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Methylation of histones: playing memory with DNA

Antoine HFM Peters and Dirk Schübeler

Nucleosomal histones can be methylated in vivo at multiple H4 (Figure 1a). Arginines can either be mono- or
residues and defined methylation patterns are related to dimethylated (symmetric or asymmetric methylation),
distinct functional readouts of chromosomal DNA. Histone while lysines can be mono-, di- or trimethylated [4].
methylation has emerged as an important post-translational Different modification levels of multiple residues give
modification involved in transcriptional regulation and genome high combinatorial complexity, enabling histone methy-
integrity. Recent progress in determining the cis and trans lation to be involved in different DNA-templated events.
determinants of this process revealed multiple roles for histone
methylation in epigenetic memory of active and silent states. The appearance of any chromatin structure involves
The analysis of imprinted, X-linked and heterochromatic establishment and subsequent propagation (re-establish-
sequences disclosed mechanistic similarities for heritable ment) through cell division (Figure 1b). Significant pro-
transcriptional repression, pointing to a common mode of gress has been made in monitoring chromatin complexity,
action. Moreover, the view of histone methylation as a stable yet we are only just starting to understand the order of
modification has recently been challenged by studies revealing events that initiate, maintain or dynamically change epi-
a number of pathways that are capable of removing histone genetic states. The basic concept of histone methylation
methylation. Thus, in addition to having great in vivo playing a role in propagating chromatin as a form of
complexity, this modification appears more dynamic then epigenetic memory is largely based on the evolutionarily
was previously thought. conserved involvement of HMTs in maintaining and
Addresses
potentially establishing different types of active and
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse repressed chromatin.
66, CH 4058 Basel, Switzerland
Here we provide a concise overview of recent advances in
Corresponding authors: Peters, Antoine HFM (antoine.peters@fmi.ch);
understanding the multiple roles of histone methylation
Schübeler, Dirk (dirk@fmi.ch)
and discuss them in the context of current models of
chromatin function.
Current Opinion in Cell Biology 2005, 17:230–238

This review comes from a themed issue on


Histone methylation and active transcription
Cell regulation Chromatin provides a barrier to RNA polymerase activity,
Edited by Brian Hemmings and Peter Parker and thus it comes as no surprise that chromatin remodel-
ing and histone modifications including methylation
play an intrinsic part in transcriptional initiation and
0955-0674/$ – see front matter elongation [5].
# 2005 Elsevier Ltd. All rights reserved.
Chromatin-immunoprecipitation (ChIP) experiments
DOI 10.1016/j.ceb.2005.02.006
have determined that active genes are methylated at
lysine 4 of histone H3 (H3K4) [6], H3K79 [7] and
H3K36 [8], suggesting a role for these modifications in
Introduction: histone methylation transcription. Interestingly monoubiquitination of H2B at
The complex of DNA and bound histones in eukaryotes lysine 123 (H2BK123ul) involving the conjugating
is called chromatin. Once viewed as static ‘packaging enzyme Rad 6/Ubc2 is required for the methylation of
material’ required to condense and neutralize nuclear H3K4 and H3K79 but not of H3K36 (Figure 2a) [9]. The
DNA, it is now evident that chromatin is dynamically current model is that H2BK123u1 facilitates recruitment
modified. Nucleosomal histones are the target of a variety of the H3K4 HMT Set-1, leading to H3K4 methylation.
of post-translational modifications including acetylation, Set-1 recruitment itself involves the Paf1 elongation
phosphorylation, ubiquitination and methylation. These complex and coincides with phosphorylation of serine 5
alterations not only regulate accessibility for DNA bind- of the C-terminal domain (CTD) of RNA polymerase II.
ing proteins, but also create recognition modules for Genetic evidence furthermore suggests that Dot1, the
effector proteins [1–3]. H3K79 HMT [10], may also be recruited to chromatin by
the elongating polymerase complex [11]. The identifica-
The basic amino acid side chains of arginine and lysine tion of Ubp8, a component of the SAGA complex, as a
residues on histones can be methylated by histone- deubiquitination factor [12] led to a sequential model in
methyl-transferases (HMTs). Most modified residues which H3K4 methylation is followed by deubiquitination,
are located in the N-terminal tails of histone H3 and allowing recruitment of Set2, which methylates H3K36, a

Current Opinion in Cell Biology 2005, 17:230–238 www.sciencedirect.com


Methylation of histones Peters and Schübeler 231

Figure 1

(a) Protruding N-terminal tail Core


domain
me
me me me me meme
ARTKQTAR STGGKAPRKQLATKAARKSAP A
S TGGVKKP K H3
1 4 9 27 36 38
79

me me
H2A H3
SGRGKGGKGLGKGGAKRHRKVLRDN H4
1 20 25 H2B H4

Nucleosome

(b)

Propagation Establishment Propagation

M
M

me me me me me me

Conversion

Current Opinion in Cell Biology

Histone methylation and chromatin states. (a) Sites of lysine (K) (individually color coded) and arginine (R) (turquoise) methylation on histones H3 and
H4. Acetylatable lysine and phosphorylatable serine (S) residues are indicated by light-green and violet lettering, respectively. Only the mono-
methylated states are presented. H3K9 can either be acetylated or methylated. Throughout text and figures histone modifications are labeled
according to the ‘Brno nomenclature’ (e.g. H3K27me3 represents tri-methylation at H3 lysine 27) [63]. Sequences of murine H3.1 (A31) and H3.3 (S31)
are given. (b) Establishment and propagation of chromatin states. In dividing cells chromatin structure needs to be propagated; resetting involves
removal and setting of new marks. In the case of histone methylation, lysine 4, 36 and 79 of H3 are mostly euchromatic, whereas lysine 9 and 27
and H4K20 mostly coincide with repression. Blue squares on nucleosomes represent 5-methylcytosine in DNA. However, although this binary
division of chromatin states into active and repressive provides a usable simplification, it does not account for the complexity of chromatin in vivo.
Thus gradual intermediate states (stable or unstable) need to be considered.

process which coincides with CTD serine 2 phosphoryla- histone methylation at active genes could serve as a long-
tion. Thus H3K4 methylation seems to be involved in term signature for the propagation of the active state
early events of transcription, whereas H3K36 methylation through cell division [14] and recent experiments in
is linked to efficient elongation. Drosophila are compatible with this model.

The above model has been derived mainly from work in Cellular memory of active and repressed
Saccharomyces cerevisiae. Although similar patterns for transcriptional states through development
H3K4 and H3K79 methylation have been observed in Metazoan development involves differentiation into
metazoa [7], the larger number of HMTs and their diverse cell types. Early genetic studies on homeobox
development-specific expression suggests greater com- (HOX) gene regulation in Drosophila demonstrated that
plexity in multicellular organisms. In any case the precise expression programs can be maintained throughout
function of each modification still needs to be demon- development in the absence of the transient factors
strated. Are they recognized by effector proteins, or do that initiated them. This ‘cellular memory’ depends on
they prevent repressive modifications [13] or even mod- antagonistically functioning chromatin-modifying com-
ulate nucleosomal interactions? One hypothesis is that plexes — the Trithorax and Polycomb group proteins

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232 Cell regulation

Figure 2

(a) Transcription (b) Transcriptional memory


?
(CTD)n PRE
me me me me
S5 ub me ub me

ph
S2 me me
Set2 me
me me
me
me
PHO
Paf1 S5 Paf1 me me
S2 SU(Z)12
ph
Rad6 Set1 E(Z) ESC
Bre1 PSC PH
RNAPII dRING PC
me
me me me me
me me
ub me me ub me me ub ub me TAFs
me me
me
me
me Promoter TFIIB ? me me me
me
PHO
me me me me
me me me me
SAGA TBP
me ?
me me ub me ub me me
me me me
me

(c) Genomic imprinting


Su(z)12 ? Su(z)12 ?
Ezh2 Ezh2
? ? Eed ? ? Eed
? me ? me

me me me me
n.d. me me
me
me me me me me me me me me
n.d. me me me
me
me me
ac ac ac
MM
M ac ac ac ac Maternal ac
M
M
me me me me

Osbpl5 Phlda2 Slc22a Cdkn1c KvDMR1 Kcnq1 Tssc4 Cd81 Ascl2 Osbpl5 Phlda2 Slc22a Cdkn1c KvDMR1 Kcnq1 Tssc4 Cd81 Ascl2
+/+
Dnmt1-/-
KvDMR1+/-
Kcnq1ot1 Kcnq1ot1
? ?
me me me me me me me me me me me me me me
ac
M M
ac
Paternal MM MM
me me me me
me me me me me me me me
me me n.d. meme ? me
? me me me n.d. me
?
me me me me me me me

Su(z)12 Su(z)12 Su(z)12


Ezh2 Ezh2 ? Ezh2
Eed Eed Eed
Placenta Embryo

(d) X-inactivation (e) Pericentric heterochromatin


Major satellite repeats
Suz12 Mpc Mph1/2
Ezh2 ? Ring ncRNA
Eed Mel18
? ? 1A/1B
Xist RNA ? me
? siRNA ?
me
me me
me me me me
me me me me Suv39h1/2 Suv4-20h1/2 ?
me me me me me
me me me
me ub ub me ub Hp1 Hp1
me
me
me me me me me
me me me me
me me me me me me me me me
Hp1 Hp1
RNA me
me
me me
? me
me me me me me me me me me
me
Hp1

Current Opinion in Cell Biology

Histone methylation and transcriptional regulation. The depicted models summarize graphically the discussed work. Genetic interactions are
indicated by regular arrows and enzyme–target relations by dashed arrows. (a) Histone methylation and polymerase activity. Diagram of interplay
between S2 and S5 phosphorylation at the C-terminal domain (CTD) of Polymerase II, H3K4 and H3K36 methylation and H2BK120 ubiquitination
during active transcription in S. cerevisiae. (b) Scheme of modifications and transacting factors present at the PcG-responsive element (PRE)
and 50 genic region of the silent Drosophila melanogaster Ubx locus. The DNA binding factors PHO (and PHO-L) and E(Z) are believed to mediate
repression by juxtaposing the PRE and 50 gene region and targeting PRC1 complexes. Hypothesized differential binding affinities of PC to
H3K27me3 and H3K9me3 in vivo are illustrated by dashed lines [28]. (c) Schematic representation of histone modifications at differentially
expressed imprinted genes within the Kcnq1 imprinting cluster in embryonic and extra-embryonic tissues. PRC2 binding is hypothesized on the
basis of experiments in embryonic stem cells (see text). Green and blue arrows and rectangles refer to mono-allelic expression at maternal and
paternal alleles, respectively, in wild-type tissues. Allelic expression states in wild-type (+/+) and Dnmt1/ and paternal deletion mutants of the
imprinting control region (ICR) (KvDMR1+/) are indicated as follows: green, maternal; grey, biallelic; black, neither expressed; yellow, not
determined. Chromatin modification status at Slc22a18 region (indicated by Slc22a) was not determined (n.d.) (d) Cartoon of Xist ncRNA
dependent targeting of HMTs and the PRC1 complex mediating H3K27me3, H4K20me1, H2AK119u1 and repression along the X-chromosome.
(e) Establishment and maintenance of constitutive heterochromatin by Suv39h HMTs (see text for details). In addition to H3K9me3, a structural
RNA (in blue) is required for HP1 localization at major satellites [64].

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Methylation of histones Peters and Schübeler 233

(TrxG, PcG) — which operate through binding to cis- Genomic imprinting


acting PcG-responsive elements (PREs). Imprinting in mammals, the second example of devel-
opmental gene regulation, is characterized by monoal-
TrxG is a heterogeneous set of proteins required for the lelic repression of either maternally or paternally
active state. They can be part of the basal transcription inherited genes. Imprinted genes are organized in clus-
machinery or associate with chromatin-remodeling com- ters and allelic expression depends on cis-acting imprint-
plexes [15]. Interestingly, the H3K4-favoring HMTs ing control regions (ICRs), which become differentially
TRX and ASH1 [16,17] are only required for activation DNA-methylated during oogenesis or spermatogenesis
in the presence of repressive PcG activity, suggesting [29,30].
they function as anti-repressors rather than as co-
activators [18]. In this context, TrxG-mediated H3K4 Allele-specific histone methylation at imprinted genes
methylation can be viewed as a mark that propagates the suggested a role for HMTs in genomic imprinting [31].
active state. Although the nature of this anti-silencing Accordingly, deficiency for Eed, the mouse homolog
needs to be demonstrated, it could involve inhibition of of ESC, leads to loss of imprinting at a subset of genes
enhancer of zeste (E(Z)) HMT activity, direct blocking of [32]. Two recent studies on the mouse distal chromo-
Pc silencing, or interference with downstream signaling of some 7 imprinting cluster point to a functional role for
for example H2AK119 ubiquitination (see below). histone methylation in maintaining imprinted gene re-
pression independently of DNA methylation (Figure 2c)
PcG proteins, which mediate the repressed state of epi- [33,34].
genetic memory, are divided into two families based on
distinct polycomb repressor complexes (PRC1 and In this cluster, the Kcnq1ot1 non-coding RNA (ncRNA) is
PRC2) [19]. PRC2 contains, among other proteins, the transcribed from the paternal ICR, which is required for
E(Z) HMT, which, together with ESC and SU(Z)12, repression in cis while the maternal promoter is DNA
methylates H3K27 and H3K9 in vitro [20,21] and addi- methylated and silent. Peculiarly, genes in proximity to
tionally, in humans, methylates H1K26 [22]. PRC1 is a the Kcnq1ot1 promoter are imprinted and differentially
large multi-protein complex with a core of four proteins DNA-methylated in embryo and placenta, whereas distal
(PC, PH, PSC, and dRING) and appears primarily genes are imprinted only in the placenta and lack differ-
responsible for repression activity. The PRC1 complex ential DNA methylation. Repressed genes are positive for
was hypothesized to create a stably repressed chromatin H3K9me2 and H3K27me3 in embryo and placenta and
structure through recognition of E(Z)-mediated H3K27 enriched in mammalian PRC2 components in embryonic
trimethylation (H3K27me3) via its chromodomain pro- stem (ES) cells [33,34]. Importantly, loss of the
tein PC, in analogy to the formation of constitutive Kcnq1ot1 ncRNA via targeted deletion of the ICR on
heterochromatin (see below). Recent evidence suggests the paternal allele leads to a loss of imprinting and
that this simple model needs refinement. differential histone methylation throughout the cluster
[33,35]. In contrast, loss of DNA methylation (in
Purified PRC1 complex contains members of the basal Dnmt1/ embryos) leads to bi-allelic expression only
transcription machinery [23,24]. In addition, RNA poly- of proximal and not distal genes [33]. These data
merase II (Pol II), general transcription and even elonga- suggest that during extra-embryonic development,
tion factors can be detected at repressed promoters, along H3K9me2 and/or PRC2-mediated H3K27me3 are
with repressive histone methylation and PcG proteins required for imprinted silencing independent of DNA
[25]. Furthermore, E(Z), PC, dRING and the DNA methylation, a model that needs to be tested in Eed/
binding protein PHO are specifically localized at the 50 placenta tissue.
end and not the upstream promoter region of the
repressed Ubx HOX gene in wing imaginal discs [26]. At proximal genes, the regulation of imprinting appears
In summary, PcG proteins seem not to block the recruit- to be different. In Eed/ embryos Kcnq1ot1 expression
ment of the transcription machinery but rather to inhibit remains mono-allelic, suggesting that silencing is main-
Pol II activity (Figure 2b, [27]). Surprisingly, PcG pro- tained by germline-derived DNA methylation [32] and/
teins and repressive histone modifications can be or H3K9me2 ([33] (Figure 2c). Yet mono-allelic repres-
detected at active promoters [25,28]. However, presence sion of the Cdkn1c gene is reduced in Eed/ embryos,
of PRC1, PRC2 and methylated lysines at both PRE and even though underlying somatically acquired DNA
gene correlates well with repression [26,28], suggesting methylation patterns are grossly unchanged [32], indi-
a cooperativity for silencing. Notably, PC can bind to the cating that H3K27me3 is necessary for Cdkn1c silencing
Ubx promoter (but not at the corresponding PRE) in the downstream of DNA methylation. This resembles the
absence of E(Z) in cultured cells [26]. Thus H3K27me3 situation at the Dlk1/Gtl2 imprinting cluster, where
and H3K9me3 may not be required solely for targeting of repression of a ncRNA, again involving somatically
PRC1 complexes, but would function particularly to aquired DNA methylation, requires Eed function
maintain and fine-tune silencing. [32,36].

www.sciencedirect.com Current Opinion in Cell Biology 2005, 17:230–238


234 Cell regulation

X inactivation H2AK119u1 at the inactive X chromosome in embryonic


Dosage compensation in mammals is achieved by inacti- and extra-embryonic cells (Figure 2d, [53,54]).
vation of one X-chromosome in females via the Xist non-
coding RNA. In vivo and during ES cell differentiation, Although H2A ubiquitination appears not to be
Xist expression and spreading along the X chromosome upstream of repressive H3 methylation, as is the case
coincides with hypomethylation at H3K4, followed by for H2BK123u1, which is required for H3K4 and H3K79
loading of PRC2 members, H3K9me2, H3K27me3, methylation (Figure 2a), the conserved crosstalk
H4K20me1 hypermethylation, subsequent macroH2A1.2 between ubiquitination and methylation is remarkable
variant incorporation and DNA methylation (Figure 2d, and understanding its function should reveal important
[37]). Importantly, maintenance of random X-inactivation insights.
in the embryo depends on DNA methylation, whereas
maintenance of imprinted X-inactivation in extra- Propagation of histone methylation through
embryonic tissues is dependent on Eed function and Xist cell division
expression but independent of DNA methylation [38– The deposition of newly synthesized nucleosomes during
40]. Thus genomic imprinting [29] (see above) and pla- DNA replication ‘dilutes’ any existing pattern of chro-
cental X-inactivation might share the same ancestral matin modification. How is histone methylation main-
mechanism of repression involving histone methylation tained during this process? One elegant mechanism is the
and ncRNA [33,34]. To address this hypothesis, the recruitment of HMTs to chromatin by existing methy-
distribution of the Kcnq1ot1 ncRNA and its role in target- lated residues, as is suggested to be the case with
ing histone methylation along the imprint cluster needs to H3K9me3 in heterochromatin (Figure 3a) [45]. This kind
be investigated. of positive feedback loop could enforce modification of
newly deposited histones; however, it does not explain
Constitutive heterochromatin how histone methylation would be restricted to a defined
Pericentromeric regions are satellite-repeat-rich and region. Other instances might only require the mainte-
remain condensed throughout the cell cycle in a cytolo- nance of upstream signals such as DNA methylation [55]
gically visible manner. In a variety of species, the Suv39h (e.g. in imprinting; see Figure 2c). In the case of methyla-
class of H3K9 HMTs have been shown to be major tion patterns of active genes, the continuation of
regulators of constitutive heterochromatin [41,42] by transcription might also be sufficient to transmit these
establishing H3K9 di- and trimethylation [43,44] and modifications to newly deposited histones.
by directing targeting of HP1, H4K20me3 and DNA
methylation (Figure 2e [45–47]). In S. pombe, heterochro- Modes of ‘demethylation’
matic H3K9me2 depends on components of the RNAi When analyzed in bulk, histone methylation is stable
machinery that process double stranded RNAs to produce in cells with a half-life time that is indistinguishable
and subsequently use small RNAs, homologous to the from that of the studied histone [56]. This stability and
underlying repeat sequences, to target the clr4 H3K9 the absence of described demethylating enzymes led to a
HMT to chromatin [48,49]. Similar mechanisms may model in which histones need to be replaced for
function in plants [50] and mammals [51] to establish demethylation of chromatin to occur [56]. In fact, in
silent chromatin. Thus, in striking similarity to imprinting metazoans, histone replacement does take place rather
and X-inactivation, repression at satellite repeats seems to frequently during interphase, preferentially at sites of
involve interplay between repressive histone methylation active transcription [57] and utilizing a distinct deposi-
and RNA. tion machinery [58]. This replication-independent
deposition involves a defined H3 variant (H3.3)
H2A/B ubiquitination and histone (Figure 3b, [57]) and provides one mechanism to ‘erase’
methylation methylation patterns. Alternatively, transient phosphor-
Ubiquitination of histone H2B and H2A are frequent ylation of neighboring residues could mediate dynamic
post-translational modifications that are not related to readouts from stable modifications. For example, H3S10
protein turnover, but have been linked to active histone phosphorylation interferes with recognition of H3K9me3
methylation (see above) and recently to repressive his- by Hp1 [59].
tone methylation. The PRC1 protein dRING is a mono-
ubiquitin E3 ligase specific for histone H2A at lysine 119 However, the view of histone methylation as enzymati-
[52], and reduction of dRING in cell culture induces cally irreversible has recently been dismantled with the
Ubx derepression without affecting H3K27me3 levels at discovery of enzymes that can demethylate arginine as
the Ubx PRE. In vivo, Ubx expression is also lost in well as lysine residues. Two studies show that mono-
catalytically inactive dRING mutants, indicating that methylated arginine can be deiminated to citrulline by
H2AK119u1 plays an intimate role in PcG function, the peptidylarginine deiminase 4 (PAD4) enzyme
downstream of E(Z) (Figure 2b). Interestingly, the mam- (Figure 3c, [60,61]). In the analyzed system, mono-
malian Ring1A and Ring1B homologs are responsible for methylation of arginine is mediated by CARM1 and is

Current Opinion in Cell Biology 2005, 17:230–238 www.sciencedirect.com


Methylation of histones Peters and Schübeler 235

Figure 3 would be required to allow remethylation of the same


residue. It remains to be determined if other enzymes can
(a) demethylate di-methylated arginine.
Suv39h1/2

Hp1 An exciting recent report by the Shi lab indicates that


me me even lysine methylation is reversible, as the human LSD1
me enzyme specifically demethylates H3K4me1 and
H3K4me2 in vitro [62]. Demethylation occurs via an
oxidation reaction that generates formaldehyde and pro-
me me me me duces an unmodified lysine residue, thus enabling
me me Suv39h1/2
immediate ‘remethylation’. As with PAD4, the demethy-
Hp1 lation activity of LSD1 is modification-state-specific, as
me me H3K4me3 seems not to be a substrate. Homologs and
me orthologs of LSD1 are present throughout the eukaryotic
kingdom but surprisingly absent in S. cerevisiae. Given the
large number of genes that have been predicted to encode
amine oxidases, other proteins might have similar activity
(b) me me
me in budding yeast or demethylate other methylated lysine
H3.3 H3.1 residues.

me me Taken together, these recent studies show that multiple


me
mechanisms exist allowing rapid removal of histone
methylation and thereby providing means to redirect
epigenetic states.

Conclusions and outlook


(c)
Research during the past two years has greatly improved
CARM1 me
me me our understanding of histone methylation and its multi-
ple functions. The number of known modified histone
residues has increased and more HMTs have been
identified. Genetic studies in several organisms estab-
lished the function of HMTs in transcription and
CARM1 epigenetic memory and different histone modification
PAD4
patterns mark active and repressed genomic regions.
?
cit Especially in the latter case, these patterns seem to be
diverse and reflect different pathways. In the mamma-
lian system, HMT activity can be upstream or down-
stream of DNA methylation, but in either case appears to
be non-redundant for silencing. In addition to further
Histone replacement ? describing functional states, the focus of research will
Aminotransferase ?
Current Opinion in Cell Biology
likely shift towards understanding how HMTs are
targeted. As small RNAs and ncRNA are required for
Propagation and resetting of methylation states. (a) During DNA histone methylation at constitutive heterochromatin and
replication, presumably unmethylated nucleosomes are deposited. Hp1 on the inactive X-chromosome, the putative role of
binds to the H3K9 methylated residue and also interacts with the Suv39h ncRNA for imprinting creates obvious excitement about
HMTs recruiting them in proximity to unmodified nucleosomes. (b) the involvement of RNA in targeting HMTases to sites
Replication-independent nucleosomal replacement can reset histone
methylation states through exchange. Since a distinct histone variant
of repression, potentially even at PREs of developmen-
(H3.3) is utilized, the inserted nucleosome could be an upstream tally regulated genes.
determinant of chromatin structure. (c) Enzymatic removal of arginine
methylation by PAD4. The HMT CARM1 can mono- or dimethylate The recent description of pathways that carry out rapid
arginine. Deimination of unmodified and monomethylated arginine by demethylation creates similar anticipation with regards to
PAD4 leads to citrulline (cit). To allow ‘remethylation’, citrulline would
have to be enzymatically converted or the nucleosome replaced.
resetting histone methylation states. With histone methy-
lation no longer viewed as stable, oscillations of gene
activity and rapid developmental reprogramming can
linked to the activation of hormone-responsive promo- coincide with dynamic chromatin methylation. If so,
ters. As citrulline is the end-product of the PAD4 demethylation could well be a pioneering event in epi-
reaction, histone exchange or an aminotransferase activity genetic reprogramming.

www.sciencedirect.com Current Opinion in Cell Biology 2005, 17:230–238


236 Cell regulation

Acknowledgements 15. Levine SS, King IF, Kingston RE: Division of labor in polycomb
group repression. Trends Biochem Sci 2004, 29:478-485.
We thank members of the Schübeler and Peters laboratories and
Robert Feil, Renato Paro, Leonie Ringrose, Mark Groudine and Bryan 16. Beisel C, Imhof A, Greene J, Kremmer E, Sauer F: Histone
Turner for helpful comments and clarifications. We apologize for the methylation by the Drosophila epigenetic transcriptional
absence of relevant recent observations and references due to space regulator Ash1. Nature 2002, 419:857-862.
limitations. This work was supported by the Novartis Research
Foundation. 17. Byrd KN, Shearn A: ASH1, a Drosophila trithorax group protein,
is required for methylation of lysine 4 residues on histone H3.
Proc Natl Acad Sci USA 2003, 100:11535-11540.
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Analyzing expression of the Ubx HOX gene in single and double mutants
 of special interest
for TrxG and PcG proteins, the authors show that the TRX and ASH1
 of outstanding interest HMTs are required throughout development to counteract the dominant
repressive function of PcG proteins.
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238 Cell regulation

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