-acetamide inducible 1 2.3
PDE5A phosphodiesterase 5A, cGMP-specific 2.3
EXOC6B exocyst complex component 6B 2.3

RI
MB21D2 Mab-21 domain containing 2 2.3
PRPF39 pre-mRNA processing factor 39 2.3
SYT7 synaptotagmin VII 2.3

SC
ARHGAP32 Rho GTPase activating protein 32 2.3
MED13 mediator complex subunit 13 2.3
C8orf46 chromosome 8 open reading frame 46 2.3
DUSP16 dual specificity phosphatase 16 2.3

U
FRAS1 Fraser extracellular matrix complex subunit 1 2.3
MCM8 minichromosome maintenance 8 homologous recombination repair factor 2.3
SOS2
NR3C2
LOC400682
AN
SOS Ras/Rho guanine nucleotide exchange factor 2
nuclear receptor subfamily 3, group C, member 2
zinc finger protein 100-like
2.3
2.3
2.3
PP12613 uncharacterized LOC100192379 2.3
M
ZNRF2P1 zinc and ring finger 2 pseudogene 1 2.2
ADGRG1 adhesion G protein-coupled receptor G1 2.2
BMS1P11 BMS1 ribosome biogenesis factor pseudogene 11 2.2
D

AIM1L absent in melanoma 1-like 2.2

HOPX HOP homeobox 2.2
FEZ2 fasciculation and elongation protein zeta 2 (zygin II) 2.2
TE

ARL5A ADP-ribosylation factor like GTPase 5A 2.2

FOXF1 forkhead box F1 2.2
OR7E91P olfactory receptor, family 7, subfamily E, member 91 pseudogene 2.2
RYR2 ryanodine receptor 2 (cardiac) 2.2
EP

KCTD4 potassium channel tetramerization domain containing 4 2.2

RGPD8 RANBP2-like and GRIP domain containing 8 2.2
WASH5P WAS protein family homolog 5 pseudogene 2.2
C

KIF27 kinesin family member 27 2.2

XRN1 5-3 exoribonuclease 1 2.1
AC

CHN1 chimerin 1 2.1

KCNK5 potassium channel, two pore domain subfamily K, member 5 2.1
CENPU centromere protein U 2.1
CCNE2 cyclin E2 2.1
EBLN2 endogenous Bornavirus-like nucleoprotein 2 2.1
CD300LG CD300 molecule-like family member g 2.1
SAMD5 sterile alpha motif domain containing 5 2.1
LOC101927305 uncharacterized LOC101927305 2.1
PDE4D phosphodiesterase 4D, cAMP-specific 2.1
TOP1 topoisomerase (DNA) I 2.1
ATP6V1B1 ATPase, H+ transporting, lysosomal 56/58kDa, V1 subunit B1 2.1
FSIP2 fibrous sheath interacting protein 2 2.0
B sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
OR5H14 olfactory receptor, family 5, subfamily H, member 14 55.1
SPRR2G small proline-rich protein 2G 18.2
LOC100132735 uncharacterized LOC100132735 15.8
NOTUM notum pectinacetylesterase homolog (Drosophila) 14.9
LINC01602 long intergenic non-protein coding RNA 1602 11.6
REPS2 RALBP1 associated Eps domain containing 2 10.3
C5orf46 chromosome 5 open reading frame 46 10.2
TNFSF10 tumor necrosis factor (ligand) superfamily, member 10 9.6
HCAR2 hydroxycarboxylic acid receptor 2 9.1

PT
RASGRF2 Ras protein-specific guanine nucleotide-releasing factor 2 8.8
GPRC5A G protein-coupled receptor, class C, group 5, member A 8.5
UPK1B uroplakin 1B 7.9
ZNF300P1 zinc finger protein 300 pseudogene 1 (functional) 7.9

RI
MT1X metallothionein 1X 7.8
MKRN3 makorin ring finger protein 3 7.0
CMTM4 CKLF-like MARVEL transmembrane domain containing 4 7.0

SC
HNRNPA1P33 heterogeneous nuclear ribonucleoprotein A1 pseudogene 33 6.5
SFRP1 secreted frizzled-related protein 1 6.5
TRIM64 tripartite motif containing 64 6.4
KRT7 keratin 7, type II 6.1

U
PLA2G10 phospholipase A2, group X 6.1
LINC00330 long intergenic non-protein coding RNA 330 6.0
DIO2
ADAM19
MYCNUT
AN
deiodinase, iodothyronine, type II
ADAM metallopeptidase domain 19
MYCN upstream transcript (non-protein coding)
5.9
5.9
5.9
COL17A1 collagen, type XVII, alpha 1 5.9
M
HN1 hematological and neurological expressed 1 5.8
FSTL3 follistatin-like 3 (secreted glycoprotein) 5.7
PTGES prostaglandin E synthase 5.7
D

PPP4R4 protein phosphatase 4, regulatory subunit 4 5.7

ISM2 isthmin 2 5.6
DOCK5 dedicator of cytokinesis 5 5.5
TE

PLAC8 placenta specific 8 5.5

AADACL3 arylacetamide deacetylase-like 3 5.4
FHOD3 formin homology 2 domain containing 3 5.3
SLC4A7 solute carrier family 4, sodium bicarbonate cotransporter, member 7 5.3
EP

GPR32 G protein-coupled receptor 32 5.2

GALNT3 polypeptide N-acetylgalactosaminyltransferase 3 5.2
UGCG UDP-glucose ceramide glucosyltransferase 5.2
C

IL2RB interleukin 2 receptor, beta 5.0

MIR181A2HG MIR181A2 host gene 4.9
AC

FAR2P1 fatty acyl-CoA reductase 2 pseudogene 1 4.8

EGLN3 egl-9 family hypoxia-inducible factor 3 4.8
TRIM64B tripartite motif containing 64B 4.8
GALNT6 polypeptide N-acetylgalactosaminyltransferase 6 4.8
PGPEP1 pyroglutamyl-peptidase I 4.7
RFPL4B ret finger protein-like 4B 4.7
PKP2 plakophilin 2 4.7
FAT1 FAT atypical cadherin 1 4.7
TNNI2 troponin I type 2 (skeletal, fast) 4.6
RAB6C-AS1 RAB6C antisense RNA 1 4.6
HLTF helicase-like transcription factor 4.6
PDE10A phosphodiesterase 10A 4.6
SDC4 syndecan 4 4.5
ART4 ADP-ribosyltransferase 4 (Dombrock blood group) 4.5
SEPT3_NM_019106
septin 3 4.5
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
SHROOM3 shroom family member 3 4.4
MEX3D mex-3 RNA binding family member D 4.4
FLNB filamin B, beta 4.4
PTPRQ protein tyrosine phosphatase, receptor type, Q 4.4
ENKUR enkurin, TRPC channel interacting protein 4.4
KIAA1211L KIAA1211-like 4.4
MGAT5 mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase 4.3
TCEA3 transcription elongation factor A (SII), 3 4.3
CSRP2BP CSRP2 binding protein 4.3

PT
LOC100128979 uncharacterized LOC100128979 4.2
CA2 carbonic anhydrase II 4.2
TPM1 tropomyosin 1 (alpha) 4.2
PIPOX pipecolic acid oxidase 4.2

RI
NRIP1 nuclear receptor interacting protein 1 4.2
LINC01338 long intergenic non-protein coding RNA 1338 4.2
LGALS3BP lectin, galactoside-binding, soluble, 3 binding protein 4.2

SC
ASPHD2 aspartate beta-hydroxylase domain containing 2 4.1
GDPD3 glycerophosphodiester phosphodiesterase domain containing 3 4.0
AQP9 aquaporin 9 3.9
HCG4 HLA complex group 4 (non-protein coding) 3.9

U
BIN2 bridging integrator 2 3.9
RRAD Ras-related associated with diabetes 3.9
SLC6A2
NUAK2
SLC1A6
AN
solute carrier family 6 (neurotransmitter transporter), member 2
NUAK family, SNF1-like kinase, 2
solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6
3.9
3.9
3.9
VIT vitrin 3.8
M
BGN biglycan 3.8
POTEM POTE ankyrin domain family, member M 3.8
F11R F11 receptor 3.8
D

LOC102723854 uncharacterized LOC102723854 3.8

CHRM5 cholinergic receptor, muscarinic 5 3.8
FABP7 fatty acid binding protein 7, brain 3.7
TE

OXGR1 oxoglutarate (alpha-ketoglutarate) receptor 1 3.7

RALBP1 ralA binding protein 1 3.7
LPCAT1 lysophosphatidylcholine acyltransferase 1 3.7
LAMA3 laminin, alpha 3 3.7
EP

PXN paxillin 3.6

FAT2 FAT atypical cadherin 2 3.5
TMEM31 transmembrane protein 31 3.5
C

CLNK cytokine-dependent hematopoietic cell linker 3.5

ASAP3 ArfGAP with SH3 domain, ankyrin repeat and PH domain 3 3.5
AC

FGFR1 fibroblast growth factor receptor 1 3.4

LOC100130476 uncharacterized LOC100130476 3.4
ELF4 E74-like factor 4 (ets domain transcription factor) 3.4
ACOT2 acyl-CoA thioesterase 2 3.4
MGAT4A mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N-acetylglucosaminyltransferase, isozyme3.4
A
TIAM1 T-cell lymphoma invasion and metastasis 1 3.4
HN1L hematological and neurological expressed 1-like 3.4
ZNF486 zinc finger protein 486 3.4
GALNT7 polypeptide N-acetylgalactosaminyltransferase 7 3.3
CORO6 coronin 6 3.3
BAIAP2L1 BAI1-associated protein 2-like 1 3.3
UBL3 ubiquitin-like 3 3.3
KIF21A kinesin family member 21A 3.3
C12orf75 chromosome 12 open reading frame 75 3.3
SERTAD4 SERTA domain containing 4 3.2
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
SIK1 salt-inducible kinase 1 3.2
CLDN19 claudin 19 3.2
UBASH3B ubiquitin associated and SH3 domain containing B 3.2
KRT14 keratin 14, type I 3.2
ANKRD50 ankyrin repeat domain 50 3.2
CDH1 cadherin 1, type 1 3.2
NKRF NFKB repressing factor 3.2
MAPRE2 microtubule-associated protein, RP/EB family, member 2 3.2
LINC00842 long intergenic non-protein coding RNA 842 3.1

PT
TEAD1 TEA domain family member 1 (SV40 transcriptional enhancer factor) 3.1
VWCE von Willebrand factor C and EGF domains 3.1
IPMK inositol polyphosphate multikinase 3.1
CDKN1C cyclin-dependent kinase inhibitor 1C (p57, Kip2) 3.1

RI
SLC35A3 solute carrier family 35 (UDP-N-acetylglucosamine (UDP-GlcNAc) transporter), member3.0
A3
KCNK12 potassium channel, two pore domain subfamily K, member 12 3.0
AFAP1 actin filament associated protein 1 3.0

SC
FAM110A family with sequence similarity 110, member A 3.0
RECK reversion-inducing-cysteine-rich protein with kazal motifs 3.0
NIM1K NIM1 serine/threonine protein kinase 3.0
NBPF1 neuroblastoma breakpoint family, member 1 3.0

U
BMS1P18 BMS1 ribosome biogenesis factor pseudogene 18 3.0
NAV1 neuron navigator 1 3.0
FHL2
PLK2
ASCL2
polo-like kinase 2
AN
four and a half LIM domains 2

achaete-scute family bHLH transcription factor 2

3.0
3.0
2.9
PARD3 par-3 family cell polarity regulator 2.9
M
NLRP2 NLR family, pyrin domain containing 2 2.9
KRT19 keratin 19, type I 2.9
PPFIBP2 PTPRF interacting protein, binding protein 2 (liprin beta 2) 2.9
D

ANKRD6 ankyrin repeat domain 6 2.9

HCAR1 hydroxycarboxylic acid receptor 1 2.9
RAD51C RAD51 paralog C 2.9
TE

MYCNOS MYCN opposite strand 2.9

TAF5L TAF5-like RNA polymerase II, p300/CBP-associated factor (PCAF)-associated factor, 65kDa
2.9
PRSS8 protease, serine, 8 2.9
TARBP1 TAR (HIV-1) RNA binding protein 1 2.8
EP

IPO9-AS1 IPO9 antisense RNA 1 2.8

CXorf58 chromosome X open reading frame 58 2.8
STC1 stanniocalcin 1 2.8
C

LSP1P3 lymphocyte-specific protein 1 pseudogene 3 2.7

TSC22D1 TSC22 domain family, member 1 2.7
AC

CXCR6 chemokine (C-X-C motif) receptor 6 2.7

ZFP57 ZFP57 zinc finger protein 2.7
SHC3 SHC (Src homology 2 domain containing) transforming protein 3 2.7
CPOX coproporphyrinogen oxidase 2.7
PADI1 peptidyl arginine deiminase, type I 2.7
DNAH11 dynein, axonemal, heavy chain 11 2.7
ANXA8L1 annexin A8-like 1 2.7
ZNF860 zinc finger protein 860 2.7
PDK3 pyruvate dehydrogenase kinase, isozyme 3 2.7
POMC proopiomelanocortin 2.7
PTBP3 polypyrimidine tract binding protein 3 2.6
PROSER2-AS1 PROSER2 antisense RNA 1 2.6
JAM2 junctional adhesion molecule 2 2.6
SLC25A37 solute carrier family 25 (mitochondrial iron transporter), member 37 2.6
LY6K lymphocyte antigen 6 complex, locus K 2.6
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
SLC2A3 solute carrier family 2 (facilitated glucose transporter), member 3 2.6
DTX4 deltex 4, E3 ubiquitin ligase 2.6
YPEL2 yippee like 2 2.6
HEXB hexosaminidase B (beta polypeptide) 2.5
CDC14C cell division cycle 14C 2.5
EFNA1 ephrin-A1 2.5
IQSEC1 IQ motif and Sec7 domain 1 2.5
YIPF2 Yip1 domain family member 2 2.5
GALNT2 polypeptide N-acetylgalactosaminyltransferase 2 2.5

PT
ACTBL2 actin, beta-like 2 2.5
GPR146 G protein-coupled receptor 146 2.5
PTPRR protein tyrosine phosphatase, receptor type, R 2.5
KHDC1L KH homology domain containing 1-like 2.5

RI
ACOX1 acyl-CoA oxidase 1, palmitoyl 2.5
CNTNAP3 contactin associated protein-like 3 2.5
DLX6-AS1 DLX6 antisense RNA 1 2.5

SC
ZNF440 zinc finger protein 440 2.4
SERPINA11 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 11 2.4
FMNL2 formin like 2 2.4
TMED9 transmembrane p24 trafficking protein 9 2.4

U
CPVL carboxypeptidase, vitellogenic-like 2.4
THRB thyroid hormone receptor, beta 2.4
INPP5B
PLOD2
SLC17A8
AN
inositol polyphosphate-5-phosphatase B
procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2
solute carrier family 17 (vesicular glutamate transporter), member 8
2.4
2.4
2.4
SEMA4C sema domain, immunoglobulin domain (Ig), transmembrane domain (TM) and short cytoplasmic
2.3
M
CTD-2201E9.1 uncharacterized LOC101929338 2.3
SNORA71C small nucleolar RNA, H/ACA box 71C 2.3
MBNL2 muscleblind-like splicing regulator 2 2.3
D

LLGL2 lethal giant larvae homolog 2 (Drosophila) 2.3

P2RX4 purinergic receptor P2X, ligand gated ion channel, 4 2.3
POTEF POTE ankyrin domain family, member F 2.3
TE

P4HA1 prolyl 4-hydroxylase, alpha polypeptide I 2.2

INADL InaD-like (Drosophila) 2.2
NKX3-1 NK3 homeobox 1 2.2
F2RL1 coagulation factor II (thrombin) receptor-like 1 2.2
EP

LOC100507140 uncharacterized LOC100507140 2.2

ENG endoglin 2.2
GALNT12 polypeptide N-acetylgalactosaminyltransferase 12 2.2
C

BIRC7 baculoviral IAP repeat containing 7 2.2

C1QTNF7 C1q and tumor necrosis factor related protein 7 2.2
AC

PDZK1 PDZ domain containing 1 2.1

CDK7 cyclin-dependent kinase 7 2.1
SLC6A11 solute carrier family 6 (neurotransmitter transporter), member 11 2.1
RNF185-AS1 RNF185 antisense RNA 1 2.1
ARSK arylsulfatase family, member K 2.0
CTAGE6 CTAGE family, member 6 2.0
C ACCEPTED MANUSCRIPT
sPE
STB iCTB eCTB Symbol Name D
CHRDL1 chordin-like 1 117.0
PRL prolactin 85.3
PAEP progestagen-associated endometrial protein 77.4
IGFBP1 insulin like growth factor binding protein 1 75.0
C3 complement component 3 56.0
OMD osteomodulin 49.6
RXFP1 relaxin/insulin-like family peptide receptor 1 49.4
RORB RAR-related orphan receptor B 44.3
EPYC epiphycan 40.7

PT
MEDAG mesenteric estrogen-dependent adipogenesis 37.6
CXCL9 chemokine (C-X-C motif) ligand 9 34.7
CFH complement factor H 29.2
DKK1 dickkopf WNT signaling pathway inhibitor 1 25.4

RI
HSD11B1 hydroxysteroid (11-beta) dehydrogenase 1 23.8
CPXM1 carboxypeptidase X (M14 family), member 1 23.3
ALDH1A1 aldehyde dehydrogenase 1 family, member A1 21.6

SC
GZMA granzyme A 21.6
CYP7B1 cytochrome P450, family 7, subfamily B, polypeptide 1 21.1
MAOB monoamine oxidase B 20.2
AVPR1A arginine vasopressin receptor 1A 18.5

U
NDP Norrie disease (pseudoglioma) 17.0
CTSK cathepsin K 16.9
CNR1
HLA-DRA
TRPC4
AN
cannabinoid receptor 1 (brain)
major histocompatibility complex, class II, DR alpha
transient receptor potential cation channel, subfamily C, member 4
16.2
16.1
15.6
KLRC1 killer cell lectin-like receptor subfamily C, member 1 15.3
M
ABI3BP ABI family, member 3 (NESH) binding protein 15.1
FGG fibrinogen gamma chain 14.8
WT1 Wilms tumor 1 14.6
D

PGR progesterone receptor 13.4

HSPB6 heat shock protein, alpha-crystallin-related, B6 13.3
MYL9 myosin light chain 9 13.3
TE

LOC100507639 uncharacterized LOC100507639 13.0

CD248 CD248 molecule, endosialin 12.9
GZMK granzyme K 12.5
PRUNE2 prune homolog 2 (Drosophila) 12.1
EP

TRDC T cell receptor delta constant 12.0

TRDJ2 T cell receptor delta joining 2 11.8
IGFBP4 insulin like growth factor binding protein 4 11.7
C

FPR3 formyl peptide receptor 3 11.7

GREB1 growth regulation by estrogen in breast cancer 1 11.2
AC

RNASE2 ribonuclease, RNase A family, 2 (liver, eosinophil-derived neurotoxin) 11.1

HAND2-AS1 HAND2 antisense RNA 1 (head to head) 11.0
F2R coagulation factor II (thrombin) receptor 11.0
RGS1 regulator of G-protein signaling 1 10.9
SULF2 sulfatase 2 10.8
TRAV20 T cell receptor alpha variable 20 10.8
PALMD palmdelphin 10.6
DEFB1 defensin, beta 1 10.5
SULF1 sulfatase 1 10.3
MGP matrix Gla protein 10.2
GPRC5B G protein-coupled receptor, class C, group 5, member B 10.1
CCL21 chemokine (C-C motif) ligand 21 10.0
SEMA3A sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin)9.9
3A
ITGB8 integrin beta 8 9.9
PRDM1 PR domain containing 1, with ZNF domain 9.8
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
LINC01320 long intergenic non-protein coding RNA 1320 9.7
KLRC3 killer cell lectin-like receptor subfamily C, member 3 9.7
WNT5A wingless-type MMTV integration site family, member 5A 9.5
PLCL1 phospholipase C-like 1 9.4
REN renin 9.4
SPOCK1 sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 1 9.4
COL12A1 collagen, type XII, alpha 1 9.4
AADAC arylacetamide deacetylase 9.4
RGS2 regulator of G-protein signaling 2 9.3

PT
MFAP4 microfibrillar associated protein 4 9.2
SQRDL sulfide quinone reductase-like (yeast) 9.0
ASPN asporin 9.0
CCL2 chemokine (C-C motif) ligand 2 9.0

RI
SERPINA3 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 9.0
SCGB2A1 secretoglobin, family 2A, member 1 8.9
CD74 CD74 molecule, major histocompatibility complex, class II invariant chain 8.8

SC
CD2 CD2 molecule 8.6
APOD apolipoprotein D 8.5
IL15 interleukin 15 8.5
MAP3K5 mitogen-activated protein kinase kinase kinase 5 8.5

U
SPARCL1 SPARC like 1 8.3
TMEM47 transmembrane protein 47 8.3
CD69
RBP4
KLRC4-KLRK1
CD69 molecule AN
retinol binding protein 4, plasma
KLRC4-KLRK1 readthrough
8.2
8.1
8.1
MMP2 matrix metallopeptidase 2 7.9
M
OGN osteoglycin 7.8
PLPP1 phospholipid phosphatase 1 7.6
PLN phospholamban 7.6
D

NAV3 neuron navigator 3 7.5

PLEKHH2 pleckstrin homology domain containing, family H (with MyTH4 domain) member 2 7.4
GAS1 growth arrest-specific 1 7.3
TE

COX7A1 cytochrome c oxidase subunit VIIa polypeptide 1 (muscle) 7.3

PDGFD platelet derived growth factor D 7.2
VCAM1 vascular cell adhesion molecule 1 7.2
SCARA5 scavenger receptor class A, member 5 7.1
EP

PTPN22 protein tyrosine phosphatase, non-receptor type 22 (lymphoid) 7.1

PARM1 prostate androgen-regulated mucin-like protein 1 7.1
HAND2 heart and neural crest derivatives expressed 2 7.0
C

ME1 malic enzyme 1, NADP(+)-dependent, cytosolic 7.0

JAKMIP2 janus kinase and microtubule interacting protein 2 7.0
AC

ADAMTS5 ADAM metallopeptidase with thrombospondin type 1 motif 5 6.9

SYT11 synaptotagmin XI 6.9
LINC00890 long intergenic non-protein coding RNA 890 6.9
PROK1 prokineticin 1 6.8
LMOD1 leiomodin 1 (smooth muscle) 6.8
DTNA dystrobrevin, alpha 6.7
TRBV3-1 T cell receptor beta variable 3-1 6.6
ZNF727 zinc finger protein 727 6.5
MACC1 metastasis associated in colon cancer 1 6.5
PTPRC protein tyrosine phosphatase, receptor type, C 6.5
IGFBP7 insulin like growth factor binding protein 7 6.5
APOO apolipoprotein O 6.5
NKG7 natural killer cell granule protein 7 6.4
FMOD fibromodulin 6.4
TMTC1 transmembrane and tetratricopeptide repeat containing 1 6.3
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
CST11 cystatin 11 6.3
AXL AXL receptor tyrosine kinase 6.3
ABCA6 ATP binding cassette subfamily A member 6 6.3
EMP3 epithelial membrane protein 3 6.2
SLAMF6 SLAM family member 6 6.1
PILRA paired immunoglobin-like type 2 receptor alpha 6.1
CXCL8 chemokine (C-X-C motif) ligand 8 6.1
PAMR1 peptidase domain containing associated with muscle regeneration 1 6.0
CD96 CD96 molecule 6.0

PT
IFI44 interferon-induced protein 44 6.0
TNC tenascin C 6.0
ANKRD1 ankyrin repeat domain 1 (cardiac muscle) 6.0
PDGFRA platelet-derived growth factor receptor, alpha polypeptide 6.0

RI
CFI complement factor I 5.9
VSIG4 V-set and immunoglobulin domain containing 4 5.8
AOX1 aldehyde oxidase 1 5.8

SC
CHI3L1 chitinase 3-like 1 (cartilage glycoprotein-39) 5.7
MSN moesin 5.7
HOXA11 homeobox A11 5.7
CEP126 centrosomal protein 126kDa 5.7

U
IL1A interleukin 1 alpha 5.7
NNMT nicotinamide N-methyltransferase 5.6
HTR2B
RBP1
DOCK10
AN
5-hydroxytryptamine (serotonin) receptor 2B, G protein-coupled
retinol binding protein 1, cellular
dedicator of cytokinesis 10
5.6
5.6
5.6
CTSS cathepsin S 5.6
M
PDLIM1 PDZ and LIM domain 1 5.6
PTPN13 protein tyrosine phosphatase, non-receptor type 13 (APO-1/CD95 (Fas)-associated phosphatase)
5.5
IGSF10 immunoglobulin superfamily, member 10 5.5
D

IGFBP2 insulin like growth factor binding protein 2 5.5

ANTXR1 anthrax toxin receptor 1 5.4
C10orf107 chromosome 10 open reading frame 107 5.4
TE

C1S complement component 1, s subcomponent 5.4

STAMBPL1 STAM binding protein-like 1 5.4
P3H2 prolyl 3-hydroxylase 2 5.4
SYNPO2 synaptopodin 2 5.3
EP

WISP1 WNT1 inducible signaling pathway protein 1 5.3

P2RY14 purinergic receptor P2Y, G-protein coupled, 14 5.3
CCL13 chemokine (C-C motif) ligand 13 5.3
C

ANPEP alanyl (membrane) aminopeptidase 5.3

APCDD1 adenomatosis polyposis coli down-regulated 1 5.3
AC

CLIC2 chloride intracellular channel 2 5.2

FGF2 fibroblast growth factor 2 (basic) 5.2
CCL5 chemokine (C-C motif) ligand 5 5.2
CD52 CD52 molecule 5.2
FBLN5 fibulin 5 5.2
EMILIN2 elastin microfibril interfacer 2 5.2
VTRNA2-1 vault RNA 2-1 5.2
DEPTOR DEP domain containing MTOR-interacting protein 5.2
IL18 interleukin 18 5.2
CLEC2D C-type lectin domain family 2, member D 5.1
LAPTM5 lysosomal protein transmembrane 5 5.1
C1R complement component 1, r subcomponent 5.1
CLMP CXADR-like membrane protein 5.1
CD163 CD163 molecule 5.1
UCHL1 ubiquitin C-terminal hydrolase L1 5.1
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
EVA1C eva-1 homolog C (C. elegans) 5.1
ZEB1 zinc finger E-box binding homeobox 1 5.1
CD226 CD226 molecule 5.1
MUC16 mucin 16, cell surface associated 5.0
LYZ lysozyme 5.0
IFI44L interferon-induced protein 44-like 4.9
LOC101928461 uncharacterized LOC101928461 4.9
KCND2 potassium channel, voltage gated Shal related subfamily D, member 2 4.9
TLR4 toll-like receptor 4 4.9

PT
EMX2 empty spiracles homeobox 2 4.9
HAMP hepcidin antimicrobial peptide 4.9
MYO16-AS1 MYO16 antisense RNA 1 4.9
MMP7 matrix metallopeptidase 7 4.8

RI
ADAMTS2 ADAM metallopeptidase with thrombospondin type 1 motif 2 4.8
PDGFRB platelet-derived growth factor receptor, beta polypeptide 4.8
CD3D CD3d molecule, delta (CD3-TCR complex) 4.8

SC
HLA-DPA1 major histocompatibility complex, class II, DP alpha 1 4.8
TUBA3E tubulin, alpha 3e 4.8
TWISTNB TWIST neighbor 4.8
FHL5 four and a half LIM domains 5 4.8

U
TAGAP T-cell activation RhoGTPase activating protein 4.8
DPYD dihydropyrimidine dehydrogenase 4.7
CD68
ECM2
BICC1
CD68 molecule AN
extracellular matrix protein 2, female organ and adipocyte specific
BicC family RNA binding protein 1
4.7
4.7
4.7
KLRB1 killer cell lectin-like receptor subfamily B, member 1 4.6
M
RASD1 RAS, dexamethasone-induced 1 4.6
LONRF2 LON peptidase N-terminal domain and ring finger 2 4.6
FAP fibroblast activation protein alpha 4.6
D

PCOLCE procollagen C-endopeptidase enhancer 4.6

MAP1B microtubule associated protein 1B 4.6
HOXA5 homeobox A5 4.6
TE

F3 coagulation factor III (thromboplastin, tissue factor) 4.5

LPAR1 lysophosphatidic acid receptor 1 4.5
CHSY3 chondroitin sulfate synthase 3 4.5
CD44 CD44 molecule (Indian blood group) 4.5
EP

GTF2A1L general transcription factor IIA 1-like 4.5

PDZK1IP1 PDZK1 interacting protein 1 4.5
CDH11 cadherin 11, type 2, OB-cadherin (osteoblast) 4.5
C

CERS6 ceramide synthase 6 4.5

IL7R interleukin 7 receptor 4.5
AC

PRR15 proline rich 15 4.4

RGS22 regulator of G-protein signaling 22 4.4
COPZ2 coatomer protein complex subunit zeta 2 4.4
LSAMP limbic system-associated membrane protein 4.4
SYTL4 synaptotagmin-like 4 4.4
INPP4B inositol polyphosphate-4-phosphatase type II B 4.4
ZFP36 ZFP36 ring finger protein 4.4
TRGJP1 T cell receptor gamma joining P1 4.3
ATP2B4 ATPase, Ca++ transporting, plasma membrane 4 4.3
CP ceruloplasmin (ferroxidase) 4.2
VCAN versican 4.2
TMEM27 transmembrane protein 27 4.2
SNCAIP synuclein alpha interacting protein 4.2
SCPEP1 serine carboxypeptidase 1 4.2
CD53 CD53 molecule 4.2
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
NAPSB napsin B aspartic peptidase, pseudogene 4.2
VWF von Willebrand factor 4.2
CLU clusterin 4.2
NFIC nuclear factor I/C (CCAAT-binding transcription factor) 4.2
CHI3L2 chitinase 3-like 2 4.1
SIPA1L2 signal-induced proliferation-associated 1 like 2 4.1
TPST1 tyrosylprotein sulfotransferase 1 4.1
PTGDR prostaglandin D2 receptor (DP) 4.1
VIM vimentin 4.1

PT
IL1B interleukin 1 beta 4.1
MXRA8 matrix-remodelling associated 8 4.1
GLUL glutamate-ammonia ligase 4.1
SRGN serglycin 4.0

RI
NPR3 natriuretic peptide receptor 3 4.0
LOC643733 caspase 4, apoptosis-related cysteine peptidase pseudogene 4.0
C5AR1 complement component 5a receptor 1 4.0

SC
DCN decorin 4.0
CST3 cystatin C 4.0
PLXDC2 plexin domain containing 2 4.0
PZP pregnancy-zone protein 4.0

U
CTSW cathepsin W 4.0
TIMP1 TIMP metallopeptidase inhibitor 1 4.0
C11orf70
MAP1LC3C
MIR99AHG
AN
chromosome 11 open reading frame 70
microtubule associated protein 1 light chain 3 gamma
mir-99a-let-7c cluster host gene
3.9
3.9
3.9
FLNA filamin A, alpha 3.9
M
ABCA8 ATP binding cassette subfamily A member 8 3.9
C1GALT1C1L C1GALT1-specific chaperone 1 like 3.8
TMEM132C transmembrane protein 132C 3.8
D

FCER1G Fc fragment of IgE, high affinity I, receptor for; gamma polypeptide 3.8
GEM GTP binding protein overexpressed in skeletal muscle 3.8
MGST1 microsomal glutathione S-transferase 1 3.8
TE

FGA fibrinogen alpha chain 3.8

KCNH1 potassium channel, voltage gated eag related subfamily H, member 1 3.8
STK39 serine threonine kinase 39 3.8
PRPS2 phosphoribosyl pyrophosphate synthetase 2 3.8
EP

SOD2 superoxide dismutase 2, mitochondrial 3.8

CAB39L calcium binding protein 39-like 3.8
TRPS1 trichorhinophalangeal syndrome I 3.8
C

C1QC complement component 1, q subcomponent, C chain 3.8

RAB31 RAB31, member RAS oncogene family 3.7
AC

SAMD9L sterile alpha motif domain containing 9-like 3.7

CORIN corin, serine peptidase 3.7
IL2RA interleukin 2 receptor, alpha 3.7
IQCK IQ motif containing K 3.7
FAM198B family with sequence similarity 198, member B 3.7
CERS6-AS1 CERS6 antisense RNA 1 3.7
ZNF516 zinc finger protein 516 3.7
CLEC2B C-type lectin domain family 2, member B 3.7
XCL2 chemokine (C motif) ligand 2 3.7
IGFBP6 insulin like growth factor binding protein 6 3.7
SFMBT2 Scm-like with four mbt domains 2 3.7
NID2 nidogen 2 (osteonidogen) 3.7
MFGE8 milk fat globule-EGF factor 8 protein 3.7
GPRIN3 GPRIN family member 3 3.7
MDM1 Mdm1 nuclear protein 3.7
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
ODC1 ornithine decarboxylase 1 3.7
FYN FYN proto-oncogene, Src family tyrosine kinase 3.6
ACSS3 acyl-CoA synthetase short-chain family member 3 3.6
TGM2 transglutaminase 2 3.6
CCL4L2 chemokine (C-C motif) ligand 4-like 2 3.6
LY96 lymphocyte antigen 96 3.6
GALNT15 polypeptide N-acetylgalactosaminyltransferase 15 3.6
MUM1L1 melanoma associated antigen (mutated) 1-like 1 3.6
CD3E CD3e molecule, epsilon (CD3-TCR complex) 3.6

PT
TNFRSF11B tumor necrosis factor receptor superfamily, member 11b 3.6
LGALS1 lectin, galactoside-binding, soluble, 1 3.6
CHST7 carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 7 3.6
C15orf65 chromosome 15 open reading frame 65 3.6

RI
SH3BGRL SH3 domain binding glutamate-rich protein like 3.6
SGCB sarcoglycan beta 3.6
CCL23 chemokine (C-C motif) ligand 23 3.6

SC
EVI2B ecotropic viral integration site 2B 3.6
LRRK2 leucine-rich repeat kinase 2 3.5
ADRA2C adrenoceptor alpha 2C 3.5
ALCAM activated leukocyte cell adhesion molecule 3.5

U
GZMB granzyme B 3.5
GJA1 gap junction protein alpha 1 3.5
GSTM5
PCDHB4
CCL4
protocadherin beta 4
AN
glutathione S-transferase mu 5

chemokine (C-C motif) ligand 4

3.5
3.5
3.5
TP53I3 tumor protein p53 inducible protein 3 3.5
M
CCL8 chemokine (C-C motif) ligand 8 3.5
PCDHB10 protocadherin beta 10 3.5
RRAS related RAS viral (r-ras) oncogene homolog 3.5
D

MLLT11 myeloid/lymphoid or mixed-lineage leukemia; translocated to, 11 3.5

EFEMP1 EGF containing fibulin-like extracellular matrix protein 1 3.5
NXPE3 neurexophilin and PC-esterase domain family, member 3 3.5
TE

CYBRD1 cytochrome b reductase 1 3.5

LUM lumican 3.5
SETDB2 SET domain, bifurcated 2 3.5
PYHIN1 pyrin and HIN domain family, member 1 3.5
EP

STAP1 signal transducing adaptor family member 1 3.5

ENTPD3 ectonucleoside triphosphate diphosphohydrolase 3 3.4
NAMPT nicotinamide phosphoribosyltransferase 3.4
C

PLXNA4 plexin A4 3.4

SLC1A1 solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag),
3.4 membe
AC

IL2RG interleukin 2 receptor, gamma 3.4

FAM134B family with sequence similarity 134, member B 3.4
AOAH acyloxyacyl hydrolase (neutrophil) 3.4
DDAH1 dimethylarginine dimethylaminohydrolase 1 3.4
CD82 CD82 molecule 3.4
ACSL1 acyl-CoA synthetase long-chain family member 1 3.4
MUC1 mucin 1, cell surface associated 3.4
NCOA7 nuclear receptor coactivator 7 3.4
ZMAT1 zinc finger, matrin-type 1 3.4
GPR155 G protein-coupled receptor 155 3.4
CELF2 CUGBP, Elav-like family member 2 3.4
SRPX2 sushi-repeat containing protein, X-linked 2 3.3
MMP19 matrix metallopeptidase 19 3.3
FOXO1 forkhead box O1 3.3
RGL1 ral guanine nucleotide dissociation stimulator-like 1 3.3
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
TOB1 transducer of ERBB2, 1 3.3
CD84 CD84 molecule 3.3
PLA2R1 phospholipase A2 receptor 1 3.3
CDK14 cyclin-dependent kinase 14 3.3
MRPL33 mitochondrial ribosomal protein L33 3.3
HLA-DQA2 major histocompatibility complex, class II, DQ alpha 2 3.3
PODNL1 podocan-like 1 3.3
ISLR immunoglobulin superfamily containing leucine-rich repeat 3.3
PRKACB protein kinase, cAMP-dependent, catalytic, beta 3.3

PT
EPDR1 ependymin related 1 3.3
KANK2 KN motif and ankyrin repeat domains 2 3.3
MYO5A myosin VA 3.3
EMCN endomucin 3.3

RI
NFE2L1 nuclear factor, erythroid 2-like 1 3.3
EMP1 epithelial membrane protein 1 3.3
PTGIS prostaglandin I2 (prostacyclin) synthase 3.3

SC
TIPARP TCDD-inducible poly(ADP-ribose) polymerase 3.3
UGT2B7 UDP glucuronosyltransferase 2 family, polypeptide B7 3.2
KLF9 Kruppel-like factor 9 3.2
WNT4 wingless-type MMTV integration site family, member 4 3.2

U
MSR1 macrophage scavenger receptor 1 3.2
C10orf10 chromosome 10 open reading frame 10 3.2
DDR2
KCNK6
MCC
AN
discoidin domain receptor tyrosine kinase 2
potassium channel, two pore domain subfamily K, member 6
mutated in colorectal cancers
3.2
3.2
3.2
CTTNBP2 cortactin binding protein 2 3.2
M
TSPAN5 tetraspanin 5 3.2
ZFP36L2 ZFP36 ring finger protein-like 2 3.2
BIRC3 baculoviral IAP repeat containing 3 3.2
D

EPCAM epithelial cell adhesion molecule 3.2

GLIPR2 GLI pathogenesis-related 2 3.2
SLC24A3 solute carrier family 24 (sodium/potassium/calcium exchanger), member 3 3.2
TE

C4B complement component 4B (Chido blood group) 3.2

EHD2 EH domain containing 2 3.2
SDC2 syndecan 2 3.2
NQO1 NAD(P)H dehydrogenase, quinone 1 3.2
EP

KIR2DL3 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3 3.1
SLAMF8 SLAM family member 8 3.1
SEC11C SEC11 homolog C, signal peptidase complex subunit 3.1
C

FAM20A family with sequence similarity 20, member A 3.1

LAMA4 laminin, alpha 4 3.1
AC

IFI16 interferon, gamma-inducible protein 16 3.1

RUNX3 runt-related transcription factor 3 3.1
APOBEC3C apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3C 3.1
CD48 CD48 molecule 3.1
MANEA mannosidase, endo-alpha 3.1
IRS2 insulin receptor substrate 2 3.1
PCDHB2 protocadherin beta 2 3.1
NAPSA napsin A aspartic peptidase 3.1
KLRF1 killer cell lectin-like receptor subfamily F, member 1 3.1
GNG4 guanine nucleotide binding protein (G protein), gamma 4 3.1
DYNC2LI1 dynein, cytoplasmic 2, light intermediate chain 1 3.1
FAM110C family with sequence similarity 110, member C 3.1
FKBP5 FK506 binding protein 5 3.1
C4A complement component 4A (Rodgers blood group) 3.1
ALDH1A2 aldehyde dehydrogenase 1 family, member A2 3.1
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
PAPSS2 3-phosphoadenosine 5-phosphosulfate synthase 2 3.1
PQLC3 PQ loop repeat containing 3 3.1
NIPAL2 NIPA-like domain containing 2 3.1
PTPRCAP protein tyrosine phosphatase, receptor type, C-associated protein 3.1
CCL14 chemokine (C-C motif) ligand 14 3.0
UBE2L6 ubiquitin-conjugating enzyme E2L 6 3.0
CHST15 carbohydrate (N-acetylgalactosamine 4-sulfate 6-O) sulfotransferase 15 3.0
BRE brain and reproductive organ-expressed (TNFRSF1A modulator) 3.0
ZNF676 zinc finger protein 676 3.0

PT
GPR137B G protein-coupled receptor 137B 3.0
ERMP1 endoplasmic reticulum metallopeptidase 1 3.0
PMCH pro-melanin-concentrating hormone 3.0
SRPX sushi-repeat containing protein, X-linked 3.0

RI
GRIA3 glutamate receptor, ionotropic, AMPA 3 3.0
NEO1 neogenin 1 3.0
ARMC9 armadillo repeat containing 9 3.0

SC
S100A3 S100 calcium binding protein A3 3.0
TTC39B tetratricopeptide repeat domain 39B 3.0
HOXD10 homeobox D10 3.0
TTC39C tetratricopeptide repeat domain 39C 3.0

U
NR4A2 nuclear receptor subfamily 4, group A, member 2 3.0
TNFSF8 tumor necrosis factor (ligand) superfamily, member 8 3.0
PI15
TMSB4X
KIAA0226L
AN
peptidase inhibitor 15
thymosin beta 4, X-linked
KIAA0226-like
3.0
3.0
3.0
RASA3 RAS p21 protein activator 3 3.0
M
HIGD2A HIG1 hypoxia inducible domain family, member 2A 3.0
CACNA2D1 calcium channel, voltage-dependent, alpha 2/delta subunit 1 3.0
ALPK2 alpha kinase 2 2.9
D

OSBPL1A oxysterol binding protein-like 1A 2.9

SALL1 spalt-like transcription factor 1 2.9
PKD2 polycystic kidney disease 2 (autosomal dominant) 2.9
TE

TRDJ3 T cell receptor delta joining 3 2.9

CXCR4 chemokine (C-X-C motif) receptor 4 2.9
COL4A5 collagen, type IV, alpha 5 2.9
C1QB complement component 1, q subcomponent, B chain 2.9
EP

KALRN kalirin, RhoGEF kinase 2.9

RGCC regulator of cell cycle 2.9
MITF microphthalmia-associated transcription factor 2.9
C

PRSS23 protease, serine, 23 2.9

ADGRE2 adhesion G protein-coupled receptor E2 2.9
AC

XAF1 XIAP associated factor 1 2.9

RCBTB1 regulator of chromosome condensation (RCC1) and BTB (POZ) domain containing protein 2.8 1
PCBD1 pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor
2.8 1 alph
SMOX spermine oxidase 2.8
LOC374443 C-type lectin domain family 2, member D pseudogene 2.8
CD99 CD99 molecule 2.8
PLCE1 phospholipase C, epsilon 1 2.8
SAMD3 sterile alpha motif domain containing 3 2.8
GNAO1 guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O 2.8
CACNB2 calcium channel, voltage-dependent, beta 2 subunit 2.8
RAB32 RAB32, member RAS oncogene family 2.8
LTBP2 latent transforming growth factor beta binding protein 2 2.8
PLD1 phospholipase D1, phosphatidylcholine-specific 2.8
HLA-DPB1 major histocompatibility complex, class II, DP beta 1 2.8
C4orf48 chromosome 4 open reading frame 48 2.8
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
ZNF804A zinc finger protein 804A 2.8
RGS18 regulator of G-protein signaling 18 2.8
SLCO3A1 solute carrier organic anion transporter family, member 3A1 2.8
SLC37A3 solute carrier family 37, member 3 2.7
BHMT2 betaine--homocysteine S-methyltransferase 2 2.7
SGTB small glutamine-rich tetratricopeptide repeat (TPR)-containing, beta 2.7
GRIK2 glutamate receptor, ionotropic, kainate 2 2.7
PLXNC1 plexin C1 2.7
FAXDC2 fatty acid hydroxylase domain containing 2 2.7

PT
ITGAM integrin, alpha M (complement component 3 receptor 3 subunit) 2.7
CLIP3 CAP-GLY domain containing linker protein 3 2.7
SSC5D scavenger receptor cysteine rich family, 5 domains 2.7
CCL3L3 chemokine (C-C motif) ligand 3-like 3 2.7

RI
LCP1 lymphocyte cytosolic protein 1 (L-plastin) 2.7
MOXD1 monooxygenase, DBH-like 1 2.7
AOC3 amine oxidase, copper containing 3 2.7

SC
SIGLEC7 sialic acid binding Ig-like lectin 7 2.7
SLC35D1 solute carrier family 35 (UDP-GlcA/UDP-GalNAc transporter), member D1 2.7
ADCY1 adenylate cyclase 1 (brain) 2.7
HEPH hephaestin 2.7

U
CXCL5 chemokine (C-X-C motif) ligand 5 2.7
WT1-AS WT1 antisense RNA 2.7
TPM2
GNPDA2
NPR2
tropomyosin 2 (beta)AN
glucosamine-6-phosphate deaminase 2
natriuretic peptide receptor 2
2.7
2.7
2.7
GGT5 gamma-glutamyltransferase 5 2.7
M
PTGDS prostaglandin D2 synthase 21kDa (brain) 2.7
CCDC170 coiled-coil domain containing 170 2.7
PLAT plasminogen activator, tissue 2.7
D

CECR1 cat eye syndrome chromosome region, candidate 1 2.7

PPM1H protein phosphatase, Mg2+/Mn2+ dependent, 1H 2.7
DNER delta/notch like EGF repeat containing 2.7
TE

MLKL mixed lineage kinase domain-like 2.6

C1QA complement component 1, q subcomponent, A chain 2.6
KERA keratocan 2.6
GALNT13 polypeptide N-acetylgalactosaminyltransferase 13 2.6
EP

LINC01197 long intergenic non-protein coding RNA 1197 2.6

MBNL1 muscleblind like splicing regulator 1 2.6
PRRX1 paired related homeobox 1 2.6
C

HERC6 HECT and RLD domain containing E3 ubiquitin protein ligase family member 6 2.6
PRTFDC1 phosphoribosyl transferase domain containing 1 2.6
AC

SH3BGRL3 SH3 domain binding glutamate-rich protein like 3 2.6

FAM213A family with sequence similarity 213, member A 2.6
TTC8 tetratricopeptide repeat domain 8 2.6
EFEMP2 EGF containing fibulin-like extracellular matrix protein 2 2.6
PRKD1 protein kinase D1 2.6
CST7 cystatin F (leukocystatin) 2.6
NR1D1 nuclear receptor subfamily 1, group D, member 1 2.6
C1orf186 chromosome 1 open reading frame 186 2.6
RNF150 ring finger protein 150 2.6
GSTM3 glutathione S-transferase mu 3 (brain) 2.5
TMX3 thioredoxin-related transmembrane protein 3 2.5
AAED1 AhpC/TSA antioxidant enzyme domain containing 1 2.5
ABLIM3 actin binding LIM protein family, member 3 2.5
C2 complement component 2 2.5
TCEAL7 transcription elongation factor A (SII)-like 7 2.5
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
THBS2 thrombospondin 2 2.5
RAMP3 receptor (G protein-coupled) activity modifying protein 3 2.5
BDH2 3-hydroxybutyrate dehydrogenase, type 2 2.5
CAPNS1 calpain, small subunit 1 2.5
LOC100507195 uncharacterized LOC100507195 2.5
F8 coagulation factor VIII, procoagulant component 2.5
CRTAP cartilage associated protein 2.5
CFL2 cofilin 2 (muscle) 2.5
CELF2-AS1 CELF2 antisense RNA 1 2.5

PT
SMAP2 small ArfGAP2 2.5
KLHL13 kelch-like family member 13 2.5
GDAP1 ganglioside induced differentiation associated protein 1 2.5
THY1 Thy-1 cell surface antigen 2.5

RI
RDH10 retinol dehydrogenase 10 (all-trans) 2.5
LRP12 LDL receptor related protein 12 2.5
DYX1C1 dyslexia susceptibility 1 candidate 1 2.5

SC
PODXL podocalyxin-like 2.5
ST6GAL1 ST6 beta-galactosamide alpha-2,6-sialyltranferase 1 2.5
MPZL2 myelin protein zero-like 2 2.5
C17orf97 chromosome 17 open reading frame 97 2.5

U
DCBLD1 discoidin, CUB and LCCL domain containing 1 2.5
ARL3 ADP-ribosylation factor like GTPase 3 2.4
CERK
SELP
ADAM23
ceramide kinase AN
selectin P (granule membrane protein 140kDa, antigen CD62)
ADAM metallopeptidase domain 23
2.4
2.4
2.4
NUDT11 nudix hydrolase 11 2.4
M
CYP1B1 cytochrome P450, family 1, subfamily B, polypeptide 1 2.4
CDKN2C cyclin-dependent kinase inhibitor 2C (p18, inhibits CDK4) 2.4
IL15RA interleukin 15 receptor, alpha 2.4
D

TMOD2 tropomodulin 2 (neuronal) 2.4

KATNAL1 katanin p60 subunit A-like 1 2.4
TMEM98 transmembrane protein 98 2.4
TE

FBP1 fructose-1,6-bisphosphatase 1 2.4

KHDRBS3 KH domain containing, RNA binding, signal transduction associated 3 2.4
HOXA11-AS HOXA11 antisense RNA 2.4
CXCL2 chemokine (C-X-C motif) ligand 2 2.4
EP

PTMS parathymosin 2.4

CXCL12 chemokine (C-X-C motif) ligand 12 2.4
PBX3 pre-B-cell leukemia homeobox 3 2.4
C

TMEM252 transmembrane protein 252 2.4

CRYAB crystallin alpha B 2.4
AC

SIGLEC1 sialic acid binding Ig-like lectin 1, sialoadhesin 2.4

ALDOC aldolase C, fructose-bisphosphate 2.4
SGPL1 sphingosine-1-phosphate lyase 1 2.3
ARL4D ADP-ribosylation factor like GTPase 4D 2.3
CABYR calcium binding tyrosine-(Y)-phosphorylation regulated 2.3
CYBA cytochrome b-245, alpha polypeptide 2.3
CMPK2 cytidine monophosphate (UMP-CMP) kinase 2, mitochondrial 2.3
SMIM10 small integral membrane protein 10 2.3
PCNXL2 pecanex-like 2 (Drosophila) 2.3
IKZF1 IKAROS family zinc finger 1 2.3
TST thiosulfate sulfurtransferase (rhodanese) 2.3
GTF3C6 general transcription factor IIIC subunit 6 2.3
IFI27L2 interferon, alpha-inducible protein 27-like 2 2.3
SLA Src-like-adaptor 2.3
CXCL16 chemokine (C-X-C motif) ligand 16 2.3
 sPE ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
EDNRB endothelin receptor type B 2.3
ACE angiotensin I converting enzyme 2.3
RGS4 regulator of G-protein signaling 4 2.3
WASF3 WAS protein family, member 3 2.3
C3orf36 chromosome 3 open reading frame 36 2.3
FAM155A family with sequence similarity 155, member A 2.3
NAP1L3 nucleosome assembly protein 1-like 3 2.3
TNS1 tensin 1 2.3
DCBLD2 discoidin, CUB and LCCL domain containing 2 2.3

PT
DMKN dermokine 2.3
NOV nephroblastoma overexpressed 2.3
KLF7 Kruppel-like factor 7 (ubiquitous) 2.2
MBNL1-AS1 MBNL1 antisense RNA 1 2.2

RI
TNS2 tensin 2 2.2
CHST2 carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2 2.2
CCDC53 coiled-coil domain containing 53 2.2

SC
LCN2 lipocalin 2 2.2
LINC00987 long intergenic non-protein coding RNA 987 2.2
AKAP13 A kinase (PRKA) anchor protein 13 2.2
DST dystonin 2.2

U
FXYD1 FXYD domain containing ion transport regulator 1 2.2
MMP8 matrix metallopeptidase 8 2.2
OAF
LOC103171574
ACYP2
out at first homolog AN
uncharacterized LOC103171574
acylphosphatase 2, muscle type
2.2
2.2
2.2
GREM1 gremlin 1, DAN family BMP antagonist 2.2
M
ALDH1L2 aldehyde dehydrogenase 1 family, member L2 2.2
NPR1 natriuretic peptide receptor 1 2.2
RPGRIP1L RPGRIP1-like 2.2
D

IFITM1 interferon induced transmembrane protein 1 2.1

CLUH clustered mitochondria (cluA/CLU1) homolog 2.1
DDX12P DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 12, pseudogene 2.1
TE

RAI2 retinoic acid induced 2 2.1

TMEM200A transmembrane protein 200A 2.1
ATP13A3 ATPase type 13A3 2.1
MICA MHC class I polypeptide-related sequence A 2.1
EP

ZEB1-AS1 ZEB1 antisense RNA 1 2.1

DNPH1 2-deoxynucleoside 5-phosphate N-hydrolase 1 2.1
IKZF3 IKAROS family zinc finger 3 2.1
C

BST1 bone marrow stromal cell antigen 1 2.1

ARSG arylsulfatase G 2.1
AC

ITK IL2-inducible T-cell kinase 2.1

EIF2B3 eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa 2.1
LRRN4CL LRRN4 C-terminal like 2.1
NAP1L5 nucleosome assembly protein 1-like 5 2.1
FAM155A-IT1 FAM155A intronic transcript 1 2.1
CREB3L1 cAMP responsive element binding protein 3-like 1 2.0
ADGRG3 adhesion G protein-coupled receptor G3 2.0
SLC5A3 solute carrier family 5 (sodium/myo-inositol cotransporter), member 3 2.0
KIR2DL2 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 2 2.0
A nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
EGFL6 EGF-like-domain, multiple 6 27.5
SCN7A sodium channel, voltage gated, type VII alpha subunit 25.1
BMP5 bone morphogenetic protein 5 22.7
OLAH oleoyl-ACP hydrolase 17.7
PSG9 pregnancy specific beta-1-glycoprotein 9 17.3
LOC100129935 lectin, galactoside-binding, soluble, 14 pseudogene 17.1
LOC100129345 uncharacterized LOC100129345 16.8
MEOX2 mesenchyme homeobox 2 16.7
ABCB1 ATP binding cassette subfamily B member 1 15.1

PT
LOC101927482 uncharacterized LOC101927482 15.1
LGR5 leucine-rich repeat containing G protein-coupled receptor 5 14.8
HGF hepatocyte growth factor (hepapoietin A; scatter factor) 14.6
P2RY1 purinergic receptor P2Y, G-protein coupled, 1 14.3

RI
SNORD114-5 small nucleolar RNA, C/D box 114-5 13.9
FAM184A family with sequence similarity 184, member A 13.8
TRPV6 transient receptor potential cation channel, subfamily V, member 6 13.4

SC
MIR1323 microRNA 1323 13.2
LGALS16 lectin, galactoside-binding, soluble, 16 13.1
AREG amphiregulin 12.8
LRP2 LDL receptor related protein 2 12.3

U
FABP4 fatty acid binding protein 4, adipocyte 12.2
PLAC4 placenta specific 4 11.9
LINC00474
GSTA3
SLC26A7
AN
long intergenic non-protein coding RNA 474
glutathione S-transferase alpha 3
solute carrier family 26 (anion exchanger), member 7
11.3
11.2
11.2
APLNR apelin receptor 11.0
M
MUC15 mucin 15, cell surface associated 10.9
RPL31P11 ribosomal protein L31 pseudogene 11 10.8
HSD17B2 hydroxysteroid (17-beta) dehydrogenase 2 10.4
D

PABPC4L poly(A) binding protein, cytoplasmic 4-like 10.3

C21orf91-OT1 C21orf91 overlapping transcript 1 10.3
PAGE4 P antigen family, member 4 (prostate associated) 10.3
TE

LOC55338 uncharacterized LOC55338 10.2

SNORD114-13 small nucleolar RNA, C/D box 114-13 10.0
HIGD1B HIG1 hypoxia inducible domain family, member 1B 9.9
IL33 interleukin 33 9.7
EP

PEG10 paternally expressed 10 9.6

ADAMTS6 ADAM metallopeptidase with thrombospondin type 1 motif 6 9.6
SPTLC3 serine palmitoyltransferase, long chain base subunit 3 9.4
C

PCDH11Y protocadherin 11 Y-linked 9.4

PSG11 pregnancy specific beta-1-glycoprotein 11 9.3
AC

LOC284561 uncharacterized LOC284561 9.2

KDR kinase insert domain receptor 9.2
LOC728755 uncharacterized LOC728755 9.2
CD36 CD36 molecule (thrombospondin receptor) 9.1
PSG8 pregnancy specific beta-1-glycoprotein 8 9.1
LOC100128988 uncharacterized LOC100128988 9.1
SLC19A3 solute carrier family 19 (thiamine transporter), member 3 9.0
CRH corticotropin releasing hormone 8.8
HSD3B1 hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 8.7
GNG11 guanine nucleotide binding protein (G protein), gamma 11 8.6
KISS1 KiSS-1 metastasis-suppressor 8.6
MIR181B1 microRNA 181b-1 8.6
ERVV-1 endogenous retrovirus group V, member 1 8.5
AGTR1 angiotensin II receptor, type 1 8.4
ZNF554 zinc finger protein 554 8.4
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
BLID BH3-like motif containing, cell death inducer 8.3
SEMA6A sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin)
8.2 6A
SNORD114-12 small nucleolar RNA, C/D box 114-12 8.0
PREX2 phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2 7.8
ERVW-1 endogenous retrovirus group W, member 1 7.7
PSG3 pregnancy specific beta-1-glycoprotein 3 7.7
LINC01483 long intergenic non-protein coding RNA 1483 7.6
TFPI2 tissue factor pathway inhibitor 2 7.5
CDO1 cysteine dioxygenase type 1 7.5

PT
MIR498 microRNA 498 7.4
SNORD114-2 small nucleolar RNA, C/D box 114-2 7.4
TBX5 T-box 5 7.4
SNORD114-7 small nucleolar RNA, C/D box 114-7 7.4

RI
SNORD114-28 small nucleolar RNA, C/D box 114-28 7.3
TLR3 toll-like receptor 3 7.3
FAM162B family with sequence similarity 162, member B 7.2

SC
ADGRL2 adhesion G protein-coupled receptor L2 7.1
EXPH5 exophilin 5 7.1
ZNF117 zinc finger protein 117 7.0
GLDN gliomedin 7.0

U
SNORD114-1 small nucleolar RNA, C/D box 114-1 7.0
LGALS14 lectin, galactoside-binding, soluble, 14 7.0
ARHGAP42
DSC3
TMEM133
desmocollin 3
AN
Rho GTPase activating protein 42

transmembrane protein 133

6.9
6.9
6.9
SNORD114-14 small nucleolar RNA, C/D box 114-14 6.8
M
GABRE gamma-aminobutyric acid (GABA) A receptor, epsilon 6.8
LAMA2 laminin, alpha 2 6.8
SNORD114-11 small nucleolar RNA, C/D box 114-11 6.8
D

DACH1 dachshund family transcription factor 1 6.7

SNORD116-21 small nucleolar RNA, C/D box 116-21 6.6
SNORD113-2 small nucleolar RNA, C/D box 113-2 6.6
TE

PSG6 pregnancy specific beta-1-glycoprotein 6 6.6

MIR30A microRNA 30a 6.6
TCL6 T-cell leukemia/lymphoma 6 (non-protein coding) 6.4
EPHA3 EPH receptor A3 6.3
EP

STS steroid sulfatase (microsomal), isozyme S 6.2

CLRN1 clarin 1 6.2
SNORD114-20 small nucleolar RNA, C/D box 114-20 6.2
C

MIR1305 microRNA 1305 6.2

PSG5 pregnancy specific beta-1-glycoprotein 5 6.2
AC

SNORD113-4 small nucleolar RNA, C/D box 113-4 6.2

IL22RA2 interleukin 22 receptor, alpha 2 6.1
LOC644919 uncharacterized LOC644919 6.1
CD34 CD34 molecule 6.1
ZNF91 zinc finger protein 91 6.1
TTPA tocopherol (alpha) transfer protein 6.1
RAPGEF5 Rap guanine nucleotide exchange factor 5 6.1
ENDOU endonuclease, polyU-specific 6.0
SNORD114-25 small nucleolar RNA, C/D box 114-25 6.0
MIR548V microRNA 548v 6.0
SNORD113-9 small nucleolar RNA, C/D box 113-9 5.9
PCDH11X protocadherin 11 X-linked 5.9
NTS neurotensin 5.9
MED12L mediator complex subunit 12 like 5.9
SNORD114-16 small nucleolar RNA, C/D box 114-16 5.9
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
MIR30C2 microRNA 30c-2 5.9
SH3TC2 SH3 domain and tetratricopeptide repeats 2 5.8
SNORD113-5 small nucleolar RNA, C/D box 113-5 5.7
SNORD113-1 small nucleolar RNA, C/D box 113-1 5.7
HBG1 hemoglobin, gamma A 5.7
RANBP3L RAN binding protein 3-like 5.7
CAPN6 calpain 6 5.6
SNORD114-6 small nucleolar RNA, C/D box 114-6 5.6
SNHG24 small nucleolar RNA host gene 24 5.6

PT
PCDH18 protocadherin 18 5.6
NDC80 NDC80 kinetochore complex component 5.6
CXorf57 chromosome X open reading frame 57 5.5
SNORD111 small nucleolar RNA, C/D box 111 5.5

RI
SNORD114-26 small nucleolar RNA, C/D box 114-26 5.4
SNORD114-23 small nucleolar RNA, C/D box 114-23 5.4
RAMP2 receptor (G protein-coupled) activity modifying protein 2 5.4

SC
LOC100288570 glycosylphosphatidylinositol anchor attachment protein 1 homolog (yeast) pseudogene
5.3
MYCT1 myc target 1 5.3
GH1 growth hormone 1 5.3
LRRC36 leucine rich repeat containing 36 5.2

U
LINC01118 long intergenic non-protein coding RNA 1118 5.2
LINC00472 long intergenic non-protein coding RNA 472 5.2
GRB14
PLA2G2A
PLCB1
AN
growth factor receptor bound protein 14
phospholipase A2, group IIA (platelets, synovial fluid)
phospholipase C, beta 1 (phosphoinositide-specific)
5.2
5.2
5.2
ENPEP glutamyl aminopeptidase (aminopeptidase A) 5.1
M
IGSF5 immunoglobulin superfamily, member 5 5.1
CASC9 cancer susceptibility candidate 9 (non-protein coding) 5.1
LOC101929660 uncharacterized LOC101929660 5.0
D

COX4I2 cytochrome c oxidase subunit IV isoform 2 (lung) 5.0

KRT23 keratin 23, type I 5.0
LNPEP leucyl/cystinyl aminopeptidase 5.0
TE

SH3BGRL2 SH3 domain binding glutamate-rich protein like 2 4.9

SNORD113-3 small nucleolar RNA, C/D box 113-3 4.9
CCDC162P coiled-coil domain containing 162, pseudogene 4.9
RYBP RING1 and YY1 binding protein 4.9
EP

CCDC68 coiled-coil domain containing 68 4.9

ADAMTS18 ADAM metallopeptidase with thrombospondin type 1 motif 18 4.9
SMAGP small cell adhesion glycoprotein 4.8
C

SNORD114-15 small nucleolar RNA, C/D box 114-15 4.8

SNORD114-8 small nucleolar RNA, C/D box 114-8 4.8
AC

CHODL-AS1 CHODL antisense RNA 1 4.8

SNORD114-24 small nucleolar RNA, C/D box 114-24 4.8
SLC19A2 solute carrier family 19 (thiamine transporter), member 2 4.7
COLEC12 collectin sub-family member 12 4.7
GUCY1B3 guanylate cyclase 1, soluble, beta 3 4.7
CATSPERB catsper channel auxiliary subunit beta 4.7
PPP1R14C protein phosphatase 1, regulatory (inhibitor) subunit 14C 4.7
GUCY1A2 guanylate cyclase 1, soluble, alpha 2 4.6
TRPC6 transient receptor potential cation channel, subfamily C, member 6 4.6
SLC16A12 solute carrier family 16, member 12 4.6
TUSC3 tumor suppressor candidate 3 4.6
TWIST1 twist family bHLH transcription factor 1 4.6
SLC16A10 solute carrier family 16 (aromatic amino acid transporter), member 10 4.5
MIR100 microRNA 100 4.5
DAB2 Dab, mitogen-responsive phosphoprotein, homolog 2 (Drosophila) 4.5
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
MIR181A1 microRNA 181a-1 4.5
IDO2 indoleamine 2,3-dioxygenase 2 4.5
MIR181A1HG MIR181A1 host gene 4.5
SLC43A2 solute carrier family 43 (amino acid system L transporter), member 2 4.5
NOSTRIN nitric oxide synthase trafficking 4.5
PTPRB protein tyrosine phosphatase, receptor type, B 4.4
CCDC102B coiled-coil domain containing 102B 4.4
EXOC6 exocyst complex component 6 4.4
KATNBL1 katanin p80 subunit B-like 1 4.4

PT
POU6F2-AS2 POU6F2 antisense RNA 2 4.4
GRIP1 glutamate receptor interacting protein 1 4.4
SNORD114-21 small nucleolar RNA, C/D box 114-21 4.4
KCTD4 potassium channel tetramerization domain containing 4 4.3

RI
DEPDC1 DEP domain containing 1 4.3
HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 4.3
SNORD114-17 small nucleolar RNA, C/D box 114-17 4.3

SC
TOP2A topoisomerase (DNA) II alpha 4.3
RAB38 RAB38, member RAS oncogene family 4.3
TACC2 transforming, acidic coiled-coil containing protein 2 4.3
RARB retinoic acid receptor, beta 4.3

U
ISM1 isthmin 1, angiogenesis inhibitor 4.2
BET1 Bet1 golgi vesicular membrane trafficking protein 4.2
GGH
PDE3B
CSF3R
AN
gamma-glutamyl hydrolase (conjugase, folylpolygammaglutamyl hydrolase)
phosphodiesterase 3B, cGMP-inhibited
colony stimulating factor 3 receptor
4.2
4.2
4.2
LRCH2 leucine-rich repeats and calponin homology (CH) domain containing 2 4.2
M
OR5AK4P olfactory receptor, family 5, subfamily AK, member 4 pseudogene 4.2
FAM26D family with sequence similarity 26, member D 4.1
CDH19 cadherin 19, type 2 4.1
D

NEBL nebulette 4.1

COLEC10 collectin sub-family member 10 (C-type lectin) 4.1
XKRX X-linked Kx blood group related, X-linked 4.1
TE

SLC13A4 solute carrier family 13 (sodium/sulfate symporter), member 4 4.1

AGPAT5 1-acylglycerol-3-phosphate O-acyltransferase 5 4.1
LINC01415 long intergenic non-protein coding RNA 1415 4.0
FAM13A family with sequence similarity 13, member A 4.0
EP

KYNU kynureninase 4.0

ARHGAP26 Rho GTPase activating protein 26 4.0
TBX3 T-box 3 4.0
C

IDO1 indoleamine 2,3-dioxygenase 1 4.0

TCF21 transcription factor 21 4.0
AC

HMMR hyaluronan-mediated motility receptor (RHAMM) 4.0

RSPO3 R-spondin 3 4.0
MTMR10 myotubularin related protein 10 4.0
NDNF neuron-derived neurotrophic factor 4.0
CRHBP corticotropin releasing hormone binding protein 4.0
CNGA1 cyclic nucleotide gated channel alpha 1 4.0
OR2F1 olfactory receptor, family 2, subfamily F, member 1 (gene/pseudogene) 4.0
CDH5 cadherin 5, type 2 (vascular endothelium) 3.9
AKR1B15 aldo-keto reductase family 1, member B15 3.9
CDS1 CDP-diacylglycerol synthase 1 3.9
MAEL maelstrom spermatogenic transposon silencer 3.9
SNORD114-22 small nucleolar RNA, C/D box 114-22 3.9
SULT1C4 sulfotransferase family 1C member 4 3.9
PART1 prostate androgen-regulated transcript 1 (non-protein coding) 3.9
ZNF354B zinc finger protein 354B 3.9
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
TMEM2 transmembrane protein 2 3.9
LINC00284 long intergenic non-protein coding RNA 284 3.9
RFTN2 raftlin family member 2 3.9
TCHH trichohyalin 3.9
FLJ34503 uncharacterized FLJ34503 3.9
SNORD114-3 small nucleolar RNA, C/D box 114-3 3.9
TYMS thymidylate synthetase 3.9
SEMA3B sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin)
3.8 3B
LOC102723439 uncharacterized LOC102723439 3.8

PT
CYP2J2 cytochrome P450, family 2, subfamily J, polypeptide 2 3.8
ATP10D ATPase, class V, type 10D 3.8
ST8SIA6-AS1 ST8SIA6 antisense RNA 1 3.8
CLIP4 CAP-GLY domain containing linker protein family, member 4 3.8

RI
RPS6KA5 ribosomal protein S6 kinase, 90kDa, polypeptide 5 3.8
LINC01119 long intergenic non-protein coding RNA 1119 3.8
FXYD3 FXYD domain containing ion transport regulator 3 3.8

SC
CCNA2 cyclin A2 3.8
PDK4 pyruvate dehydrogenase kinase, isozyme 4 3.8
LINC01336 long intergenic non-protein coding RNA 1336 3.8
LINC00622 long intergenic non-protein coding RNA 622 3.8

U
GULP1 GULP, engulfment adaptor PTB domain containing 1 3.8
C14orf37 chromosome 14 open reading frame 37 3.8
PCDH10
CARD18
C4orf32
AN
protocadherin 10
caspase recruitment domain family, member 18
chromosome 4 open reading frame 32
3.7
3.7
3.7
RALGAPA2 Ral GTPase activating protein, alpha subunit 2 (catalytic) 3.7
M
PSG4 pregnancy specific beta-1-glycoprotein 4 3.7
RPS6KA6 ribosomal protein S6 kinase, 90kDa, polypeptide 6 3.7
ERV3-1 endogenous retrovirus group 3, member 1 3.7
D

GPR171 G protein-coupled receptor 171 3.7

LINC01004 long intergenic non-protein coding RNA 1004 3.7
SNORD113-7 small nucleolar RNA, C/D box 113-7 3.6
TE

CLDN1 claudin 1 3.6

SCNN1B sodium channel, non voltage gated 1 beta subunit 3.6
CMYA5 cardiomyopathy associated 5 3.6
GS1-594A7.3 uncharacterized LOC104798195 3.6
EP

S100A9 S100 calcium binding protein A9 3.6

PBK PDZ binding kinase 3.6
ANKRD20A2 ankyrin repeat domain 20 family, member A2 3.6
C

RHOBTB3 Rho-related BTB domain containing 3 3.5

LYVE1 lymphatic vessel endothelial hyaluronan receptor 1 3.5
AC

ANKFN1 ankyrin-repeat and fibronectin type III domain containing 1 3.5

FSIP2 fibrous sheath interacting protein 2 3.5
ADAMTSL3 ADAMTS like 3 3.5
CYYR1 cysteine/tyrosine-rich 1 3.5
TFRC transferrin receptor 3.5
LINC01099 long intergenic non-protein coding RNA 1099 3.5
HSPA4L heat shock 70kDa protein 4-like 3.5
CA8 carbonic anhydrase VIII 3.5
BTG3 BTG family, member 3 3.4
LOC220729 succinate dehydrogenase complex, subunit A, flavoprotein (Fp) pseudogene 3.4
KDM7A lysine (K)-specific demethylase 7A 3.4
MIR126 microRNA 126 3.4
DLGAP5 discs, large (Drosophila) homolog-associated protein 5 3.4
OPHN1 oligophrenin 1 3.4
PRSS12 protease, serine, 12 (neurotrypsin, motopsin) 3.4
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
LOC255187 uncharacterized LOC255187 3.4
FBN2 fibrillin 2 3.4
TRIM40 tripartite motif containing 40 3.4
EGFEM1P EGF-like and EMI domain containing 1, pseudogene 3.4
RBMS3 RNA binding motif, single stranded interacting protein 3 3.4
STEAP4 STEAP family member 4 3.4
FOXO4 forkhead box O4 3.4
MIR561 microRNA 561 3.4
MIR329-1 microRNA 329-1 3.3

PT
FRAS1 Fraser extracellular matrix complex subunit 1 3.3
SAMD5 sterile alpha motif domain containing 5 3.3
GATM glycine amidinotransferase (L-arginine:glycine amidinotransferase) 3.3
OMG oligodendrocyte myelin glycoprotein 3.3

RI
SCARNA2 small Cajal body-specific RNA 2 3.3
CNN3 calponin 3, acidic 3.3
FAM188B2 family with sequence similarity 188, member B2 3.3

SC
HES1 hes family bHLH transcription factor 1 3.3
CSTA cystatin A (stefin A) 3.3
TMEM88 transmembrane protein 88 3.3
PARD6B par-6 family cell polarity regulator beta 3.2

U
LDB2 LIM domain binding 2 3.2
ZNF521 zinc finger protein 521 3.2
HELLS
ITM2A
ZFP2
AN
helicase, lymphoid-specific
integral membrane protein 2A
ZFP2 zinc finger protein
3.2
3.2
3.2
MAN1C1 mannosidase, alpha, class 1C, member 1 3.2
M
MB21D2 Mab-21 domain containing 2 3.2
FDX1 ferredoxin 1 3.2
SLC13A3 solute carrier family 13 (sodium-dependent dicarboxylate transporter), member 3 3.2
D

SCML2 sex comb on midleg-like 2 (Drosophila) 3.2

ZNF711 zinc finger protein 711 3.2
SCML1 sex comb on midleg-like 1 (Drosophila) 3.2
TE

CDKN3 cyclin-dependent kinase inhibitor 3 3.2

SDC1 syndecan 1 3.2
JAM3 junctional adhesion molecule 3 3.2
RBMS3-AS3 RBMS3 antisense RNA 3 3.2
EP

PTPRD protein tyrosine phosphatase, receptor type, D 3.1

MIR503HG MIR503 host gene 3.1
EFNB2 ephrin-B2 3.1
C

ADRB1 adrenoceptor beta 1 3.1

LONP2 lon peptidase 2, peroxisomal 3.1
AC

ADHFE1 alcohol dehydrogenase, iron containing 1 3.1

LINC00113 long intergenic non-protein coding RNA 113 3.1
LOC100288911 uncharacterized LOC100288911 3.1
STXBP6 syntaxin binding protein 6 (amisyn) 3.1
TREML2 triggering receptor expressed on myeloid cells-like 2 3.1
CKAP2L cytoskeleton associated protein 2-like 3.1
SKA3 spindle and kinetochore associated complex subunit 3 3.1
ZNF750 zinc finger protein 750 3.1
LOC101927359 uncharacterized LOC101927359 3.1
CASC5 cancer susceptibility candidate 5 3.1
PLEKHA6 pleckstrin homology domain containing, family A member 6 3.1
ETFDH electron-transferring-flavoprotein dehydrogenase 3.1
LINC01446 long intergenic non-protein coding RNA 1446 3.0
ARHGEF6 Rac/Cdc42 guanine nucleotide exchange factor 6 3.0
EGFLAM EGF-like, fibronectin type III and laminin G domains 3.0
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
ZFAT zinc finger and AT hook domain containing 3.0
HOXA13 homeobox A13 3.0
LOC101929461 uncharacterized LOC101929461 3.0
SLC18B1 solute carrier family 18, subfamily B, member 1 3.0
TMEM100 transmembrane protein 100 3.0
OCLN occludin 3.0
AHSP alpha hemoglobin stabilizing protein 3.0
ETV5 ets variant 5 3.0
CDKL5 cyclin-dependent kinase-like 5 3.0

PT
CROT carnitine O-octanoyltransferase 3.0
OR52N1 olfactory receptor, family 52, subfamily N, member 1 3.0
RBP7 retinol binding protein 7, cellular 2.9
ZNF292 zinc finger protein 292 2.9

RI
COL15A1 collagen, type XV, alpha 1 2.9
MYLIP myosin regulatory light chain interacting protein 2.9
PDE5A phosphodiesterase 5A, cGMP-specific 2.9

SC
USP46 ubiquitin specific peptidase 46 2.9
ACER3 alkaline ceramidase 3 2.9
DYSF dysferlin 2.9
CSGALNACT1 chondroitin sulfate N-acetylgalactosaminyltransferase 1 2.9

U
NCAPG non-SMC condensin I complex subunit G 2.9
MAD2L1 MAD2 mitotic arrest deficient-like 1 (yeast) 2.9
NFE2L3
PDE4D
ARL15
AN
nuclear factor, erythroid 2-like 3
phosphodiesterase 4D, cAMP-specific
ADP-ribosylation factor like GTPase 15
2.9
2.9
2.9
RBL1 retinoblastoma-like 1 2.9
M
CLIP1 CAP-GLY domain containing linker protein 1 2.9
METTL21C methyltransferase like 21C 2.9
NRP1 neuropilin 1 2.9
D

MAP7D2 MAP7 domain containing 2 2.9

CAP2 CAP, adenylate cyclase-associated protein, 2 (yeast) 2.8
GMFG glia maturation factor, gamma 2.8
TE

SLC22A11 solute carrier family 22 (organic anion/urate transporter), member 11 2.8

DTL denticleless E3 ubiquitin protein ligase homolog (Drosophila) 2.8
CECR2 cat eye syndrome chromosome region, candidate 2 2.8
MAN1A2 mannosidase, alpha, class 1A, member 2 2.8
EP

PLAGL1 pleiomorphic adenoma gene-like 1 2.8

HECW2 HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2 2.8
TP53INP1 tumor protein p53 inducible nuclear protein 1 2.8
C

CCNB1 cyclin B1 2.8

ABCA5 ATP binding cassette subfamily A member 5 2.8
AC

SLC6A4 solute carrier family 6 (neurotransmitter transporter), member 4 2.8

MEST mesoderm specific transcript 2.8
HMGCLL1 3-hydroxymethyl-3-methylglutaryl-CoA lyase-like 1 2.8
CNOT6L CCR4-NOT transcription complex subunit 6-like 2.8
FBXO5 F-box protein 5 2.8
BCL2 B-cell CLL/lymphoma 2 2.8
MIR20B microRNA 20b 2.8
KANK1 KN motif and ankyrin repeat domains 1 2.8
CRNDE colorectal neoplasia differentially expressed (non-protein coding) 2.8
ASPM abnormal spindle microtubule assembly 2.8
DUSP16 dual specificity phosphatase 16 2.8
FIGN fidgetin 2.8
NHSL1 NHS-like 1 2.7
C8orf46 chromosome 8 open reading frame 46 2.7
TMEM247 transmembrane protein 247 2.7
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
SMAD6 SMAD family member 6 2.7
ZFAT-AS1 ZFAT antisense RNA 1 2.7
GTF2IP1 general transcription factor IIi pseudogene 1 2.7
C10orf131 chromosome 10 open reading frame 131 2.7
CKMT1B creatine kinase, mitochondrial 1B 2.7
CENPU centromere protein U 2.7
MIR520E microRNA 520e 2.7
FCGR2B Fc fragment of IgG, low affinity IIb, receptor (CD32) 2.7
CDK1 cyclin-dependent kinase 1 2.7

PT
TTBK2 tau tubulin kinase 2 2.7
SPIRE2 spire-type actin nucleation factor 2 2.7
FAM135A family with sequence similarity 135, member A 2.7
GABRA3 gamma-aminobutyric acid (GABA) A receptor, alpha 3 2.7

RI
HOOK1 hook microtubule-tethering protein 1 2.7
ACOXL acyl-CoA oxidase-like 2.7
OGFRL1 opioid growth factor receptor-like 1 2.7

SC
WDSUB1 WD repeat, sterile alpha motif and U-box domain containing 1 2.7
BEX2 brain expressed X-linked 2 2.7
VSTM5 V-set and transmembrane domain containing 5 2.7
CHN1 chimerin 1 2.7

U
GTF2IP4 general transcription factor IIi, pseudogene 4 2.7
CARD17 caspase recruitment domain family, member 17 2.7
PLK4
TAS2R19
FABP5
AN
polo-like kinase 4
taste receptor, type 2, member 19
fatty acid binding protein 5 (psoriasis-associated)
2.7
2.7
2.7
SGOL1 shugoshin-like 1 (S. pombe) 2.7
M
SNORA2C small nucleolar RNA, H/ACA box 2C 2.7
KRTAP26-1 keratin associated protein 26-1 2.6
NEIL3 nei-like DNA glycosylase 3 2.6
D

ZNRF2P1 zinc and ring finger 2 pseudogene 1 2.6

EPHB4 EPH receptor B4 2.6
AUNIP aurora kinase A and ninein interacting protein 2.6
TE

GJC3 gap junction protein gamma 3 2.6

SYNJ1 synaptojanin 1 2.6
LOC101929337 uncharacterized LOC101929337 2.6
NUSAP1 nucleolar and spindle associated protein 1 2.6
EP

LOC101928794 uncharacterized LOC101928794 2.6

GALNT11 polypeptide N-acetylgalactosaminyltransferase 11 2.6
TRAPPC3L trafficking protein particle complex 3-like 2.6
C

MYLK myosin light chain kinase 2.6

CENPK centromere protein K 2.6
AC

HS6ST2 heparan sulfate 6-O-sulfotransferase 2 2.6

SNORD114-9 small nucleolar RNA, C/D box 114-9 2.6
ZNF366 zinc finger protein 366 2.6
KIF18A kinesin family member 18A 2.6
KBTBD8 kelch repeat and BTB (POZ) domain containing 8 2.6
FAM124B family with sequence similarity 124 member B 2.6
EXO1 exonuclease 1 2.6
KIAA0319 KIAA0319 2.6
PHACTR2 phosphatase and actin regulator 2 2.6
KCTD3 potassium channel tetramerization domain containing 3 2.6
CDK6 cyclin-dependent kinase 6 2.6
KIF14 kinesin family member 14 2.6
GRAMD3 GRAM domain containing 3 2.6
LOC101927305 uncharacterized LOC101927305 2.5
PRC1 protein regulator of cytokinesis 1 2.5
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
PSMD6-AS2 PSMD6 antisense RNA 2 2.5
CRISPLD1 cysteine-rich secretory protein LCCL domain containing 1 2.5
MAP3K13 mitogen-activated protein kinase kinase kinase 13 2.5
COL28A1 collagen, type XXVIII, alpha 1 2.5
SLC16A12-AS1 SLC16A12 antisense RNA 1 2.5
SERINC5 serine incorporator 5 2.5
PLEKHG1 pleckstrin homology domain containing, family G (with RhoGef domain) member 12.5
MIR520A microRNA 520a 2.5
BRWD1 bromodomain and WD repeat domain containing 1 2.5

PT
ANXA6 annexin A6 2.5
CADM1 cell adhesion molecule 1 2.5
CASP4 caspase 4 2.5
PLEKHH1 pleckstrin homology domain containing, family H (with MyTH4 domain) member 1 2.5

RI
TFCP2L1 transcription factor CP2-like 1 2.5
ARHGAP32 Rho GTPase activating protein 32 2.5
MEF2C myocyte enhancer factor 2C 2.5

SC
TPRXL tetra-peptide repeat homeobox-like 2.5
FAM156B family with sequence similarity 156, member B 2.5
SPX spexin hormone 2.5
RICTOR RPTOR independent companion of MTOR, complex 2 2.5

U
MYO9A myosin IXA 2.5
HSPB8 heat shock 22kDa protein 8 2.5
ACADL
MCM6
TBC1D32
AN
acyl-CoA dehydrogenase, long chain
minichromosome maintenance complex component 6
TBC1 domain family, member 32
2.5
2.5
2.5
SCARNA1 small Cajal body-specific RNA 1 2.5
M
GRAMD1C GRAM domain containing 1C 2.5
CCNB2 cyclin B2 2.4
TPPP3 tubulin polymerization-promoting protein family member 3 2.4
D

MMD monocyte to macrophage differentiation-associated 2.4

LRP6 LDL receptor related protein 6 2.4
BMP2 bone morphogenetic protein 2 2.4
TE

MPP1 membrane protein, palmitoylated 1 2.4

SLC7A11-AS1 SLC7A11 antisense RNA 1 2.4
AP1S3 adaptor-related protein complex 1 sigma 3 subunit 2.4
RIMKLB ribosomal modification protein rimK-like family member B 2.4
EP

STK3 serine/threonine kinase 3 2.4

BBOX1 butyrobetaine (gamma), 2-oxoglutarate dioxygenase (gamma-butyrobetaine hydroxylase)
2.4 1
MKL2 MKL/myocardin-like 2 2.4
C

WFDC1 WAP four-disulfide core domain 1 2.4

KIF27 kinesin family member 27 2.4
AC

CCNE2 cyclin E2 2.4

PDZD2 PDZ domain containing 2 2.4
LOC645513 uncharacterized LOC645513 2.4
ATXN7 ataxin 7 2.4
DGKG diacylglycerol kinase gamma 2.4
SOS2 SOS Ras/Rho guanine nucleotide exchange factor 2 2.4
MIR503 microRNA 503 2.4
ATAD1 ATPase family, AAA domain containing 1 2.4
SOX5 SRY box 5 2.4
KPNA5 karyopherin alpha 5 (importin alpha 6) 2.4
LGALS8 lectin, galactoside-binding, soluble, 8 2.3
SVIP small VCP/p97-interacting protein 2.3
CNTN5 contactin 5 2.3
LOC101928324 uncharacterized LOC101928324 2.3
LINC01605 long intergenic non-protein coding RNA 1605 2.3
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
NOS3 nitric oxide synthase 3 (endothelial cell) 2.3
SNORA2A small nucleolar RNA, H/ACA box 2A 2.3
PAG1 phosphoprotein membrane anchor with glycosphingolipid microdomains 1 2.3
RGPD6 RANBP2-like and GRIP domain containing 6 2.3
SEMA3E sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin)
2.3 3E
LINC01376 long intergenic non-protein coding RNA 1376 2.3
SMC4 structural maintenance of chromosomes 4 2.3
RPIA ribose 5-phosphate isomerase A 2.3
CCDC109B coiled-coil domain containing 109B 2.3

PT
RGPD8 RANBP2-like and GRIP domain containing 8 2.3
CD99P1 CD99 molecule pseudogene 1 2.3
LOC400682 zinc finger protein 100-like 2.3
MTM1 myotubularin 1 2.3

RI
TAB3 TGF-beta activated kinase 1/MAP3K7 binding protein 3 2.3
HTR1F 5-hydroxytryptamine (serotonin) receptor 1F, G protein-coupled 2.3
IKZF2 IKAROS family zinc finger 2 2.3

SC
NEK7 NIMA-related kinase 7 2.3
TCTEX1D1 Tctex1 domain containing 1 2.3
SLC20A1 solute carrier family 20 (phosphate transporter), member 1 2.3
ACSS1 acyl-CoA synthetase short-chain family member 1 2.3

U
EXOC2 exocyst complex component 2 2.3
SNORD4B small nucleolar RNA, C/D box 4B 2.3
CLDN16
ARID2
SECISBP2L
claudin 16 AN
AT rich interactive domain 2 (ARID, RFX-like)
SECIS binding protein 2-like
2.3
2.3
2.3
NREP neuronal regeneration related protein 2.3
M
PCP4 Purkinje cell protein 4 2.3
LOC730101 uncharacterized LOC730101 2.2
RTTN rotatin 2.2
D

TMTC2 transmembrane and tetratricopeptide repeat containing 2 2.2

CFL1P1 cofilin 1 (non-muscle) pseudogene 1 2.2
DDX28 DEAD (Asp-Glu-Ala-Asp) box polypeptide 28 2.2
TE

ARHGAP29 Rho GTPase activating protein 29 2.2

CYSLTR2 cysteinyl leukotriene receptor 2 2.2
FUT9 fucosyltransferase 9 (alpha (1,3) fucosyltransferase) 2.2
GLDC glycine dehydrogenase (decarboxylating) 2.2
EP

TAPT1 transmembrane anterior posterior transformation 1 2.2

ZNF790-AS1 ZNF790 antisense RNA 1 2.2
DLG5 discs, large homolog 5 (Drosophila) 2.2
C

RAD51AP1 RAD51 associated protein 1 2.2

ZNF165 zinc finger protein 165 2.2
AC

SLC4A4 solute carrier family 4 (sodium bicarbonate cotransporter), member 4 2.2

ACBD6 acyl-CoA binding domain containing 6 2.2
LOC401585 uncharacterized LOC401585 2.2
ATP6V1B1 ATPase, H+ transporting, lysosomal 56/58kDa, V1 subunit B1 2.2
TTC7B tetratricopeptide repeat domain 7B 2.2
RBM22 RNA binding motif protein 22 2.2
DOCK9-AS1 DOCK9 antisense RNA 1 2.2
MIR223 microRNA 223 2.1
STK17A serine/threonine kinase 17a 2.1
PEX3 peroxisomal biogenesis factor 3 2.1
EXOC6B exocyst complex component 6B 2.1
NUP54 nucleoporin 54kDa 2.1
LOC100289230 uncharacterized LOC100289230 2.1
PSMA3-AS1 PSMA3 antisense RNA 1 2.1
B3GLCT beta 3-glucosyltransferase 2.1
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
GABRA4 gamma-aminobutyric acid (GABA) A receptor, alpha 4 2.1
MOCOS molybdenum cofactor sulfurase 2.1

PT
RI
U SC
AN
M
D
TE
C EP
AC
B ACCEPTED MANUSCRIPT
nPTB
STB iCTB eCTB Symbol Name D
GKN1 gastrokine 1 43.3
NOTUM notum pectinacetylesterase homolog (Drosophila) 21.5
LINC01602 long intergenic non-protein coding RNA 1602 17.7
C5orf46 chromosome 5 open reading frame 46 12.9
RASGRF2 Ras protein-specific guanine nucleotide-releasing factor 2 9.6
GALNT3 polypeptide N-acetylgalactosaminyltransferase 3 8.8
PLAC8 placenta specific 8 8.2
RFPL4B ret finger protein-like 4B 7.7
REPS2 RALBP1 associated Eps domain containing 2 7.6

PT
PLA2G10 phospholipase A2, group X 7.0
TRIM64B tripartite motif containing 64B 6.5
SERPINE2 serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member
6.3 2
ADAM19 ADAM metallopeptidase domain 19 6.1

RI
DEPDC7 DEP domain containing 7 6.1
CRABP2 cellular retinoic acid binding protein 2 6.0
LOC100132735 uncharacterized LOC100132735 6.0

SC
LINC00330 long intergenic non-protein coding RNA 330 5.9
TNFSF10 tumor necrosis factor (ligand) superfamily, member 10 5.9
HCG4 HLA complex group 4 (non-protein coding) 5.9
MKRN3 makorin ring finger protein 3 5.3

U
PPP4R4 protein phosphatase 4, regulatory subunit 4 5.1
AADACL3 arylacetamide deacetylase-like 3 4.9
LINC01296
SFRP1
FGFBP1
AN
long intergenic non-protein coding RNA 1296
secreted frizzled-related protein 1
fibroblast growth factor binding protein 1
4.5
4.5
4.4
DOCK5 dedicator of cytokinesis 5 4.1
M
CSF2RB colony stimulating factor 2 receptor, beta, low-affinity (granulocyte-macrophage) 4.0
PTN pleiotrophin 3.9
SEPT3_NM_019106septin 3 3.9
D

SLC6A2 solute carrier family 6 (neurotransmitter transporter), member 2 3.9

ENKUR enkurin, TRPC channel interacting protein 3.8
MGAT4A mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N-acetylglucosaminyltransferase, isozyme 3.7 A
TE

HCAR2 hydroxycarboxylic acid receptor 2 3.7

MGAT5 mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase 3.6
CLDN19 claudin 19 3.5
GATA3 GATA binding protein 3 3.4
EP

GJA5 gap junction protein alpha 5 3.4

KRT19 keratin 19, type I 3.3
ZNF300P1 zinc finger protein 300 pseudogene 1 (functional) 3.2
C

SLC25A15 solute carrier family 25 (mitochondrial carrier; ornithine transporter) member 15 3.2
KIAA1211L KIAA1211-like 3.1
AC

RAB9BP1 RAB9B, member RAS oncogene family pseudogene 1 3.0

SLC35A3 solute carrier family 35 (UDP-N-acetylglucosamine (UDP-GlcNAc) transporter), member 3.0 A3
KHDC1L KH homology domain containing 1-like 2.9
PRSS8 protease, serine, 8 2.8
TACR3 tachykinin receptor 3 2.8
TMEM31 transmembrane protein 31 2.8
PKP2 plakophilin 2 2.8
BAIAP2L1 BAI1-associated protein 2-like 1 2.8
PTPRQ protein tyrosine phosphatase, receptor type, Q 2.8
EFNA1 ephrin-A1 2.7
STC1 stanniocalcin 1 2.7
TNNI2 troponin I type 2 (skeletal, fast) 2.7
SERTAD4 SERTA domain containing 4 2.7
HN1L hematological and neurological expressed 1-like 2.6
ANKRD6 ankyrin repeat domain 6 2.6
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
CA2 carbonic anhydrase II 2.6
CDH1 cadherin 1, type 1 2.6
F2RL1 coagulation factor II (thrombin) receptor-like 1 2.6
CLDN4 claudin 4 2.6
PDK3 pyruvate dehydrogenase kinase, isozyme 3 2.6
VLDLR very low density lipoprotein receptor 2.4
KIF21A kinesin family member 21A 2.4
CORO6 coronin 6 2.4
FLT1 fms-related tyrosine kinase 1 2.3

PT
PYCR1 pyrroline-5-carboxylate reductase 1 2.3
ZNF486 zinc finger protein 486 2.2

RI
U SC
AN
M
D
TE
C EP
AC
C nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
PAEP progestagen-associated endometrial protein 111.1
CHRDL1 chordin-like 1 78.1
PRL prolactin 71.8
IGFBP1 insulin like growth factor binding protein 1 64.2
EPYC epiphycan 60.9
FGG fibrinogen gamma chain 43.0
OMD osteomodulin 39.5
RORB RAR-related orphan receptor B 32.1
RXFP1 relaxin/insulin-like family peptide receptor 1 31.7

PT
MEDAG mesenteric estrogen-dependent adipogenesis 25.4
OGN osteoglycin 20.0
RBP4 retinol binding protein 4, plasma 19.1
C3 complement component 3 17.5

RI
AADAC arylacetamide deacetylase 16.3
FGB fibrinogen beta chain 16.2
DKK1 dickkopf WNT signaling pathway inhibitor 1 15.4

SC
LOC100507639
uncharacterized LOC100507639 14.8
ABI3BP ABI family, member 3 (NESH) binding protein 14.7
MAOB monoamine oxidase B 14.2
ALDH1A1 aldehyde dehydrogenase 1 family, member A1 13.9

U
TRPC4 transient receptor potential cation channel, subfamily C, member 4 13.8
LINC01320 long intergenic non-protein coding RNA 1320 13.4
HSPB6
CFH complement factor H
AN
heat shock protein, alpha-crystallin-related, B6

CYP7B1 cytochrome P450, family 7, subfamily B, polypeptide 1

13.1
12.9
12.8
CNR1 cannabinoid receptor 1 (brain) 12.6
M
FGA fibrinogen alpha chain 12.5
GZMA granzyme A 11.6
NDP Norrie disease (pseudoglioma) 11.6
D

DEFB1 defensin, beta 1 10.9

CP ceruloplasmin (ferroxidase) 10.7
CPXM1 carboxypeptidase X (M14 family), member 1 10.5
TE

AVPR1A arginine vasopressin receptor 1A 10.3

PRUNE2 prune homolog 2 (Drosophila) 10.3
HSD11B1 hydroxysteroid (11-beta) dehydrogenase 1 10.1
KLRC1 killer cell lectin-like receptor subfamily C, member 1 9.7
EP

CTSK cathepsin K 9.7

WT1 Wilms tumor 1 9.3
PGR progesterone receptor 9.0
C

SEMA3A sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A 9.0
SULF2 sulfatase 2 9.0
AC

IGFBP4 insulin like growth factor binding protein 4 8.4

TRDJ2 T cell receptor delta joining 2 8.4
AOX1 aldehyde oxidase 1 8.3
CD248 CD248 molecule, endosialin 8.2
SCGB2A1 secretoglobin, family 2A, member 1 8.1
TRDC T cell receptor delta constant 7.9
SERPINA3 serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 3 7.7
CXCL8 chemokine (C-X-C motif) ligand 8 7.5
SCARA5 scavenger receptor class A, member 5 7.1
GSTA1 glutathione S-transferase alpha 1 6.9
HAND2-AS1HAND2 antisense RNA 1 (head to head) 6.9
TMEM47 transmembrane protein 47 6.8
TMEM45A transmembrane protein 45A 6.6
GPRC5B G protein-coupled receptor, class C, group 5, member B 6.5
MYL9 myosin light chain 9 6.5
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
PRDM1 PR domain containing 1, with ZNF domain 6.4
PARM1 prostate androgen-regulated mucin-like protein 1 6.4
WNT5A wingless-type MMTV integration site family, member 5A 6.4
F2R coagulation factor II (thrombin) receptor 6.3
ITGB8 integrin beta 8 6.2
IL1A interleukin 1 alpha 6.2
ADAMTS5 ADAM metallopeptidase with thrombospondin type 1 motif 5 6.1
PLPP1 phospholipid phosphatase 1 6.0
MYO16-AS1MYO16 antisense RNA 1 6.0

PT
ASPN asporin 6.0
TNC tenascin C 5.8
TUBA3E tubulin, alpha 3e 5.8
NPR3 natriuretic peptide receptor 3 5.7

RI
HLA-DRA major histocompatibility complex, class II, DR alpha 5.7
PLCL1 phospholipase C-like 1 5.6
MFAP4 microfibrillar associated protein 4 5.6

SC
GREB1 growth regulation by estrogen in breast cancer 1 5.6
IL15 interleukin 15 5.6
EMP3 epithelial membrane protein 3 5.5
MAP3K5 mitogen-activated protein kinase kinase kinase 5 5.5

U
KLRC3 killer cell lectin-like receptor subfamily C, member 3 5.4
CCL2 chemokine (C-C motif) ligand 2 5.4

PILRA
NAMPT
AN
C10orf107 chromosome 10 open reading frame 107
paired immunoglobin-like type 2 receptor alpha
nicotinamide phosphoribosyltransferase
5.4
5.4
5.3
DEPTOR DEP domain containing MTOR-interacting protein 5.3
M
IGSF10 immunoglobulin superfamily, member 10 5.3
PLEKHH2 pleckstrin homology domain containing, family H (with MyTH4 domain) member 2 5.2
ROS1 ROS proto-oncogene 1 , receptor tyrosine kinase 5.2
D

ZNF727 zinc finger protein 727 5.1

PMCH pro-melanin-concentrating hormone 5.1
NAV3 neuron navigator 3 5.0
TE

PCDHB4 protocadherin beta 4 5.0

RGS2 regulator of G-protein signaling 2 5.0
FAM110C family with sequence similarity 110, member C 4.9
GAS1 growth arrest-specific 1 4.9
EP

CRISPLD2 cysteine-rich secretory protein LCCL domain containing 2 4.9

LINC00890 long intergenic non-protein coding RNA 890 4.9
SPOCK1 sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican) 1 4.8
C

MGP matrix Gla protein 4.8

PTPN13 protein tyrosine phosphatase, non-receptor type 13 (APO-1/CD95 (Fas)-associated phosphatase)
4.8
AC

CHI3L2 chitinase 3-like 2 4.8

PAMR1 peptidase domain containing associated with muscle regeneration 1 4.8
HTR2B 5-hydroxytryptamine (serotonin) receptor 2B, G protein-coupled 4.8
FAM66A family with sequence similarity 66, member A 4.6
LSAMP limbic system-associated membrane protein 4.6
IGFBP6 insulin like growth factor binding protein 6 4.6
ZFP36 ZFP36 ring finger protein 4.6
PDGFD platelet derived growth factor D 4.6
TMTC1 transmembrane and tetratricopeptide repeat containing 1 4.5
GZMK granzyme K 4.5
MXRA8 matrix-remodelling associated 8 4.4
CAB39L calcium binding protein 39-like 4.4
ATP2B4 ATPase, Ca++ transporting, plasma membrane 4 4.4
NKG7 natural killer cell granule protein 7 4.4
LONRF2 LON peptidase N-terminal domain and ring finger 2 4.4
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
CD69 CD69 molecule 4.3
RBP1 retinol binding protein 1, cellular 4.3
ENTPD3 ectonucleoside triphosphate diphosphohydrolase 3 4.3
MACC1 metastasis associated in colon cancer 1 4.3
CHSY3 chondroitin sulfate synthase 3 4.3
SEMA3C sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3C
4.3
TNFRSF11Btumor necrosis factor receptor superfamily, member 11b 4.3
SLC16A6 solute carrier family 16, member 6 4.3
ECM2 extracellular matrix protein 2, female organ and adipocyte specific 4.3

PT
SYNPO2 synaptopodin 2 4.2
IGFBP2 insulin like growth factor binding protein 2 4.2
TMEM27 transmembrane protein 27 4.2
COX7A1 cytochrome c oxidase subunit VIIa polypeptide 1 (muscle) 4.2

RI
STAP1 signal transducing adaptor family member 1 4.2
CD96 CD96 molecule 4.2
CLU clusterin 4.2

SC
KLRB1 killer cell lectin-like receptor subfamily B, member 1 4.2
RGS22 regulator of G-protein signaling 22 4.2
PRPS2 phosphoribosyl pyrophosphate synthetase 2 4.1
CCL4L2 chemokine (C-C motif) ligand 4-like 2 4.1

U
UCHL1 ubiquitin C-terminal hydrolase L1 4.1
MMP7 matrix metallopeptidase 7 4.1
APOO apolipoprotein O
C1GALT1C1L
AN
C1GALT1-specific chaperone 1 like
EMILIN2 elastin microfibril interfacer 2
4.1
4.1
4.0
FGF2 fibroblast growth factor 2 (basic) 4.0
M
CD74 CD74 molecule, major histocompatibility complex, class II invariant chain 4.0
DTNA dystrobrevin, alpha 4.0
SYT11 synaptotagmin XI 4.0
D

JAKMIP2 janus kinase and microtubule interacting protein 2 4.0

GNG4 guanine nucleotide binding protein (G protein), gamma 4 4.0
APOD apolipoprotein D 4.0
TE

ATP8A2 ATPase, aminophospholipid transporter, class I, type 8A, member 2 3.9

AXL AXL receptor tyrosine kinase 3.9
CST11 cystatin 11 3.9
HAND2 heart and neural crest derivatives expressed 2 3.8
EP

CEP126 centrosomal protein 126kDa 3.8

SIPA1L2 signal-induced proliferation-associated 1 like 2 3.8
ME1 malic enzyme 1, NADP(+)-dependent, cytosolic 3.8
C

ADRA2C adrenoceptor alpha 2C 3.8

UGT2B7 UDP glucuronosyltransferase 2 family, polypeptide B7 3.7
AC

SOD2 superoxide dismutase 2, mitochondrial 3.7

TIPARP TCDD-inducible poly(ADP-ribose) polymerase 3.7
IL1B interleukin 1 beta 3.7
FHL5 four and a half LIM domains 5 3.7
TMEM132Ctransmembrane protein 132C 3.7
KLRC4-KLRK1
KLRC4-KLRK1 readthrough 3.6
APCDD1 adenomatosis polyposis coli down-regulated 1 3.6
FBLN5 fibulin 5 3.6
CD2 CD2 molecule 3.6
IGFBP7 insulin like growth factor binding protein 7 3.6
EPCAM epithelial cell adhesion molecule 3.6
C5AR1 complement component 5a receptor 1 3.6
EPDR1 ependymin related 1 3.6
EMCN endomucin 3.6
PDGFRB platelet-derived growth factor receptor, beta polypeptide 3.5
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
C1S complement component 1, s subcomponent 3.5
CDH11 cadherin 11, type 2, OB-cadherin (osteoblast) 3.5
HOXA11 homeobox A11 3.5
CLMP CXADR-like membrane protein 3.5
C1R complement component 1, r subcomponent 3.5
XCL2 chemokine (C motif) ligand 2 3.5
PLAT plasminogen activator, tissue 3.5
GALNT15 polypeptide N-acetylgalactosaminyltransferase 15 3.5
TWISTNB TWIST neighbor 3.5

PT
MGST1 microsomal glutathione S-transferase 1 3.5
IFI44 interferon-induced protein 44 3.5
CCL13 chemokine (C-C motif) ligand 13 3.4
SQRDL sulfide quinone reductase-like (yeast) 3.4

RI
TLR4 toll-like receptor 4 3.4
MMP10 matrix metallopeptidase 10 3.4
ABCA8 ATP binding cassette subfamily A member 8 3.4

SC
KLRF1 killer cell lectin-like receptor subfamily F, member 1 3.4
P4HA3 prolyl 4-hydroxylase, alpha polypeptide III 3.4
SCPEP1 serine carboxypeptidase 1 3.4
PRR15 proline rich 15 3.4

U
EVA1C eva-1 homolog C (C. elegans) 3.3
KLF9 Kruppel-like factor 9 3.3
FMOD
NCAM1
KERA
fibromodulin AN
neural cell adhesion molecule 1
keratocan
3.3
3.3
3.3
WDR72 WD repeat domain 72 3.3
M
TRGJP1 T cell receptor gamma joining P1 3.3
WISP1 WNT1 inducible signaling pathway protein 1 3.3
KLRF2 killer cell lectin-like receptor subfamily F, member 2 3.2
D

TAGAP T-cell activation RhoGTPase activating protein 3.2

MLLT11 myeloid/lymphoid or mixed-lineage leukemia; translocated to, 11 3.2
KCNH1 potassium channel, voltage gated eag related subfamily H, member 1 3.2
TE

ZEB1 zinc finger E-box binding homeobox 1 3.2

SMCO3 single-pass membrane protein with coiled-coil domains 3 3.2
ALDH1A2 aldehyde dehydrogenase 1 family, member A2 3.2
HLA-DPA1 major histocompatibility complex, class II, DP alpha 1 3.2
EP

GNAO1 guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O 3.2
ERMP1 endoplasmic reticulum metallopeptidase 1 3.2
PFKFB3 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 3.2
C

PDZK1IP1 PDZK1 interacting protein 1 3.2

OSR2 odd-skipped related transciption factor 2 3.1
AC

TOB1 transducer of ERBB2, 1 3.1

KCND2 potassium channel, voltage gated Shal related subfamily D, member 2 3.1
EMX2 empty spiracles homeobox 2 3.1
CERS6 ceramide synthase 6 3.1
MUC16 mucin 16, cell surface associated 3.1
GRIA3 glutamate receptor, ionotropic, AMPA 3 3.1
GLB1L2 galactosidase beta 1 like 2 3.1
CLEC2B C-type lectin domain family 2, member B 3.1
GPRIN3 GPRIN family member 3 3.1
SLC1A1 solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag),3.1
membe
MFGE8 milk fat globule-EGF factor 8 protein 3.0
JUNB jun B proto-oncogene 3.0
PDLIM1 PDZ and LIM domain 1 3.0
PZP pregnancy-zone protein 3.0
FOXO1 forkhead box O1 3.0
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
ADAMTS2 ADAM metallopeptidase with thrombospondin type 1 motif 2 3.0
LGALS1 lectin, galactoside-binding, soluble, 1 3.0
LUM lumican 3.0
KLHL13 kelch-like family member 13 2.9
TSKU tsukushi, small leucine rich proteoglycan 2.9
CLIC2 chloride intracellular channel 2 2.9
TPST1 tyrosylprotein sulfotransferase 1 2.9
PLA2R1 phospholipase A2 receptor 1 2.9
SYTL4 synaptotagmin-like 4 2.9

PT
IL2RG interleukin 2 receptor, gamma 2.9
DNER delta/notch like EGF repeat containing 2.9
LOC643733caspase 4, apoptosis-related cysteine peptidase pseudogene 2.9
WNT4 wingless-type MMTV integration site family, member 4 2.9

RI
STAMBPL1STAM binding protein-like 1 2.9
ISLR immunoglobulin superfamily containing leucine-rich repeat 2.9
NNMT nicotinamide N-methyltransferase 2.8

SC
STMN2 stathmin 2 2.8
KCNA4 potassium channel, voltage gated shaker related subfamily A, member 4 2.8
VIM vimentin 2.8
KHDRBS3 KH domain containing, RNA binding, signal transduction associated 3 2.8

U
CXCL5 chemokine (C-X-C motif) ligand 5 2.8
SETDB2 SET domain, bifurcated 2 2.8
CYBRD1 cytochrome b reductase 1

BICC1
AN
FAM229B family with sequence similarity 229, member B
BicC family RNA binding protein 1
2.8
2.8
2.8
MSN moesin 2.8
M
MCC mutated in colorectal cancers 2.8
PLCE1 phospholipase C, epsilon 1 2.7
ZFP36L2 ZFP36 ring finger protein-like 2 2.7
D

CNKSR2 connector enhancer of kinase suppressor of Ras 2 2.7

RNLS renalase, FAD-dependent amine oxidase 2.7
NPR2 natriuretic peptide receptor 2 2.7
TE

DCN decorin 2.7

C4B complement component 4B (Chido blood group) 2.7
LINC00924 long intergenic non-protein coding RNA 924 2.7
CACNB2 calcium channel, voltage-dependent, beta 2 subunit 2.7
EP

NAPSA napsin A aspartic peptidase 2.7

MIR99AHG mir-99a-let-7c cluster host gene 2.7
CCL5 chemokine (C-C motif) ligand 5 2.7
C

SAMD9L sterile alpha motif domain containing 9-like 2.7

SMIM10 small integral membrane protein 10 2.7
AC

CCL4 chemokine (C-C motif) ligand 4 2.7

NR4A2 nuclear receptor subfamily 4, group A, member 2 2.7
LAMA4 laminin, alpha 4 2.7
PRSS23 protease, serine, 23 2.7
LINC00706 long intergenic non-protein coding RNA 706 2.7
PTPRC protein tyrosine phosphatase, receptor type, C 2.7
CTSW cathepsin W 2.6
ZMAT1 zinc finger, matrin-type 1 2.6
ARL3 ADP-ribosylation factor like GTPase 3 2.6
PCDHB16 protocadherin beta 16 2.6
TSPAN1 tetraspanin 1 2.6
AHNAK2 AHNAK nucleoprotein 2 2.6
CORIN corin, serine peptidase 2.6
CCL3L3 chemokine (C-C motif) ligand 3-like 3 2.6
PCDHB2 protocadherin beta 2 2.6
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
NCOA7 nuclear receptor coactivator 7 2.6
NFE2L1 nuclear factor, erythroid 2-like 1 2.6
PLXNA4 plexin A4 2.6
RASD1 RAS, dexamethasone-induced 1 2.6
KANK2 KN motif and ankyrin repeat domains 2 2.6
CERS6-AS1CERS6 antisense RNA 1 2.6
FAP fibroblast activation protein alpha 2.6
KIR2DL2 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 2 2.6
LOC101928461
uncharacterized LOC101928461 2.6

PT
GJA1 gap junction protein alpha 1 2.6
HOXA5 homeobox A5 2.5
LINC00987 long intergenic non-protein coding RNA 987 2.5
DDR2 discoidin domain receptor tyrosine kinase 2 2.5

RI
C4A complement component 4A (Rodgers blood group) 2.5
MX2 MX dynamin-like GTPase 2 2.5
NR1D1 nuclear receptor subfamily 1, group D, member 1 2.5

SC
PCOLCE procollagen C-endopeptidase enhancer 2.5
HSD17B6 hydroxysteroid (17-beta) dehydrogenase 6 2.5
TNFRSF21 tumor necrosis factor receptor superfamily, member 21 2.5
ADGRD1 adhesion G protein-coupled receptor D1 2.5

U
MDM1 Mdm1 nuclear protein 2.5
ARL4D ADP-ribosylation factor like GTPase 4D 2.5
CD3E
IRS2
MMP8
AN
CD3e molecule, epsilon (CD3-TCR complex)
insulin receptor substrate 2
matrix metallopeptidase 8
2.5
2.5
2.5
PPDPF pancreatic progenitor cell differentiation and proliferation factor 2.5
M
PRF1 perforin 1 (pore forming protein) 2.5
RGCC regulator of cell cycle 2.5
SNAP91 synaptosome associated protein 91kDa 2.5
D

SMOX spermine oxidase 2.5

LOC100507195
uncharacterized LOC100507195 2.5
RCBTB1 regulator of chromosome condensation (RCC1) and BTB (POZ) domain containing protein2.5 1
TE

EHD2 EH domain containing 2 2.5

DSTNP2 destrin (actin depolymerizing factor) pseudogene 2 2.4
SNCAIP synuclein alpha interacting protein 2.4
GALNT13 polypeptide N-acetylgalactosaminyltransferase 13 2.4
EP

CES1 carboxylesterase 1 2.4

C11orf70 chromosome 11 open reading frame 70 2.4
NFKBIZ nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta 2.4
C

NUPR1 nuclear protein 1, transcriptional regulator 2.4

C1orf186 chromosome 1 open reading frame 186 2.4
AC

ODC1 ornithine decarboxylase 1 2.4

MIR511 microRNA 511 2.4
DCBLD1 discoidin, CUB and LCCL domain containing 1 2.4
C8orf48 chromosome 8 open reading frame 48 2.4
TMEM176Atransmembrane protein 176A 2.4
ANPEP alanyl (membrane) aminopeptidase 2.4
ALDOC aldolase C, fructose-bisphosphate 2.4
MAP1LC3Cmicrotubule associated protein 1 light chain 3 gamma 2.4
RAB31 RAB31, member RAS oncogene family 2.4
INE2 inactivation escape 2 (non-protein coding) 2.4
ID4 inhibitor of DNA binding 4, dominant negative helix-loop-helix protein 2.4
SLC18A2 solute carrier family 18 (vesicular monoamine transporter), member 2 2.4
KREMEN1 kringle containing transmembrane protein 1 2.3
TSPAN5 tetraspanin 5 2.3
TWIST2 twist family bHLH transcription factor 2 2.3
 nPTB ACCEPTED MANUSCRIPT
STB iCTB eCTB Symbol Name D
NIPAL2 NIPA-like domain containing 2 2.3
ZNF239 zinc finger protein 239 2.3
FYN FYN proto-oncogene, Src family tyrosine kinase 2.3
RAI2 retinoic acid induced 2 2.3
GPR155 G protein-coupled receptor 155 2.3
BHMT2 betaine--homocysteine S-methyltransferase 2 2.3
LINC00473 long intergenic non-protein coding RNA 473 2.3
RDH10 retinol dehydrogenase 10 (all-trans) 2.3
DYX1C1 dyslexia susceptibility 1 candidate 1 2.3

PT
PPM1H protein phosphatase, Mg2+/Mn2+ dependent, 1H 2.3
FXYD1 FXYD domain containing ion transport regulator 1 2.3
SIGLEC14 sialic acid binding Ig-like lectin 14 2.3
SLC24A3 solute carrier family 24 (sodium/potassium/calcium exchanger), member 3 2.3

RI
NPR1 natriuretic peptide receptor 1 2.3
PRRX1 paired related homeobox 1 2.3
PCBD1 pterin-4 alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor
2.31 alp

SC
MRPL33 mitochondrial ribosomal protein L33 2.3
WDR86-AS1WDR86 antisense RNA 1 2.2
C4orf48 chromosome 4 open reading frame 48 2.2
SGCB sarcoglycan beta 2.2

U
KIR2DL3 killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3 2.2
TMX3 thioredoxin-related transmembrane protein 3 2.2
ACSL1
NAP1L3
AN
acyl-CoA synthetase long-chain family member 1
nucleosome assembly protein 1-like 3
ZDHHC15 zinc finger, DHHC-type containing 15
2.2
2.2
2.2
C15orf65 chromosome 15 open reading frame 65 2.2
M
NEO1 neogenin 1 2.2
VSIG1 V-set and immunoglobulin domain containing 1 2.2
HOMER2 homer scaffolding protein 2 2.2
D

BRE brain and reproductive organ-expressed (TNFRSF1A modulator) 2.2

DDX24 DEAD (Asp-Glu-Ala-Asp) box helicase 24 2.2
ATP13A3 ATPase type 13A3 2.2
TE

AR androgen receptor 2.2

KCNB1 potassium channel, voltage gated Shab related subfamily B, member 1 2.2
CELF2 CUGBP, Elav-like family member 2 2.2
WASF3 WAS protein family, member 3 2.2
EP

RBKS ribokinase 2.1

CRYAB crystallin alpha B 2.1
CD82 CD82 molecule 2.1
C

ITGAM integrin, alpha M (complement component 3 receptor 3 subunit) 2.1

ICAM1 intercellular adhesion molecule 1 2.1
AC

BRINP2 bone morphogenetic protein/retinoic acid inducible neural-specific 2 2.1

MOXD1 monooxygenase, DBH-like 1 2.1
ADAMTS8 ADAM metallopeptidase with thrombospondin type 1 motif 8 2.1
FAM159B family with sequence similarity 159, member B 2.1
MANEA mannosidase, endo-alpha 2.0
AXDND1 axonemal dynein light chain domain containing 1 2.0
TNXB tenascin XB 2.0
 STB ACCEPTED MANUSCRIPT
sPE nPTB Symbol Name D
PRG2 proteoglycan 2, bone marrow (natural killer cell activator, eosinophil granule major basic protein)
6.4
UCA1 urothelial cancer associated 1 (non-protein coding) 6.0
FOS FBJ murine osteosarcoma viral oncogene homolog 4.3
FSTL3 follistatin-like 3 (secreted glycoprotein) 3.7
MTSS1L metastasis suppressor 1-like 3.5
FOSB FBJ murine osteosarcoma viral oncogene homolog B 3.5
FABP4 fatty acid binding protein 4, adipocyte 3.5
KEL Kell blood group, metallo-endopeptidase 3.4
FN1 fibronectin 1 3.2
CP ceruloplasmin (ferroxidase) 3.1

PT
DNAPTP3 histone demethylase UTY-like 3.1
RDH13 retinol dehydrogenase 13 (all-trans/9-cis) 3.1
JUNB jun B proto-oncogene 3.1
SLCO2A1 solute carrier organic anion transporter family, member 2A1 2.9

RI
EPS8L1 EPS8-like 1 2.9
ST8SIA6 ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 6 2.8
QPCT glutaminyl-peptide cyclotransferase 2.8
MT1F metallothionein 1F 2.8

SC
PVRL4 poliovirus receptor-related 4 2.8
SASH1 SAM and SH3 domain containing 1 2.8
MT1G metallothionein 1G 2.7
SH3PXD2A SH3 and PX domains 2A 2.6

U
LINC01150 long intergenic non-protein coding RNA 1150 2.6
INHBA inhibin beta A 2.5
TBC1D3G
BCL6
LENG8
B-cell CLL/lymphoma 6
AN
TBC1 domain family, member 3G

leukocyte receptor cluster (LRC) member 8

2.5
2.5
2.5
SPDYE2 speedy/RINGO cell cycle regulator family member E2 2.5
M
ALAS2 5-aminolevulinate synthase 2 2.4
MIG7 mig-7 2.4
SPDYE8P speedy/RINGO cell cycle regulator family member E8, pseudogene 2.4
SPDYE2B speedy/RINGO cell cycle regulator family member E2B 2.4
D

FLT1 fms-related tyrosine kinase 1 2.4

ASXL3 additional sex combs like transcriptional regulator 3 2.3
BTBD16 BTB (POZ) domain containing 16
TE

2.3
C5orf46 chromosome 5 open reading frame 46 2.3
TMEM45A transmembrane protein 45A 2.3
OR6W1P olfactory receptor, family 6, subfamily W, member 1 pseudogene 2.2
TBC1D3B TBC1 domain family, member 3B 2.2
EP

ZBTB4 zinc finger and BTB domain containing 4 2.2

ENG endoglin 2.2
NNAT neuronatin 2.2
CCDC183 coiled-coil domain containing 183 2.2
C

WASH7P WAS protein family homolog 7 pseudogene 2.2

TAS2R39 taste receptor, type 2, member 39 2.2
AC

SH3BGRL3 SH3 domain binding glutamate-rich protein like 3 2.1

NDRG1 N-myc downstream regulated 1 2.1
FBXL19-AS1 FBXL19 antisense RNA 1 (head to head) 2.1
PLOD2 procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 2.1
SRRM2 serine/arginine repetitive matrix 2 2.1
LOC729737 uncharacterized LOC729737 2.1
IGFBP3 insulin like growth factor binding protein 3 2.1
AMD1 adenosylmethionine decarboxylase 1 2.1
MAN1C1 mannosidase, alpha, class 1C, member 1 2.1
SIGLEC6 sialic acid binding Ig-like lectin 6 2.1
AQP1 aquaporin 1 (Colton blood group) 2.1
PLEKHA6 pleckstrin homology domain containing, family A member 6 2.0
TCF7L2 transcription factor 7-like 2 (T-cell specific, HMG-box) 2.0
MIR339 microRNA 339 2.0
ATN1 atrophin 1 2.0
 STB ACCEPTED MANUSCRIPT
sPE nPTB Symbol Name D
PRKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta -2.0
ACPP acid phosphatase, prostate -2.0
MIR181A1 microRNA 181a-1 -2.0
DUBR DPPA2 upstream binding RNA -2.0
LRRTM2 leucine rich repeat transmembrane neuronal 2 -2.0
LOC101927482uncharacterized LOC101927482 -2.0
FAM26D family with sequence similarity 26, member D -2.1
WNK3 WNK lysine deficient protein kinase 3 -2.1
CLDN1 claudin 1 -2.1
KIAA0319 KIAA0319 -2.1

PT
CRHBP corticotropin releasing hormone binding protein -2.1
AFF2 AF4/FMR2 family, member 2 -2.1
DLGAP5 discs, large (Drosophila) homolog-associated protein 5 -2.1
MIR561 microRNA 561 -2.1

RI
KCTD4 potassium channel tetramerization domain containing 4 -2.1
RAB39A RAB39A, member RAS oncogene family -2.1
USP46 ubiquitin specific peptidase 46 -2.1
P2RY1 purinergic receptor P2Y, G-protein coupled, 1 -2.2

SC
HIST1H2BC histone cluster 1, H2bc -2.2
LGR5 leucine-rich repeat containing G protein-coupled receptor 5 -2.2
CYP1B1 cytochrome P450, family 1, subfamily B, polypeptide 1 -2.2
OR5AK4P olfactory receptor, family 5, subfamily AK, member 4 pseudogene -2.2

U
LDHB lactate dehydrogenase B -2.2
ITGB8 integrin beta 8 -2.2
LGALS16
GCNT4
ZNF502
AN
lectin, galactoside-binding, soluble, 16
glucosaminyl (N-acetyl) transferase 4, core 2
zinc finger protein 502
-2.2
-2.2
-2.2
SH3TC2 SH3 domain and tetratricopeptide repeats 2 -2.2
M
C14orf37 chromosome 14 open reading frame 37 -2.2
PKIB protein kinase (cAMP-dependent, catalytic) inhibitor beta -2.2
MIR20B microRNA 20b -2.2
CARD18 caspase recruitment domain family, member 18 -2.2
D

NIPAL1 NIPA-like domain containing 1 -2.3

PDE10A phosphodiesterase 10A -2.3
RANBP17 RAN binding protein 17
TE

-2.3
FAM188B2 family with sequence similarity 188, member B2 -2.3
ZNF711 zinc finger protein 711 -2.3
GEN1 GEN1 Holliday junction 5 flap endonuclease -2.3
NDC80 NDC80 kinetochore complex component -2.3
EP

GS1-594A7.3 uncharacterized LOC104798195 -2.3

FAM171B family with sequence similarity 171, member B -2.3
LINC01091 long intergenic non-protein coding RNA 1091 -2.3
LINC01119 long intergenic non-protein coding RNA 1119 -2.3
C

RASSF6 Ras association (RalGDS/AF-6) domain family member 6 -2.3

ZNF117 zinc finger protein 117 -2.3
AC

MICU3 mitochondrial calcium uptake family, member 3 -2.4

IL33 interleukin 33 -2.4
GSTA4 glutathione S-transferase alpha 4 -2.5
SNORD111 small nucleolar RNA, C/D box 111 -2.5
ANK3 ankyrin 3, node of Ranvier (ankyrin G) -2.5
P3H2 prolyl 3-hydroxylase 2 -2.5
LINC00845 long intergenic non-protein coding RNA 845 -2.5
SNORD126 small nucleolar RNA, C/D box 126 -2.6
CSTA cystatin A (stefin A) -2.6
LOC100128386uncharacterized LOC100128386 -2.6
OTOGL otogelin-like -2.6
GH1 growth hormone 1 -2.7
CLRN1-AS1 CLRN1 antisense RNA 1 -2.7
OR2F1 olfactory receptor, family 2, subfamily F, member 1 (gene/pseudogene) -2.7
XDH xanthine dehydrogenase -2.7
 STB ACCEPTED MANUSCRIPT
sPE nPTB Symbol Name D
CFH complement factor H -2.7
CLRN1 clarin 1 -2.8
IDO1 indoleamine 2,3-dioxygenase 1 -2.8
HIST1H4H histone cluster 1, H4h -2.8
GNGT1 guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 1 -2.8
CCDC54 coiled-coil domain containing 54 -2.9
LINC00284 long intergenic non-protein coding RNA 284 -2.9
OMG oligodendrocyte myelin glycoprotein -2.9
PCDH11Y protocadherin 11 Y-linked -2.9
LINC00882 long intergenic non-protein coding RNA 882 -3.0

PT
SLC27A2 solute carrier family 27 (fatty acid transporter), member 2 -3.0
SLC6A15 solute carrier family 6 (neutral amino acid transporter), member 15 -3.0
CATSPERB catsper channel auxiliary subunit beta -3.0
ERVFRD-1 endogenous retrovirus group FRD, member 1 -3.0

RI
NAALADL2 N-acetylated alpha-linked acidic dipeptidase-like 2 -3.1
TXLNGY taxilin gamma pseudogene, Y-linked -3.1
POU6F2-AS2 POU6F2 antisense RNA 2 -3.1
LINC01483 long intergenic non-protein coding RNA 1483 -3.1

SC
EIF1AY eukaryotic translation initiation factor 1A, Y-linked -3.1
MATN3 matrilin 3 -3.2
HSD17B1 hydroxysteroid (17-beta) dehydrogenase 1 -3.3
TMPRSS11F transmembrane protease, serine 11F -3.4

U
PLAC1 placenta specific 1 -3.4
FRZB frizzled-related protein -3.4
NTS
LOC650226
SCN7A
neurotensin AN
ankyrin repeat domain 26 pseudogene
sodium channel, voltage gated, type VII alpha subunit
-3.5
-3.5
-3.7
LOC100129345uncharacterized LOC100129345 -3.8
M
KMO kynurenine 3-monooxygenase (kynurenine 3-hydroxylase) -3.9
KL klotho -3.9
NAALADL2-AS3NAALADL2 antisense RNA 3 -4.0
TTTY15 testis-specific transcript, Y-linked 15 (non-protein coding) -4.1
D

ABCG2 ATP binding cassette subfamily G member 2 (Junior blood group) -4.1
SERPINI1 serpin peptidase inhibitor, clade I (neuroserpin), member 1 -4.4
ANKRD20A5P ankyrin repeat domain 20 family, member A5, pseudogene
TE

-4.5
USP9Y ubiquitin specific peptidase 9, Y-linked -4.6
CPS1 carbamoyl-phosphate synthase 1 -4.7
GSTA3 glutathione S-transferase alpha 3 -4.8
CSHL1 chorionic somatomammotropin hormone-like 1 -5.3
EP

ABCB1 ATP binding cassette subfamily B member 1 -7.0

C
AC
 iCTB ACCEPTED MANUSCRIPT
sPE nPTB Symbol Name D
MT1G metallothionein 1G 6.5
SPRR2G small proline-rich protein 2G 5.3
GK3P glycerol kinase 3 pseudogene 5.1
CXCL8 chemokine (C-X-C motif) ligand 8 3.5
KRT7 keratin 7, type II 3.0
VIT vitrin 3.0
CYP4F62P cytochrome P450, family 4, subfamily F, polypeptide 62, pseudogene 2.9
F8A1 coagulation factor VIII-associated 1 2.8
LOC729737 uncharacterized LOC729737 2.7
LOC101929504 uncharacterized LOC101929504 2.7

PT
SLC6A8 solute carrier family 6 (neurotransmitter transporter), member 8 2.6
LOC729218 uncharacterized LOC729218 2.5
HMOX1 heme oxygenase 1 2.5
HCAR2 hydroxycarboxylic acid receptor 2 2.5

RI
AQP9 aquaporin 9 2.5
LOC648987 uncharacterized LOC648987 2.5
ZNF300P1 zinc finger protein 300 pseudogene 1 (functional) 2.5
UCA1 urothelial cancer associated 1 (non-protein coding) 2.4

SC
AHNAK2 AHNAK nucleoprotein 2 2.4
PADI1 peptidyl arginine deiminase, type I 2.3
EFNB2 ephrin-B2 2.2
LOC102724784 uncharacterized LOC102724784 2.2

U
GPRC5A G protein-coupled receptor, class C, group 5, member A 2.2
NYNRIN NYN domain and retroviral integrase containing 2.2
GPT
PGPEP1
LOC102546229
AN
glutamic-pyruvate transaminase (alanine aminotransferase)
pyroglutamyl-peptidase I
uncharacterized LOC102546229
2.1
2.1
2.1
MTSS1L metastasis suppressor 1-like 2.1
M
SHC3 SHC (Src homology 2 domain containing) transforming protein 3 2.1
VEGFA vascular endothelial growth factor A 2.1
TNNI2 troponin I type 2 (skeletal, fast) 2.1
NDRG1 N-myc downstream regulated 1 2.1
D

LPCAT1 lysophosphatidylcholine acyltransferase 1 2.1

KRT14 keratin 14, type I 2.1
SLC2A3 solute carrier family 2 (facilitated glucose transporter), member 3
TE

2.1
MYOZ1 myozenin 1 2.1
PORCN porcupine homolog (Drosophila) 2.0
KSR1 kinase suppressor of ras 1 2.0
POMC proopiomelanocortin 2.0
EP

CROCCP2 ciliary rootlet coiled-coil, rootletin pseudogene 2 -2.0

CLN5 ceroid-lipofuscinosis, neuronal 5 -2.0
NFYB nuclear transcription factor Y subunit beta -2.0
ZNF266 zinc finger protein 266 -2.0
C

CD47 CD47 molecule -2.0

GSTA4 glutathione S-transferase alpha 4 -2.0
AC

DUBR DPPA2 upstream binding RNA -2.0

MXRA5 matrix-remodelling associated 5 -2.0
SNORA13 small nucleolar RNA, H/ACA box 13 -2.0
AK3 adenylate kinase 3 -2.0
VRK1 vaccinia related kinase 1 -2.0
TMEM62 transmembrane protein 62 -2.1
FKBP14 FK506 binding protein 14 -2.1
ZNF732 zinc finger protein 732 -2.1
COL5A2 collagen, type V, alpha 2 -2.1
LOC100128988 uncharacterized LOC100128988 -2.1
PRKACB protein kinase, cAMP-dependent, catalytic, beta -2.1
DPY19L3 dpy-19-like 3 (C. elegans) -2.1
SNTB2 syntrophin, beta 2 (dystrophin-associated protein A1, 59kDa, basic component 2) -2.1
WDR41 WD repeat domain 41 -2.2
PKD2 polycystic kidney disease 2 (autosomal dominant) -2.2
 iCTB ACCEPTED MANUSCRIPT
sPE nPTB Symbol Name D
STARD4 StAR-related lipid transfer domain containing 4 -2.2
COL12A1 collagen, type XII, alpha 1 -2.2
HIST1H2BI histone cluster 1, H2bi -2.2
HAPLN3 hyaluronan and proteoglycan link protein 3 -2.2
TP53INP1 tumor protein p53 inducible nuclear protein 1 -2.2
PDE3B phosphodiesterase 3B, cGMP-inhibited -2.2
TMEM55A transmembrane protein 55A -2.2
SGCB sarcoglycan beta -2.2
CLIC2 chloride intracellular channel 2 -2.2
SAMHD1 SAM domain and HD domain 1 -2.2

PT
SPDYE3 speedy/RINGO cell cycle regulator family member E3 -2.2
RPS4Y1 ribosomal protein S4, Y-linked 1 -2.2
NSUN3 NOP2/Sun domain family, member 3 -2.2
LINC00845 long intergenic non-protein coding RNA 845 -2.2

RI
MMP2 matrix metallopeptidase 2 -2.2
TWIST1 twist family bHLH transcription factor 1 -2.2
FAM105A family with sequence similarity 105, member A -2.3
GNGT1 guanine nucleotide binding protein (G protein), gamma transducing activity polypeptide 1-2.3

SC
SEMA6A-AS1 SEMA6A antisense RNA 1 -2.3
ANGPTL1 angiopoietin like 1 -2.3
IKZF3 IKAROS family zinc finger 3 -2.3
TYW5 tRNA-yW synthesizing protein 5 -2.3

U
RAB27B RAB27B, member RAS oncogene family -2.3
RPGRIP1L RPGRIP1-like -2.3
HSD17B1
BIRC3
PIP5K1B
AN
hydroxysteroid (17-beta) dehydrogenase 1
baculoviral IAP repeat containing 3
phosphatidylinositol-4-phosphate 5-kinase, type I, beta
-2.3
-2.3
-2.3
ACSL5 acyl-CoA synthetase long-chain family member 5 -2.3
M
PSG10P pregnancy specific beta-1-glycoprotein 10, pseudogene -2.4
MELK maternal embryonic leucine zipper kinase -2.4
C4orf36 chromosome 4 open reading frame 36 -2.4
SNORD114-17 small nucleolar RNA, C/D box 114-17 -2.4
D

CDYL2 chromodomain protein, Y-like 2 -2.4

HS3ST3B1 heparan sulfate (glucosamine) 3-O-sulfotransferase 3B1 -2.4
PSMD5-AS1 PSMD5 antisense RNA 1 (head to head)
TE

-2.4
MIR520E microRNA 520e -2.4
DAB2 Dab, mitogen-responsive phosphoprotein, homolog 2 (Drosophila) -2.4
ADAMTS3 ADAM metallopeptidase with thrombospondin type 1 motif 3 -2.4
PSG4 pregnancy specific beta-1-glycoprotein 4 -2.4
EP

SLC12A2 solute carrier family 12 (sodium/potassium/chloride transporter), member 2 -2.5

KRT23 keratin 23, type I -2.5
PMAIP1 phorbol-12-myristate-13-acetate-induced protein 1 -2.5
PIWIL4 piwi-like RNA-mediated gene silencing 4 -2.5
C

ADAMDEC1 ADAM-like, decysin 1 -2.5

SLC25A15 solute carrier family 25 (mitochondrial carrier; ornithine transporter) member 15 -2.5
AC

CD36 CD36 molecule (thrombospondin receptor) -2.5

ABCG2 ATP binding cassette subfamily G member 2 (Junior blood group) -2.6
PSG3 pregnancy specific beta-1-glycoprotein 3 -2.6
ITGA4 integrin alpha 4 -2.6
ELOVL2 ELOVL fatty acid elongase 2 -2.6
GPR171 G protein-coupled receptor 171 -2.6
ARL13B ADP-ribosylation factor like GTPase 13B -2.6
RAB3B RAB3B, member RAS oncogene family -2.6
ERV3-1 endogenous retrovirus group 3, member 1 -2.6
IL18 interleukin 18 -2.7
USP27X ubiquitin specific peptidase 27, X-linked -2.7
SLC19A3 solute carrier family 19 (thiamine transporter), member 3 -2.7
A2M alpha-2-macroglobulin -2.7
RHOBTB1 Rho-related BTB domain containing 1 -2.7
PTPRJ protein tyrosine phosphatase, receptor type, J -2.7
 iCTB ACCEPTED MANUSCRIPT
sPE nPTB Symbol Name D
EGFL6 EGF-like-domain, multiple 6 -2.7
SLIT2 slit guidance ligand 2 -2.8
FGFBP1 fibroblast growth factor binding protein 1 -2.8
IQGAP2 IQ motif containing GTPase activating protein 2 -2.8
HSD17B2 hydroxysteroid (17-beta) dehydrogenase 2 -2.8
AHR aryl hydrocarbon receptor -2.8
TGFBR2 transforming growth factor beta receptor II -2.8
ANTXR1 anthrax toxin receptor 1 -2.8
MBNL3 muscleblind-like splicing regulator 3 -2.8
PSG8 pregnancy specific beta-1-glycoprotein 8 -2.9

PT
EIF1AY eukaryotic translation initiation factor 1A, Y-linked -2.9
P2RY12 purinergic receptor P2Y, G-protein coupled, 12 -2.9
TFPI2 tissue factor pathway inhibitor 2 -2.9
FBN2 fibrillin 2 -2.9

RI
SLAMF6 SLAM family member 6 -3.0
ERVFRD-1 endogenous retrovirus group FRD, member 1 -3.0
LOC101929633 uncharacterized LOC101929633 -3.1
CD200 CD200 molecule -3.1

SC
PLXDC2 plexin domain containing 2 -3.1
ANK3 ankyrin 3, node of Ranvier (ankyrin G) -3.1
PLAC1 placenta specific 1 -3.2
JAG1 jagged 1 -3.2

U
DEPDC1B DEP domain containing 1B -3.2
FPR3 formyl peptide receptor 3 -3.2
PLN
INSL4
PKIB
phospholamban AN
insulin-like 4 (placenta)
protein kinase (cAMP-dependent, catalytic) inhibitor beta
-3.2
-3.3
-3.3
SESN3 sestrin 3 -3.3
M
MICU3 mitochondrial calcium uptake family, member 3 -3.3
ADGRF5 adhesion G protein-coupled receptor F5 -3.3
VSIG4 V-set and immunoglobulin domain containing 4 -3.4
FAM171B family with sequence similarity 171, member B -3.4
D

DAW1 dynein assembly factor with WDR repeat domains 1 -3.4

CRH corticotropin releasing hormone -3.4
PLCE1-AS1 PLCE1 antisense RNA 1
TE

-3.4
RAB39A RAB39A, member RAS oncogene family -3.5
PVRL3 poliovirus receptor-related 3 -3.5
C3AR1 complement component 3a receptor 1 -3.5
BMP5 bone morphogenetic protein 5 -3.5
EP

LGALS14 lectin, galactoside-binding, soluble, 14 -3.6

KMO kynurenine 3-monooxygenase (kynurenine 3-hydroxylase) -3.6
ADGRG6 adhesion G protein-coupled receptor G6 -3.6
PCGF5 polycomb group ring finger 5 -3.7
C

ZNF25 zinc finger protein 25 -3.7

ANKRD20A5P ankyrin repeat domain 20 family, member A5, pseudogene -3.8
AC

SNORD114-12 small nucleolar RNA, C/D box 114-12 -3.9

PAGE4 P antigen family, member 4 (prostate associated) -4.3
PSG6 pregnancy specific beta-1-glycoprotein 6 -4.5
AIM1 absent in melanoma 1 -4.6
SVEP1 sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 -4.6
C7 complement component 7 -4.8
MS4A4A membrane-spanning 4-domains, subfamily A, member 4A -5.1
PDK4 pyruvate dehydrogenase kinase, isozyme 4 -5.6
CYP19A1 cytochrome P450, family 19, subfamily A, polypeptide 1 -5.8
F5 coagulation factor V (proaccelerin, labile factor) -5.8
USP9Y ubiquitin specific peptidase 9, Y-linked -7.3
TTTY15 testis-specific transcript, Y-linked 15 (non-protein coding) -7.7
CGA glycoprotein hormones, alpha polypeptide -7.9
GPR34 G protein-coupled receptor 34 -9.0
PSG1 pregnancy specific beta-1-glycoprotein 1 -9.5
 iCTB ACCEPTED MANUSCRIPT
sPE nPTB Symbol Name D
LGALS13 lectin, galactoside-binding, soluble, 13 -10.3
POSTN periostin, osteoblast specific factor -10.7
GH2 growth hormone 2 -14.2
CXCL9 chemokine (C-X-C motif) ligand 9 -16.9

PT
RI
U SC
AN
M
D
TE
C EP
AC
 eCTB ACCEPTED MANUSCRIPT
sPE nPTB Symbol Name D
REN renin 6.0
CHI3L1 chitinase 3-like 1 (cartilage glycoprotein-39) 3.7
VTRNA2-1 vault RNA 2-1 3.6
HMOX1 heme oxygenase 1 2.6
LOC645752 golgin A6 family, member A pseudogene 2.5
KDR kinase insert domain receptor 2.4
PRB1 proline-rich protein BstNI subfamily 1 2.1
C10orf10 chromosome 10 open reading frame 10 2.1
LAPTM5 lysosomal protein transmembrane 5 2.0

PT
GPRC5B G protein-coupled receptor, class C, group 5, member B 2.0
CLIC5 chloride intracellular channel 5 -2.0
LOC440173 uncharacterized LOC440173 -2.0
HOOK1 hook microtubule-tethering protein 1 -2.0

RI
CPED1 cadherin-like and PC-esterase domain containing 1 -2.0
FAM171B family with sequence similarity 171, member B -2.1
GALNT3 polypeptide N-acetylgalactosaminyltransferase 3 -2.1

SC
HAPLN1 hyaluronan and proteoglycan link protein 1 -2.1
KLRF2 killer cell lectin-like receptor subfamily F, member 2 -2.1
SPTLC3 serine palmitoyltransferase, long chain base subunit 3 -2.1
C18orf54 chromosome 18 open reading frame 54 -2.1

U
CHRM5 cholinergic receptor, muscarinic 5 -2.2
KRT23 keratin 23, type I -2.2
RAB27B
LINC00882
RASSF6
AN
RAB27B, member RAS oncogene family
long intergenic non-protein coding RNA 882
Ras association (RalGDS/AF-6) domain family member 6
-2.2
-2.2
-2.2
NMU neuromedin U -2.2
M
SEMA6D sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6D-2.2
ESRP1 epithelial splicing regulatory protein 1 -2.2
CLEC9A C-type lectin domain family 9, member A -2.2
D

FAT2 FAT atypical cadherin 2 -2.2

CHMP4C charged multivesicular body protein 4C -2.3
PLCE1-AS1 PLCE1 antisense RNA 1 -2.3
TE

IL1RAPL2 interleukin 1 receptor accessory protein-like 2 -2.3

ACE2 angiotensin I converting enzyme 2 -2.3
NCAM1 neural cell adhesion molecule 1 -2.3
EP

TFPI2 tissue factor pathway inhibitor 2 -2.4

ACKR2 atypical chemokine receptor 2 -2.4
ADAMDEC1 ADAM-like, decysin 1 -2.5
SNORD4B small nucleolar RNA, C/D box 4B -2.6
C

RPS4Y1 ribosomal protein S4, Y-linked 1 -2.6

JAG1 jagged 1 -2.6
AC

ADGRF5 adhesion G protein-coupled receptor F5 -2.7

CYP19A1 cytochrome P450, family 19, subfamily A, polypeptide 1 -2.7
LOC101929633 uncharacterized LOC101929633 -2.7
SNORD114-3 small nucleolar RNA, C/D box 114-3 -2.8
VLDLR very low density lipoprotein receptor -2.8
GPC3 glypican 3 -2.8
DAW1 dynein assembly factor with WDR repeat domains 1 -2.8
ADGRG2 adhesion G protein-coupled receptor G2 -2.8
ADGRG6 adhesion G protein-coupled receptor G6 -3.1
OGN osteoglycin -3.3
ELOVL2 ELOVL fatty acid elongase 2 -3.4
FGA fibrinogen alpha chain -3.4
FAM66A family with sequence similarity 66, member A -3.7
FGB fibrinogen beta chain -4.3
SNORD114-14 small nucleolar RNA, C/D box 114-14 -4.3
 eCTB ACCEPTED MANUSCRIPT
sPE nPTB Symbol Name D
SHROOM3 shroom family member 3 -4.5
PSG1 pregnancy specific beta-1-glycoprotein 1 -4.5
CGA glycoprotein hormones, alpha polypeptide -5.5
SNORD41 small nucleolar RNA, C/D box 41 -5.9

PT
RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC