Documente Academic
Documente Profesional
Documente Cultură
The jumonji (jmj) gene was identied by a mouse gene trap approach and has essential roles in the
development of multiple tissues. The Jmj protein has a DNA binding domain, ARID, and two conserved jmj
domains (jmjN and jmjC). In many diverse species including bacteria, fungi, plants, and animals, there are
many jumonji family proteins that have only the jmjC domain or both jmj domains. Recently, Jmj protein
was found to be a transcriptional repressor. Several proteins in the jumonji family are involved in
transcriptional repression and/or chromatin regulation. Most recently, one of the human members has been
shown to be a histone demethylase, and the jmjC domain is essential for the demethylase activity.
Meanwhile, more and more evidence indicating that the jumonji family proteins play important roles
during development is accumulating. Many proteins in the jumonji family may regulate chromatin and gene
expression, and control development through various signaling pathways. Here, we highlight the roles of
jmj and jumonji family proteins in chromatin regulation and development. Developmental Dynamics 235:
2449 2459, 2006. 2006 Wiley-Liss, Inc.
Key words: jumonji; jumonji family; jmjC; chromatin remodeling; histone demethylase; cell proliferation; cell
differentiation
Accepted 19 April 2006
INTRODUCTION
In the past, we have attempted to
identify novel genes that have important roles in development using a
mouse gene trap method and have
successfully identied jumonji (jmj;
Takeuchi et al., 1995; Takeuchi,
1997). The gene was named for the
morphology produced by the normal
neural groove and abnormal grooves
on the neural plates of jmj mutant
mice. The morphology resembles a
cross, and jumonji means cruciform
in Japanese (Takeuchi et al., 1995).
We rst reported that Jmj protein
has two conserved domains (Takeuchi
Dr. Kondos present address is JEOL Ltd. 3-1-2 Musashino, Akishima, Tokyo 196-8558 Japan.
*Correspondence to: Takashi Takeuchi, Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya, Machida,
Tokyo, 194-8511 Japan. E-mail: take@libra.ls.m-kagaku.co.jp
2
DOI 10.1002/dvdy.20851
Published online 16 May 2006 in Wiley InterScience (www.interscience.wiley.com).
STRUCTURE AND
EVOLUTION OF JUMONJI
FAMILY PROTEINS
The jumonji family proteins comprise a large family. We constructed
a dendrogram of human, Drosophila,
and yeast jumonji family proteins
(Fig. 1) based on their jmjC domain
sequences. Almost all proteins containing jmjC domain in Pfam (http://
pfam.wustl.edu/cgi-bin/getdesc?name
JmjC), SMART (http://smart.emblheidelberg.de/smart/do_annotation.
pl?DOMAIN
JmjC&BLAST
DUMMY), and InterPro (http://www.
ebi.ac.uk/interpro/DisplayIproEntry?
acIPR003347) data bases were
analyzed after redundant, variant,
hypothetical, or low score (e1.0E04, SMART program) proteins were
removed. Recent structure analysis
of jmjC of HIF1AN/FIH, which has a
2-oxoglutarate (2-OG)-Fe(II) dependent dioxygenase activity, revealed
residues binding to the cofactors
2-OG and Fe(II), and showed that
the domain contains a doublestranded -helix motif (Elkins et al.,
2003). A sequence alignment of the
jmjC domains of various jumonji
family proteins suggested that these
features are conserved (Elkins et al.,
2003; Trewick et al., 2005). Recently,
one jumonji family protein, FBXL11/
JHDM1A was shown to be a 2-OG-
Fig. 1. Unrooted neighbor-joining tree for 44 jumonji family proteins based on jmjC domain sequences. The tree was constructed by using Poisson correction distance for amino acid sequences and
the MEGA package. Percentage bootstrap values ( 90%) are shown on internal branches. Protein
names in humans, Drosophila, and budding and ssion yeasts are represented as black, magenta, blue
and orange, respectively. Accession numbers are presented in Drosophila and yeast proteins; those of
human proteins are given in Figure 2. Boxes beside protein names show domains that each protein
contains. Colored boxes show characteristic domains in each cluster. Asterisks mark proteins that have
been reported to be involved in gene repression or histone modication.
FUNCTIONS OF JUMONJI
FAMILY PROTEINS IN
TRANSCRIPTION AND
CHROMATIN REGULATION
Many jumonji family proteins have
domains involved in DNA binding,
chromatin binding, or transcription,
such as ARID (Kortschak et al., 2000;
Wilsker et al., 2005), PHD nger
(Bienz, 2006), or Zn-ngers, and jmjC
domains showing metalloenzyme-like
structures, suggesting that jumonji
family proteins regulate transcription
or chromatin function or both (Balciunas and Ronne, 2000; Clissold and
Ponting, 2001; Trewick et al., 2005).
In fact, the potential activities of
FUNCTIONS OF JUMONJI
IN DEVELOPMENT
As described above, the jumonji (jmj)
gene was identied by a mouse gene
FUNCTIONS OF OTHER
JUMONJI FAMILY
PROTEINS IN
DEVELOPMENT
RBP2
RBP2 is a member of the JARID1 subfamily (Fig. 1). It is ubiquitously expressed in adult tissues and has jmjN,
jmjC, PHD, and ARID sequences.
Among the over 100 pRB binding proteins, RBP1 and RBP2 were identied
as the rst cellular pRB binding proteins (Defeo-Jones et al., 1991). Although the function has remained unknown for a long time, roles in cell
differentiation were recently proposed
(Benevolenskaya et al., 2005). It is
well known that pRB regulates cell
differentiation in addition to cell proliferation. Benevolenskaya et al. suggested that RBP2 represses expression of the genes required for
differentiation of various types of cells
such as myeloid, bone, and muscle,
and binding to pRB neutralizes the
functions of free RBP2 and then promotes differentiation. They also suggested that the binding is involved in
euchromatin maintenance. It is interesting to consider that pRB may act as
a negative regulator of RBP2 in cell
PTDSR
PTDSR has only a jmjC domain as
an apparent domain (Fig. 1). The
protein was initially identied as the
receptor of phosphatidylserine, a
specic marker present at the surface of apoptotic cells, and is involved in apoptotic cell phagocytosis
(Fadok et al., 2000). However,
PTDSR is localized in the nucleus
(Cikala et al., 2004; Cui et al., 2004).
Moreover, an antibody against phosphatidylserine receptor, used for
original screening, still recognizes
the receptor in mice lacking PTDSR
(Bose et al., 2004). These results
strongly suggest that PTDSR is not
the phosphatidylserine receptor and,
therefore, that the name should be
changed.
Several studies using KO or
knockdown animals (worm, zebrash, and mouse) have shown that
PTDSR is required for clearance of
apoptotic cells (Li et al., 2003; Wang
et al., 2003; Hong et al., 2004; Kunisaki et al., 2004). However, PTDSR
was not essential for clearance of apoptotic cells in an analysis of another
PTDSR KO mouse line (Bose et al.,
2004). Apart from the function related to the clearance of apoptotic
cells, PTDSR would be required for
normal embryogenesis, at least in
zebra shes and mice (Li et al., 2003;
Bose et al., 2004; Hong et al., 2004;
Kunisaki et al., 2004; Schneider et
al., 2004). PTDSR KO mice died at
the perinatal stage and showed various abnormalities in many tissues
such as the heart, brain, lung, kidney, eye, and hematopoietic system.
However, these phenotypes are also
different among KO mouse strains.
For example, neuroepithelial cells in
the retina showed enhanced proliferation in Flavells KO mice (Li et al.,
2003). On the other hand, 14.1% of
Lengelings KO mice lacked eyes
unilaterally or bilaterally (anophthalmia), or the retinal development
Hairless
Hairless is in cluster 3 and has a jmjC
domain as the only apparent domain
(Fig. 1). The gene was identied as the
responsible gene for the mouse mutant hairless (Cachon-Gonzalez et al.,
1994). The hairless mouse was rst
recognized in 1926 for its characteristic hair loss phenotype, in which initial hair growth is normal, but after
shedding, the hair does not grow back
(Brooke, 1926), suggesting abnormalities in hair follicle regeneration. Mutations of the human hairless gene revealed congenital hair loss disorders.
Some mutant alleles in both mice and
humans show skin wrinkling and papular rash (Panteleyev et al., 1998).
Hairless null KO mice show both hair
and skin phenotypes (Zarach et al.,
2004). Analysis of the KO mice revealed increased proliferation and
changes of cell types in the epidermis,
suggesting that Hairless is required
for normal balance of cell proliferation
and differentiation in the epidermis
cells (Zarach et al., 2004). The rescue
experiments using transgenic mice
showed that expression of Hairless in
progenitor keratinocytes is required
for hair follicle regeneration (Beaudoin et al., 2005). Hairless represses
expression of Wise, a modulator of
Wnt signaling, coincident with the
timing of follicle regeneration. From
these studies, a model in which Hair-
FUTURE PERSPECTIVES
The molecular functions of jmjC and
jumonji family proteins will be analyzed extensively and intensively.
However, it will also be important to
link the molecular functions to biological events such as development. Several points or questions that require
attention when conducting these studies are discussed below.
NOTE
Most recently, ve jumonji family
members, JMJD1A/TSGA (renamed
to JHDM2A in the following paper)
and JMJD2A-D have been shown to be
H3K9 demethylases (Whetstine et al.,
2006; Yamane et al., 2006). JMJD2A
and JMJD2C are also H3K36 demethylases (Whetstine et al., 2006). Importantly, JMJD1A/TSGA can demethylate mono- and di-methyl H3K9,
and
JMJD2
family
can
demethylate di- and tri-methyl H3K9/K36. These results showed that jumonji family members can demethylate residues in three methylation
states of histones.
ACKNOWLEDGMENT
We thank Ms. Mizuyo Kojima and Ms.
Kuniko Nakajima for their excellent
technical assistance.
REFERENCES
Ahmed S, Palermo C, Wan S, Walworth
NC. 2004. A novel protein with similarities to Rb binding protein 2 compensates
for loss of Chk1 function and affects histone modication in ssion yeast. Mol
Cell Biol 24:3660 3669.
Anzai H, Kamiya A, Shirato H, Takeuchi
T, Miyajima A. 2003. Impaired differentiation of fetal hepatocytes in homozygous jumonji mice. Mech Dev 120:791
800.
Ayoub N, Noma K, Isaac S, Kahan T, Grewal SI, Cohen A. 2003. A novel jmjC
domain protein modulates heterochromatization in ssion yeast. Mol Cell Biol
23:4356 4370.
Baker RK, Haendel MA, Swanson BJ,
Shambaugh JC, Micales BK, Lyons GE.
1997. In vitro preselection of genetrapped embryonic stem cell clones for
characterizing novel developmentally
regulated genes in the mouse. Dev Biol
185:201214.
Balciunas D, Ronne H. 2000. Evidence of
domain swapping within the jumonji
family of transcription factors. Trends
Biochem Sci 25:274 276.
Beaudoin GM, 3rd, Sisk JM, Coulombe PA,
Thompson CC. 2005. Hairless triggers
reactivation of hair growth by promoting