M I N I R E V I E W
Mixed lineage leukemia: histone H3 lysine 4 methyltransferases from yeast to human Shivani Malik and Sukesh R. Bhaumik
Department of Biochemistry and Molecular Biology, Southern Illinois University School of Medicine, Carbondale, IL, USA
Keywords ASH1; ASH2; COMPASS; histone H3 lysine 4; histone methyltransferase; MLL; Set1; TAC1; TRX; WDR5
Correspondence S. R. Bhaumik, Department of Biochemistry and Molecular Biology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA Fax: +1 618 453 6440 Tel: +1 618 453 6479 E-mail: sbhaumik@siumed.edu
The fourth lysine of histone H3 is post-translationally modified by a methyl group via the action of histone methyltransferase, and such a covalent modification is associated with transcriptionally active and ⁄ or repressed chromatin states. Thus, histone H3 lysine 4 methylation has a crucial role in maintaining normal cellular functions. In fact, misregulation of this covalent modification has been implicated in various types of cancer and other diseases. Therefore, a large number of studies over recent years have been directed towards histone H3 lysine 4 methylation and the enzymes involved in this covalent modification in eukaryotes ranging from yeast to human. These studies revealed a set of histone H3 lysine 4 methyltransfe- rases with important cellular functions in different eukaryotes, as discussed here.
(Received 16 November 2009, revised 12 January 2010, accepted 22 January 2010)
doi:10.1111/j.1742-4658.2010.07607.x
Introduction
DNA-transacting processes such as transcription, repli- cation, recombination and DNA repair. However, the chromatin structure has to be dynamic in nature in order for DNA-transacting processes to occur [5–10], and such dynamic states are regulated by ATP-depen- dent chromatin remodelers as well as by ATP-indepen- dent histone covalent modifications.
The DNA in eukaryotes is compacted in the form of chromatin. The fundamental unit of chromatin is the nucleosome which consists of a core histone particle with 146 bp of DNA wrapped around it [1,2]. The core histone particle comprises a tetramer of histones H3 and H4 and dimers of histones H2A and H2B [2]. Each of these histones has a structured core globular domain and an unstructured flexible N-terminal tail protruding from the core domain. The linker histone H1 associates with the core domain to form a higher order structure, thus further compacting the DNA [3,4]. Such compac- tion of DNA in a higher order chromatin structure makes it inaccessible for proteins involved in different
There are several ATP-dependent chromatin remo- delers. These include the switching–defective ⁄ sucrose non-fermenting (SWI ⁄ SNF), imitation switch (ISW1), nucleosome remodeling and histone deacetylation (Mi-2 ⁄ NuRD), and INO80 complexes [11–25]. These complexes have a catalytic ATPase subunit with
Abbreviations ASH1, absent, small or homeotic discs 1; ASH2, absent, small or homeotic discs 2; BRM, brahma; CBP, CREB-binding protein; EcR, ecdysone receptor; HAT, histone acetyl transferase; H3K4, histone H3 lysine 4; HMT, histone methyltransferase; MLL, mixed lineage leukemia; MOF, male absent on the first; Paf1, RNA polymerase II-associated factor 1; PcG, polycomb group; PHD, plant homeodomain; TAC1, trithorax acetylation complex 1; TRR, trithorax-related; TRX, trithorax.
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1805
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
DNA-dependent ATPase activity. ATP-independent histone covalent modifications are acetylation, phos- phorylation, ubiquitylation, methylation, sumoylation and ADP ribosylation [8,10,26–33]. Although most of these modifications occur on the N-terminal tails of
histones, some also occur on the C-terminal tails of histones H2A and H2B [29,30,34] and the core region of histone H3 [30,31,35,36]. These covalent modifica- tions have profound effects on chromatin structure and hence gene regulation [5,8,9,30,33].
A
s n o
Gene activation, telomeric silencing & DNA repair
i t c n u F
Gene activation & silencing, splicing, & DNA repair
Hetero- chromatin formation & silencing
Hetero- chromatin formation & silencing
Inhibition of intragenic transcription & hetero- chromatin spreading, & regulation of transcriptional elongation
me
me
me
me
me
79
N-A R T K ... R K S T ... K ... R K ... K ... R K S ... K...
...-C
.....K H3
9
4
14
18
23
27
36
Dot1 (Sc) Dot1 (Sp) DOT1L (Hs)
l
i
Set2 (Sc) Set2 (Sp) Set2 (Dm) ASH1 (Dm) NSD1 (Hs) SETD2/HYPB (Hs)
MES-2 (Ce) E (Z) (Dm) G9a (Dm) EZH2 (Hs) EZH1 (Hs) G9a (Hs)
e n s y L
s e s a y h t e m
Clr4 (Sp) SU(VAR)3-9 (Dm) G9a (Dm) ASH1 (Dm) Eu-HMTase 1 (Hs) SUV39 H1 (Hs) SUV39 H2 (Hs) G9a (Hs) ESET or SETDB1 (Hs)
Set1 (Sc) Set1 (Sp) SET1 (Ce) TRX (Dm) ASH2 (Dm) TRR (Dm) ASH1 (Dm) ASH1 (Hs) MLL 1-4 (Hs) SET1A (Hs) SET1B (Hs) SMYD3 (Hs) SET7/9 (Hs) Meisetz (Hs)
B
Heterochromatin formation & silencing
s n o i t c n u F
me
N-S G R G K G G K G L G K G G A K R H R K V...
...-C
H4
8
5
12
16
20
l
i
e n s y L
Set9 (Sp) Pr-SET7 (Dm) ASH1 (Dm) SUV4-20 (Hs) Pr-SET7/SET8 (Hs)
s e s a y h t e m
Fig. 1. Methylation of different lysine (K) residues of histones H3 (A) and H4 (B) with associated methylases and functions in genome expression and integrity. Sc, Saccharomyces cerevisiae; Sp, Schizosaccharomyces pombe; Ce, Caenorhabditis elegans; Dm, Drosophila melanogaster; Hs, Homo sapiens.
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1806
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
factor 1
(Paf1)
[33,49,51,54,55], and the
(fission
The lysine (K) residues of histones H3 and H4 can be mono-, di- and trimethylated, and such methylation is associated with active and ⁄ or repressed chromatin (Fig. 1). Thus, histone methylation is linked to diverse cellular regulatory functions [27,30,31,33]. Indeed, sev- eral studies have implicated histone methylation in var- ious types of cancer and other diseases [30,33,37–39]. Therefore, a large number of studies over several years have focused on histone methylation at different K residues and the enzymes involved in this covalent modification in diverse eukaryotes [27,30,31,33,40–45]. These studies have revealed several histone meth- yltransferases (HMTs) involved in the K methylation of histones H3 and H4 with crucial roles in maintain- ing normal cellular functions in eukaryotes ranging from yeast to humans (Fig. 1). Here, we discuss his- tone H3 lysine 4 (H3K4) methylation and the HMTs involved in this covalent modification, highlighting the similarities and differences in several eukaryotes such as Saccharomyces cerevisiae (budding yeast), Schizosac- charomyces pombe yeast), Caenorhabditis (roundworm), Drosophila melanogaster elegans (fruit fly), Mus musculus (mouse) and Homo sapiens (human).
di- and trimethylation of histone H3 at K4 [29,30,33, 48,49]. Set1 is enzymatically active only when assem- bled into the multi-subunit COMPASS complex. The ability of COMPASS to mono-, di- and trimethylate K4 of histone H3 depends on its subunit composition. For example, COMPASS lacking Cps60 ⁄ Bre2 cannot trimethylate K4 of histone H3, whereas the Cps25 subunit of COMPASS is essential for histone H3 K4 di- and trimethylation [29,33,49,50]. The COMPASS complex preferentially associates with RNA polymer- ase II which is phosphorylated at Ser 5 in its C-termi- nal domain at the onset of transcriptional elongation [33,49,51–54]. The interaction between COMPASS and RNA polymerase II is further facilitated by the RNA polymerase II-associated complex which associates with the coding sequence in an RNA polymerase II-dependent manner during transcriptional elongation [33,49,51–54]. Thus, COMPASS is found to be predominantly associated with the coding sequences of active genes coding sequences of the actively transcribing genes are there- fore trimethylated at the K4 of histone H3 [33,51,54– 58].
H3K4 methylation and HMTs in Saccharomyces cerevisiae
cross-talk
and
Cps25 ⁄ Sdc1
In S. cerevisiae, H3K4 methylation is involved in the stimulation of transcription [29–31,33]. Further, H3K4 methylation in S. cerevisiae has been implicated in silencing at telomeres, ribosomal DNA and the mat- ing-type locus [30,33,46,47]. Thus, H3K4 methylation participates in both gene activation and repression. The enzyme responsible for this covalent modification was first identified in a multiprotein complex, named COMPASS, in S. cerevisiae [48]. COMPASS consists of the catalytic subunit, Set1, and seven other proteins (Cps60 ⁄ Bre2, Cps50 ⁄ Swd1, Cps40 ⁄ Spp1, Cps35 ⁄ Swd2, Cps30 ⁄ Swd3, Cps15 ⁄ Shg1) (Tables 1–3) [29,33,48,49]. Set1 is essential for mono-,
Interestingly, the methyltransferase activity of the COMPASS complex is intimately regulated by ubiqui- tylation of histone H2B at K123 [30,33,59–63]. Both di- and trimethylation of histone H3 at K4 are impaired in the absence of histone H2B K123 ubiqui- tylation, which is catalyzed by E2 ubiquitin conjugase and E3 ubiquitin ligase, Rad26 and Bre1, respectively. However, histone H2B K123 ubiquitylation does not regulate H3K4 monomethylation [33,62,64]. Such a trans-tail histone H2B K123 between ubiquitylation and H3K4 di- and trimethylation is mediated via alteration of the subunit composition of COMPASS [33,55]. It was recently demonstrated that histone H2B K123 ubiquitylation is essential for the recruitment of Cps35 ⁄ Swd2 independent of Set1 [33,55]. Set1 maintains the structural integrity of the [33,55]. COMPASS without COMPASS complex
Table 1. The histone H3 lysine 4 methyltransferases in different eukaryotes (references are cited in the text).
Saccharomyces cerevisiae
Schizosaccharomyces pombe
Caenorhabditis elegans
Drosophila
Mammals (mouse and human)
Set1C
COMPASS-like complex
COMPASS ⁄ Set1C
TAC1 ASH1 ASH2 TRR
MLL1 MLL2 MLL3 MLL4 SET1A SET1B SET7 ⁄ 9 SMYD3 ASH1 Meisetz
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1807
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
Table 2. The components of characterized histone H3 lysine 4 methyltransferase complexes in different eukaryotes (references are cited in the text).
Saccharomyces cerevisae
Schizosaccharomyces pombe
Caenorhabditis elegans
Drosophila
Mammals
COMPASS-like complex SET-2 ⁄ SET1 ASH2 ⁄ Y17G7B.2 CFPL-1 SWD-3 SWD-2 ⁄ C33H5.6 SPP-1 ⁄ F52B11.1 DPY-30
Set1C Set1 Ash2 Swd1 Spp1 Swd2 Swd3 Sdc1 Shg1
COMPASS ⁄ Set1C Set1 Cps60 ⁄ Bre2 Cps50 ⁄ Swd1 Cps40 ⁄ Spp1 Cps35 ⁄ Swd2 Cps30 ⁄ Swd3 Cps25 ⁄ Sdc1 Cps15 ⁄ Shg1
TAC1 TRX CBP SBF1 ASH1 ASH1 ? ASH2 ASH2 ? TRR TRR ?
MLL1 MLL1 ASH2L WDR5 RBBP5 DPY-30 HCF1 ⁄ HCF2 Menin MOF MLL2 MLL1 ASH2L WDR5 RBBP5 DPY-30 Menin HCF2 RPB2 MLL3 ⁄ MLL4 MLL3 ⁄ MLL4 ASH2L WDR5 RBBP5 DPY-30 NCOA6 PA1 PTIP UTX SET1A ⁄ SET1B SET1A ⁄ SET1B ASH2L WDR5 RBBP5 WDR82 ⁄ SWD2a CFP1 ⁄ CGBPa DPY-30 HCF1
a Wdr82 and CFP1 ⁄ CGBP are present in human SET1A and SET1B complexes, but not in mouse [117,165,166].
K123 ubiquitylation. Further, H3K4 methylation is controlled by a demethylase with the Jumonji C (JmjC) domain, namely Jhd2, which specifically deme- thylates the trimethylated K4 of histone H3 (Table 4) [65]. Such demethylation provides an additional level of regulation of H3K4 methylation in S. cerevisae.
H3K4 methylation and HMTs in Schizosaccharomyces pombe
Although the first H3K4 methyltransferase was identified in S. cerevisiae, the chromatin structure in S. cerevisiae is not similar to that of Sch. pombe or higher eukaryotes. For example, S. cerevisiae lacks
Cps35 ⁄ Swd2 is consistently recruited to the coding sequence of the active gene in an RNA polymerase II- dependent manner in the absence of histone H2B K123 ubiquitylation [33,55]. COMPASS without Cps35 ⁄ Swd2 monomethylates K4 of histone H3, but does not have catalytic activity for di- and trimethyla- tion of histone H3 at K4 [33,55]. When histone H2B is ubiquitylated by the combined actions of Rad26 and Bre1, it recruits Cps35 ⁄ Swd2, which interacts with the rest of COMPASS recruited by elongating RNA poly- merase II. Such interaction leads to the formation of a fully active COMPASS capable of H3K4 mono-, di- and trimethylation [33,55]. Thus, H3K4 methylation is regulated by upstream factors involved in histone H2B
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1808
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
Table 3. Homologous subunits of histone H3 lysine 4 methyltransferase complexes in different eukaryotes (references are cited in the text).
Saccharomyces cerevisiae
Schizosaccharomyces pombe
Caenorhabditis elegans
Drosophila
Mammals
TRX ASH2
WDR5
SET-2 ⁄ SET1 ASH-2 CFPL-1 SWD-3 SWD-2 SPP-1 DPY-30
MLL1-4, SET1A ⁄ SET1B ASH2L ⁄ ASH2 RBBP5 WDR5 WDR82 ⁄ SWD2 CFP1 DPY-30
Set1 Ash2 Swd1 Swd3 Swd2 Spp1 Sdc1 Shg1
Set1 Cps60 ⁄ Bre2 Cps50 ⁄ Swd1 Cps30 ⁄ Swd3 Cps35 ⁄ Swd2 Cps40 ⁄ Spp1 Cps25 ⁄ Sdc1 Cps15 ⁄ Shg1
ASH1L ⁄ ASH1
ASH1 TRR
Menin; HCF1 ⁄ HCF2; NCOA6; PA1; PTIP; UTX; MOF; SET7 ⁄ 9; SMYD3; Meisetz
Table 4. Histone H3 lysine 4 demethylases in different eukaryotes (references are cited in the text). me3, trimethyl; me2, dimethyl; me3 ⁄ 2, tri- and dimethyl; and me2 ⁄ 1, di- and monomethyl.
Saccharomyces cerevisae
Schizosaccharomyces pombe
Caenorhabditis elegans
Drosophila
Mammals (mouse and human)
Jhd2 (me3)
Lid (me3)
Swm1 (me2) Swm2 (me2)
SPR-5 (me2) T08D10.2 (me2) R13G10.2 (me2)
LSD1 (me2 ⁄ 1) JARID1A (me3 ⁄ 2) JARID1B (me3 ⁄ 2) JARID1C (me3 ⁄ 2) JARID1D (me3 ⁄ 2)
homologs of the repressive histone H3K9 methyltransfe- rases and the heterochromatin proteins (e.g. HP1) present in Sch. pombe or higher eukaryotes [66–68]. Thus, Sch. pombe serves as a better eukaryotic model system to study the roles of H3K4 methylation in regulation of chromatin structure and gene expression. As in S. cerevisae, H3K4 methylation in Sch. pombe is catalyzed by a SET domain-containing protein, Set1. The Sch. pombe Set1 protein is homologous to S. cerevi- siae Set1. Set1 proteins in budding and fission yeasts share a high degree of similarity in their SET domains. However, these two proteins exhibit 26% sequence iden- tity overall [69]. The N-termini of Set1 in S. cerevisae and Sch. pombe are considerably different [69–71]. Such difference might have crucial roles in governing the specific functions of Set1 in S. cerevisae and Sch. pombe. For example, a recombinant Sch. pombe Set1 methylates K4 in a 20-amino acid peptide corresponding to the tail of histone H3 in vitro. By contrast, N-terminal recombinant S. cerevisae Set1 does not have methyl- transferase activity in vitro. Further, phylogenetic analy- sis indicates that Sch. pombe Set1 is more closely related to human Set1 than to S. cerevisae Set1 [69]. Sch. pombe Set1 mutants have slow growth, exhibit temperature- sensitive growth defects and have a slightly longer dou- bling time compared with wild-type cells [69].
DNA sequence analysis reveals that homologs of the components of S. cerevisae COMPASS are also pres- ent in Sch. pombe. Indeed, Set1 methyltransferase com- plex (Set1C) has been purified in Sch. pombe, which shares many features of S. cerevisae COMPASS (Tables 1–3). However, these two complexes differ in several ways. For example, the Ash2 component of Set1C in Sch. pombe has a plant homeodomain (PHD) finger domain, whereas the homologous protein, in S. cerevisae does not [70]. Cps60 ⁄ Bre2 (Table 3), The Cps40 ⁄ Spp1 component (that bears the PHD fin- ger domain) is required for methylation in Sch. pombe, but not in S. cerevisae [70]. Furthermore, Set1C in Sch. pombe shows a hyperlink to Lid2C (little imaginal discs 2 complex) through Ash2 and Sdc1 [70]. How- ever, such a hyperlink is absent in S. cerevisae. In addition, the identified hyperlink, Swd2 (which is also a subunit of the cleavage and polyadenylation factor) in S. cerevisae COMPASS is not found in Sch. pombe [70–72]. Together, these observations support the fact that the Set1 HMTs from S. cerevisae and Sch. pombe are highly conserved (Tables 1–3), but their proteomic environments appear to differ. However, such differ- ences in the proteomic environments may be related to the absence of histone H3 K9 methylation in S. cerevi- siae, as suggested previously [70].
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1809
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
have revealed that SET-2 (also known as SET- 2 ⁄ SET1) forms a complex with SWD-3, CFPL-1, DPY-30, Y17G7B.2 ⁄ ASH-2, C33H5.6 ⁄ WDR82 ⁄ SWD- 2 and F52B11.1 ⁄ SPP-1 (Tables 1 and 2) [78]. These proteins are homologous to the budding yeast COM- PASS (Table 3). Thus, as in S. cerevisae, SET-2 ⁄ SET1 in C. elegans forms a COMPASS-like complex. Fur- like in fission yeast, SET-2 ⁄ SET1 may be thermore, is homologus to hyperlinked to the complex that Sch. pombe’s Lid2C-containing Sdc1. In support of this notion, DPY-30 in C. elegans was found to be the homolog of fission yeast Sdc1 (Table 3), and it plays an important role in dosage compensation [79]. Thus, it is likely that SET-2 ⁄ SET1 in C. elegans is connected to another complex via DPY-30, which remains to be elucidated.
As in yeast, the subunits of
H3K4 methylation is correlated with active chroma- tin in Sch. pombe [69], as in S. cerevisae. However, unlike in S. cerevisiae, H3K4 methylation is not required for silencing and heterochromatin assembly at the centromeres and mating type locus in Sch. pombe [69], possibly because of the presence of repressive histone H3 K9 methylation in Sch. pombe [69]. Fur- thermore, previous studies [69] have demonstrated that H3K4 methylation is correlated with histone H3 acety- lation in Sch. pombe, and hence is associated with active genes. However, transcriptional stimulation by H3K4 methylation is also closely regulated by histone demethylase, LSD1, which is absent in S. cerevisae. LSD1 is an amine oxidase which demethylates the K residue in a FAD-dependent manner. Because it functions through oxidation, it can only demethylate mono- and dimethylated K4 of histone H3. There are two LSD1-like proteins, namely Swm1 and Swm2 in Sch. pombe (after SWIRM1 and SWIRM2), (Table 4) [73,74] which form a complex and are involved in the demethylation of methylated K4 and K9 of histone H3. Such a demethylation process has important roles in the regulation of chromatin struc- ture and hence gene expression.
level of
residual
H3K4 methylation and HMTs in Caenorhabditis elegans
the COMPASS-like complex in C. elegans differentially regulate global H3K4 methylation [78]. For example, no decrease in the global level of H3K4 methylation was observed upon RNAi-based depletion of swd-2 [78]. A moderate decrease in H3K4 methylation was observed in the set-2, absence of Y17G7B.2 ⁄ ASH-2. Depletion of swd-3, cfpl-1 and dpy-30 led to a drastic decrease in global H3K4 methylation, with the most severe defect observed in swd-3 mutants. However, unlike in yeast, the global H3K4 methylation was observed in the absence of SET-2 ⁄ SET1 activity [78]. This observation suggests that additional H3K4 methyltransferase(s) may exist in C. elegans.
in
an
has
role
important
two other proteins
Although H3K4 methylation is associated with active transcription in C. elegans, it is reset during gametogenesis. A demethylase, SPR-5, has recently been identified in C. elgans, and it shows 45% similar- ity with human LSD1 [80]. SPR-5 is responsible for demethylation of dimethylated K4 of histone H3 (Table 4). It interacts with the (co)repressor for ele- ment-1-silencing transcription factor repressor protein, SPR-1 [81–83]. Such an interaction is correlated with the repressive role of SPR-5 in gene regulation. Like in C. elegans, namely SPR-5, T08D10.2 and R13G10.2, have a LSD1-like amine oxi- dase domain, as revealed by the NCBI Conserved Domain Search Program (Table 4) [84]. Knockdown of T08D10.2 by RNAi extends the longevity, thus implicating the role of histone methyaltion in regula- tion of aging [85].
C. elegans is a multicellular, yet simple, eukaryotic sys- tem with technical advantages for studying the chro- matin structure in greater detail. Thus, C. elegans can serve as a model system to understand the role of histone covalent modifications in developmental pro- cesses. As in S. cerevisae and Sch. pombe, H3K4 meth- ylation promoting transcription in C. elegans [75]. However, early C. ele- gans embryos have a transcriptionally repressed chro- matin state, even though both di- and trimethylation of histone H3 at K4 are present in the chromatin of the germline blastomere [75]. Such repression perhaps results from the lack of Ser 2 phosphorylation in the C-terminal domain of the largest RNA polymerase II subunit in the germline cells [76]. Following division of the germline lineage P4 cells into the primordial germ cells, H3K4 methylation is lost [75]. However, H3K4 methylation is regained prior to postembryonic prolif- eration. Such covalent modification activates gene expression in the postembryonic germ cells [75,77].
Although studies in C. elegans have been quite help- ful in understanding the role of H3K4 methylation in gene expression and development, the pattern of cell lineage in C. elegans is highly invariant [86]. However, the development of embryos of Drosophila and mam- mals largely relies on cellular cues, thus making it a
The enzyme involved in H3K4 methylation in C. ele- gans was identified recently via an RNAi screen of the suppressors of heterochromatin protein mutants (hpl-1 and hpl-2). The RNAi screen identified set-2 as the homolog of yeast SET1 [78]. Further, several studies
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1810
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
more complex process. Therefore, studies in Drosophila will provide a better understanding of the regulatory roles of H3K4 methylation in gene expression and development.
H3K4 methylation and HMTs in Drosophila
[94,104] which are associated with active transcription. The components of TAC1 are found to be associated with specific sites on salivary gland polytene chromo- including Hox genes [104], and thus exist somes, together in vivo. Mutations in either trx or the gene encoding CBP reduce the expression of a Hox gene, namely Ultrabithorax (Ubx) [104]. Thus, the two differ- ent enzymatic activities of TAC1 are closely linked to Hox gene expression [104]. Moreover, the HAT activ- ity of TAC1 may be counteracted by the deacetylase activity of the PcG complex, ESC ⁄ E(Z), accounting in part for the antagonistic functions of the trxG and PcG protein complexes on chromatin. Unlike its role in the regulation of Hox gene expression, TAC1 also promotes transcription of heat shock genes in a differ- ent mechanism through activation of poised or stalled RNA polymerase II. Heat shock genes are rapidly expressed by heat shock factor and other transcription factors [94,105]. TAC1 is recruited to several heat shock gene loci following heat induction, and conse- quently, its components are required for heat shock gene expression [94,105]. Smith et al. [94] demonstrate that TAC1 associates with transcription-competent stalled RNA polymerase II at the heat shock gene, and subsequently modifies histone H3 by methylation and acetylation. Such modifications of histone H3 facilitate stalled RNA polymerase II to begin transcriptional elongation [94,105]. In contrast to the results at heat shock genes, poised or stalled RNA polymerase II is not found at the Hox genes [94,105]. Thus, TAC1 appears to regulate the transcription of Hox and heat shock genes in distinct pathways.
two other
In addition to TRX,
Drosophila has long been a model organism for studying developmental processes, because development in humans and Drosophila are homologous processes. Dro- sophila and humans share a number of related develop- mental genes working in conserved pathways. Studies analyzing the interplay of the SET domain-containing trithorax group (trxG) and polycomb group (PcG) pro- teins in regulating transcription patterns during develop- ment and differentiation have been an area of extensive research in Drosophila [87–91]. PcG and trxG proteins play a crucial role in the epigenetic control of a large including the Hox number of developmental genes, (Homeotic) genes [92–99]. Hox are a cluster of genes that defines the anterior–posterior axis and segment identity during early embryogenesis. The expression pat- tern of the Hox genes is established early in development and is propagated in appropriate cell lineages [100]. However, transcription of Hox genes is closely regulated by the antagonistic actions of PcG and trxG proteins through different patterns of histone methylation. The PcG protein, E(Z), methylates histone H3 at K27 [100]. Further, histone H3 methylated at K27 is recognized by a chromodomain-containing PcG protein, PC [100]. These events repress Hox and other target genes. How- ever, the trxG proteins such as trithorax (TRX) and absent, small or homeotic discs 1 (ASH1) are H3K4 methyltransferases which promote transcription of the target genes including Hox [100]. Thus, a close interplay between the specific PcG and trxG proteins maintains a tight regulation of Hox gene expression. Consistently, genetic studies in Drosophila have revealed that muta- tions in specific PcG and trxG genes result in flies with homeotic transformations because of the misregulation of Hox genes [100–103].
acetylation complex
called trithorax
trxG proteins, namely ASH1 and ASH2, methylate K4 of histone H3 [106–110]. Mutations in the Ash1 and Ash2 genes gen- erate abnormal imaginal discs in flies [106–110], consis- tent with their roles in the regulation of Hox gene expression. Amorphic and antimorphic mutations in the Ash1 gene lead to a drastic decrease in the global level of H3K4 methyaltion [106–110]. The catalytic domain of ASH1 is 588 amino acids long, and com- prises the SET domain and cysteine-rich pre-SET and post-SET domains [106,107]. However, biochemical studies demonstrate that the 149-amino acid SET domain alone can methylate histone H3 at K4 in vitro [107]. ASH1 also contains a PHD finger, and a bromo-associated homology domain [111]. The bromo- associated homology domain of ASH1 might be responsible for protein–protein interactions during chromatin remodeling at the target genes. ASH1 is an integral component of a large 2 MDa complex [112]. In addition to H3K4 methylation, the ASH1 complex also methylates K9 of histone H3 and K20 of
As mentioned above, TRX is a member of the trxG proteins with H3K4 methyltransferase activity in Drosophila, and it contains SET and PHD finger domains. TRX is the homolog of yeast Set1 in Dro- sophila, and is an integral component of a 1 MDa complex, 1 (TAC1). TAC1 consists of TRX, CREB-binding pro- tein (CBP) and an anti-phosphatase SBF1 (Tables 2 and 3) [104]. Like mammalian CBP, Drosophila CBP has histone acetyl transferase (HAT) activity [104]. Thus, TAC1 possesses both HMT and HAT activities
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1811
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
histone H4 [106,107]. Recently, Tanaka et al. [113] implicated ASH1 in methylation of histone H3 at K36. Apart from its role in histone methylation, ASH1 is also linked to histone acetylation via its interaction with CBP [114] which is an integral component of TAC1. Thus, ASH1 and TAC1 appear to have com- mon roles via CBP.
three distinct complexes,
Like ASH1, ASH2 is present in a 500 kDa complex [112]. ASH2 has been proposed to be the associated form of Bre2 and Spp1 of S. cerevisae COMPASS [48,71,115]. In mammals, ASH2 is a shared component of different complexes including a HMT bound by host cell factor 1 (HCF-1), Menin-containing complex and the COMPASS counterpart [116–120], indicating that it might be involved in the regulation of many dif- ferent processes. However, its role in histone methyla- tion is not known. Recently, Steward et al. [121] demonstrated that ASH2 in mammalian system has an important role in H3K4 trimethylation. Consistent with this observation, Beltran et al. [122] observed a severe reduction in H3K4 trimethylation in ash2 mutants. This observation indicates that ASH2 might play a crucial role in H3K4 methyltransferase activity. However, ASH2 does not contain a SET domain, but it has the PHD finger and SPRY domains [123]. In addition to its role in H3K4 methylation, ASH2 is also linked to histone deacetylation through its interaction with Sin3A, a histone deacetylase [116]. Further, ASH2 has been implicated in the regulation of cell- cycle progression via its interaction with HCF-1 [116].
the BRM complex [128]. Together,
H3K4 methylation functions as a platform for the binding of different chromatin remodelers. One such remodeler is the BRM complex which contains at least seven proteins [112]. Three components of the BRM complex are trxG proteins. These are BRM (brahma), Osa and Moira. However, these trxG protein compo- nents of the BRM complex do not have the SET domain as well as HMT activity. The BRM complex is the homolog of the yeast SWI ⁄ SNF complex, and shares four components including the ATPase BRM [112]. BRM also contains a high-mobility-group B pro- tein, namely BAP111, which binds nonspecifically to the minor groove of the double-helix and bends the DNA [125,126]. The BRM complex has ATP-depen- dent chromatin-remodeling activity. Mutations in ash1 enhance brm mutations, suggesting that they might be functioning together [110]. Consistent with this obser- vation, Beisel et al. [106] demonstrated that epigenetic activation of Ubx transcription coincides with H3K4 trimethylation by ASH1 and recruitment of the BRM complex. Similarly, mutations of ash2 and brm cause developmental defects in adult sensory organs includ- ing campaniform sensilla and mechanosensory bristles [108,127]. Thus, although ASH1, ASH2 and BRM are the components of they appear to function in concert to regulate transcription. Furthermore, the H3K4 methyltransferase activity of TAC1 has been implicated to be linked to the BRM complex [112,128]. Such linkage is mediated by the interaction of TRX of TAC1 with the SNR1 compo- nent of these results indicate that H3K4 methylation and ATP- dependent chromatin remodeler, BRM, function in a to regulate transcription. Apart concerted manner from the BRM complex, two other chromatin remo- delers, namely nucleosome remodeling factor and ATP-utilizing chromatin assembly and remodeling fac- tor, have been implicated in transcriptional stimulation through their binding to methylated-K4 of histone H3 which is mediated by TRX or other HMTs [100]. Both nucleosome remodeling factor and ATP-utilizing chro- matin assembly and remodeling factor are ATP-depen- dent remodelers and carry ISW1 as an ATPase subunit [100]. Thus, the HMTs mark a modification pattern on histone H3 at K4 that is ‘read’ by chromatin remodel- ers which, in turn, regulate the chromatin structure and hence gene expression.
Apart
Like trxG proteins, a trithorax-related (TRR) protein in Drosophila is also involved in the methylation of his- tone H3 at K4 [124]. TRR contains the SET domain, and has H3K4 methyltransferase activity [124]. TRR functions upstream of hedgehog (hh) in the progression of the morphogenic furrow [124]. It also participates in retinal differentiation [124]. TRR and trimethylated his- tone H3 at K4 are detected at the ecdysone-inducible promoters of hh and BR-C (broad complex) [124]. Ecdysone functions through binding to a nuclear recep- tor, ecdysone receptor (EcR), which heterodimerizes with the retinoid X receptor homolog ultraspiracle. The heterodimer is then recruited to the promoters of the target genes to regulate their expression, and hence ecdysone triggers molting and metamorphosis. Thus, the association of EcR along with TRR and H3K4 the hh and BR-C methylation is also observed at promoters following ecdysone treatment in cultured cells [124]. Consistent with these observations, H3K4 methylation is decreased at these promoters in embryos lacking functional TRR [124]. Thus, TRR appears to function as a coactivator at the ecdysone-responsive promoters by modulating the chromatin structure.
from H3K4 methyltransferase and ATP- dependent chromatin remodeling activities, trxG pro- tein is also involved in histone demethylation. Recent studies [129,130] have demonstrated that a trxG pro- tein, namely Lid, contains a JmjC domain and other found in mammalian Jumonji, functional domains
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1812
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
these,
AT-rich interactive domain 1 (JARID1) proteins. Lid has demethylase activity which can demethylate the trimethylated form of histone H3 at K4 (Table 4). Such demethylase activity of the trxG protein adds an layer to gene regulation by the PcG and additional trxG proteins. Further, Lid interacts with the proteins associated with heterochromatin formation such as H3 K9 methyltransferase [Su(var)3-9], heterochromatin protein (HP1) and deacetylase (RPD3). Thus, Lid plays crucial roles in removing the activation marks, hence facilitating gene silencing.
The role of H3K4 methylation and its regulation in Drosophila is largely conserved in mammals. However, the complexity of mammals demands a more intricate mechanism of regulation in determining the cell lin- eages and developmental fates. Thus, a large number of studies have focused on H3K4 methylation and HMTs, and their roles in gene regulation with implica- tions for development in mammals. Below we discuss H3K4 methyltransferases and H3K4 methylation in mouse and humans with their regulatory roles in gene expression.
H3K4 methylation and HMTs in mouse and humans
multiple genes with the intergenic regions are observed at HOX gene clusters in mouse and humans [132]. Unlike in yeast, which has just one H3K4 methyltrans- ferase, mammals have at least 10 (Table 1) [33,133– six members containing the SET 138]. Of domain (MLL1, MLL2, MLL3, MLL4, SET1A and SET1B) belong to the mixed lineage leukemia (MLL) family bearing homology to yeast Set1 and Drosophila TRX (Tables 2 and 3) [30,33,49,133,134]. Other H3K4 methyltransferases identified are ASH1, SET7 ⁄ 9, SMYD3 and a meiosis-specific factor, Meisetz [33,133– 138]. The presence of several HMTs in humans might be because of the role of different HMTs at different developmental stages in determining cell fate. The MLL family of HMT proteins has an important role in regulating HOX gene expression. This is particularly significant because deregulation of HOX genes is asso- ciated with leukemia via rearrangements in the MLL1 gene. In addition to HOX genes, MLL1 also targets non-HOX genes like p27 and p18 [139]. Interestingly, deletions or truncations in MLL1, MLL2 and MLL3 in mice [140–144]. For have different phenotypes example, deletion of MLL1 shows misregulation in a number of HOXA genes, including HOXA1 [140–143], whereas MLL2 controls expression of HOXB2 and HOXB5, and loss of MLL3 causes severe growth retar- dation and widespread apoptosis [141–143]. Thus, MLL1, MLL2 and MLL3 appear to have nonredun- dant functions.
significant H3K4 methylation is
As is true for yeast and other eukaryotes, MLL fam- ily HMTs are assembled into multi-subunit complexes (Table 2). These complexes have three common subun- its, WD repeat domain 5 (WDR5), retinoblastoma binding protein 5 (RBPB5) and Drosophila ASH2-like (ASH2L) [49,116,117,119,120,133,143] which form the core of the complex. MLL SET is active only when it associates with the core complex, a feature reminiscent of S. cerevisae COMPASS [145]. The WDR5 subunit of the MLL complex is essential for binding of MLL HMT to dimethylated-K4 of histone H3. It is also a key player in the conversion of di- to trimethylation of histone H3 at K4. Consistent with this observation, a reduced level of H3K4 trimethylation is observed following knockdown of WDR5. Consequently, HOX gene expression in human cells is decreased signifi- cantly in the absence of WDR5 [146]. Thus, WDR5 appears to play a crucial role in regulating the actitivi- ties of MLL HMTs.
Histones are among the most conserved proteins dur- ing evolution of eukaryotes. As discussed for other eukaryotes, roles of histone methylation in gene regu- lation and development are largely conserved in mam- mals. Genomic studies have revealed that both mouse and humans have (cid:2) 30 000 genes, and mouse has orthologs for 99% of human genes (Mouse Genome Sequencing Consortium, 2002). Given the close conser- vation between these two systems, we have reviewed progresses made towards H3K4 methylation and the corresponding HMTs in both mouse and humans. H3K4 trimethylation patterns in mammals are similar to yeast, and are associated with transcriptional start sites. H3K4 dimethylation, however, has a distinct dis- tribution pattern. Genomic mapping studies have revealed that H3K4 dimethylation overlaps with H3K4 trimethylation in the vicinity of active genes [131,132]. However, also observed at the inactive genes within b-globin locus. This observation suggests that H3K4 methylation may have important roles in maintaining the transcriptional ‘poised state’ [131], in addition to its role in transcrip- tional stimulation.
Although H3K4 methylation is usually localized to punctuate sites, a unique pattern of H3K4 methylation is found at the HOX gene cluster in mammals. Broad regions of continuous H3K4 methylation spanning
In addition to its role in H3K4 methylation, MLL complex interacts with a TATA-box binding protein transcription (TBP)-associated factor component of factor IID, components of E2F transcription factor 6 subcomplex, and MOF (a MYST family (E2F6)
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1813
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
expression of
at K27
histone acetyl transferase involved in histone H3 K16 acetylation) [147]. The interaction between the MLL1 complex and MOF is particularly interesting as both histone H3 K4 methylation and histone H4 K16 acety- lation are marks of active transcription, and hint towards the coordinated actions of histone H4 K16 acetylation and H3K4 methylation in transcriptional regulation. Indeed, it has been shown that MLL1 HMT and male absent on the first (MOF) HAT acti- vities are required for the proper expression of HoxA9 [145,147]. Further, the MLL3 ⁄ MLL4 complex coor- dinates H3K4 methylation with demethylation of its UTX subunit through histone H3 [49,133,134,148,149]. Furthermore, H3K4 methylation is coupled to histone deacetylation by the interaction of HMTs SET1 ⁄ ASH2 with SIN3 deacetylase [116]. Thus, HMTs in human appears to play diverse func- tions in regulation of gene expression, and hence development.
In addition to its role in mammalian development, H3K4 methylation also participates in the maintenance of pluripotency. It has been demonstrated that embry- onic stem cells maintain ‘bivalent domains’ of repres- sive (histone H3 K27 methylation) and activating (H3K4 methylation) marks. The bivalent domains silence developmental genes in embryonic stem cells while still preserving their ability to be activated in response to appropriate developmental cues [150]. However, bivalent domains are also maintained at other genes in fully differentiated cell types [151,152].
cated in leukemia; SMYD3 is overexpressed in colorec- tal cancer, liver, breast and cervical cancers; and the demethylase, LSD1, is overexpressed in prostate can- cer. The implication of HMTs and demethylases in cancer and human diseases has led to the idea of utiliz- ing them as therapeutic targets. In fact, biguanide and bisguanidine polyamine analogs inhibit the demethy- lase, LSD1, in human colon carcinoma cells. Inhibition the aberrantly of LSD1 facilitates silenced genes in cancer cells [156]. In addition to tar- geting a single enzyme, epigenetic therapy combining related proteins ⁄ pathways is a promising alternative. Thus, combinatorial therapy targeting HMTs, demeth- ylases, histone deacetylases, DNA methyltransferases and others may work efficiently in treating diseases caused by epigenetic misregulations. In fact, a combi- therapy targeting histone deacetylases and natorial DNA methyltransferases has been shown to have a synergistic role in gene regulation, and clinical trials have consistently yielded encouraging results [157–161]. Structural and functional studies have shown specific similarities and differences among the HMTs in diverse organisms. In mammals, the core components of the MLL complex, RBBP5, WDR5 and ASH2L, form a structural platform with which the catalytic SET1 can associate, whereas Set1 in S. cerevisiae is required for the integrity of the COMPASS complex. In S. cerevisi- ae, Cps60 ⁄ Bre2 does not interact directly with Cps50 ⁄ Swd1. However, in mammals their homologs RBBP5 and ASH2L interact strongly in the complex. These different interactions imply diverse regulatory mechanisms for the HMTs. This suggests that in higher eukaryotes, the core complex can be similar, but different subunits can associate with this core com- plex at different stages of cell development to provide HMT activity. Thus, there are several HMT complexes in higher eukaryotes dedicated to diverse cellular roles. Further, the C-terminal SET domain is invariant in different HMTs, although the N-terminal domains are divergent. This enables the HMTs to associate with a broad spectrum of proteins to ensure the downstream events. Given the increasing complexity in higher eukaryotes, the diversity of H3K4 HMTs is not sur- prising. However, the conservation of the fundamental SET domain in these HMTs is intriguing. In addition, many of the H3K4 HMTs share several domains ⁄ com- ponents, indicating a common mechanism of action.
Methylation is dynamically regulated by demethylas- es like LSD1 and JmjC domain-containing enzymes. Demethylase, LSD1, can demethylate mono- and dimethylated-K4 of histone H3 (Table 4). LSD1 has been shown to interact with repressors like (co)repres- sor for element-1-silencing transcription factor and activation complexes like MLL1. These observations implicated that MLL1 is involved in transcriptional activation as well as repression [33,49,153,154]. Deme- thylation of trimethylated-K4 of histone H3 is cata- lyzed by JmjC domain-containing proteins. Mammals have four JARID family members with the JmjC domain (Table 4). These are JARID1A or Rbp2, JARID1B or PLU-1, JARID1C or SMCX and JAR- ID1D or SMCY [33,155]. Both H3K4 methyltransfe- rases and demethylases function in a coordinated fashion to delicately regulate H3K4 methylation, and hence gene expression.
Concluding remarks
Studies in several eukaryotes demonstrate the conser- vation of H3K4 HMTs from yeast to humans. The roles of H3K4 methylation in gene regulation, chroma-
The significance of understanding regulation of H3K4 methylation is exemplified by the occurrence of cancers and other diseases following mutations of H3K4 methyltransferases and demethylases or their altered expression [33]. For example, MLL1 is translo-
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1814
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
8 Li B, Carey M & Workman JL (2007) The role of chromatin during transcription. Cell 128, 707–719. 9 Razin SV, Iarovaia OV, Sjakste N, Sjakste T, Bagdoni-
ene L, Rynditch AV, Eivazova ER, Lipinski M & Vassetzky YS (2007) Chromatin domains and regula- tion of transcription. J Mol Biol 369, 597–607.
10 Groth A, Rocha W, Verreault A & Almouzni G (2007) Chromatin challenges during DNA replication and repair. Cell 128, 721–733.
tin structure and development have been extensively investigated in a variety of organisms, and we are closer than ever to understanding the intricate regula- tory functions of H3K4 methylation and HMTs in gene expression [162–164]. However, several baffling questions remain. For example, why do mammals need several HMTs, whereas yeast survives with a sole HMT? How do different states (mono-, di- and trime- thylation) of H3K4 methylation translate into distinct biological cues? What signals the precise balance of methylation and demethylation in a cell? A deeper understanding of this important epigenetic mark will be helpful in the quest of drugs for treatment of disor- ders caused due to aberrations in this covalent modifi- cation.
11 Becker PB & Horz W (2002) ATP-dependent nucleo- some remodeling. Annu Rev Biochem 71, 247–273. 12 Gangaraju VK & Bartholomew B (2007) Mechanisms of ATP dependent chromatin remodeling. Mutat Res 618, 3–17.
Acknowledgements
13 Peterson CL (1996) Multiple SWItches to turn on chromatin? Curr Opin Genet Dev 6, 171–175.
14 Peterson CL (1998) SWI ⁄ SNF complex: dissection of a chromatin remodeling cycle. Cold Spring Harb Symp Quant Biol 63, 545–552. 15 Vary JC Jr, Gangaraju VK, Qin J, Landel CC, Koop-
(06-52)
We apologize to the authors whose work could not be cited owing to space limitations. The work in the Bhaumik laboratory was supported by a National (1R15GM088798-01), a Institutes of Health grant National Scientist Development Grant (0635008N) from American Heart Association, a Research Scholar Grant from American Cancer Society, a Mallinckrodt Foundation award, and several internal grants from Southern Illinois University.
erberg C, Bartholomew B & Tsukiyama T (2003) Yeast Isw1p forms two separable complexes in vivo. Mol Cell Biol 23, 80–91.
References
16 Deuring R, Fanti L, Armstrong JA, Sarte M, Papoulas O, Prestel M, Daubresse G, Verardo M, Moseley SL, Berloco M et al. (2000) The ISWI chromatin-remodel- ing protein is required for gene expression and the maintenance of higher order chromatin structure in vivo. Mol Cell 5, 355–365.
1 Kornberg RD (1977) Structure of chromatin. Annu Rev Biochem 46, 931–954.
2 Luger K, Mader AW, Richmond RK, Sargent DF & Richmond TJ (1997) Crystal structure of the nucleo- some core particle at 2.8 A˚ resolution. Nature 389, 251–260.
17 Racki LR & Narlikar GJ (2008) ATP-dependent chro- matin remodeling enzymes: two heads are not better, just different. Curr Opin Genet Dev 18, 137–144. 18 Tsukiyama T, Palmer J, Landel CC, Shiloach J & Wu C (1999) Characterization of the imitation switch sub- family of ATP-dependent chromatin-remodeling factors in Saccharomyces cerevisiae. Genes Dev 13, 686–697. 19 Feng Q & Zhang Y (2003) The NuRD complex: link- ing histone modification to nucleosome remodeling. Curr Top Microbiol Immunol 274, 269–290. 20 Bowen NJ, Fujita N, Kajita M & Wade PA (2004) 3 Kornberg RD & Lorch Y (1999) Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98, 285–294.
Mi-2 ⁄ NuRD: multiple complexes for many purposes. Biochim Biophys Acta 1677, 52–57. 21 Denslow SA & Wade PA (2007) The human Mi-
4 Woodcock CL, Skoultchi AI & Fan Y (2006) Role of linker histone in chromatin structure and function: H1 stoichiometry and nucleosome repeat length. Chromo- some Res 14, 17–25. 2 ⁄ NuRD complex and gene regulation. Oncogene 26, 5433–5438. 22 Kunert N & Brehm A (2009) Novel Mi-2 related
5 Berger SL (2002) Histone modifications in trans- criptional regulation. Curr Opin Genet Dev 12, 142–148. ATP-dependent chromatin remodelers. Epigenetics 4, 209–211.
23 Shen X, Mizuguchi G, Hamiche A & Wu C (2000) A chromatin remodelling complex involved in transcrip- tion and DNA processing. Nature 406, 541–544.
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1815
6 Bryk M, Briggs SD, Strahl BD, Curcio MJ, Allis CD & Winston F (2002) Evidence that Set1, a factor required for methylation of histone H3, regulates rDNA silencing in S. cerevisiae by a Sir2-independent mechanism. Curr Biol 12, 165–170. 7 Fischle W, Wang Y & Allis CD (2003) Histone and 24 Conaway RC & Conaway JW (2009) The INO80 chro- matin remodeling complex in transcription, replication and repair. Trends Biochem Sci 34, 71–77. chromatin cross-talk. Curr Opin Cell Biol 15, 172–183.
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
differentiation by histone methyltransferases and de- methylases. Cold Spring Harb Symp Quant Biol 73, 253–263.
43 Cloos PA, Christensen J, Agger K & Helin K (2008) Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev 22, 1115–1140. 25 Bao Y & Shen X (2007) INO80 subfamily of chroma- tin remodeling complexes. Mutat Res 618, 18–29. 26 Rice JC, Briggs SD, Ueberheide B, Barber CM, Shab- anowitz J, Hunt DF, Shinkai Y & Allis CD (2003) Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell 12, 1591–1598. 44 Lan F, Nottke AC & Shi Y (2008) Mechanisms
involved in the regulation of histone lysine demethylas- es. Curr Opin Cell Biol 20, 316–325. 27 Ehrenhofer-Murray AE (2004) Chromatin dynamics at DNA replication, transcription and repair. Eur J Bio- chem 271, 2335–2349. 28 Cosgrove MS & Wolberger C (2005) How does the his-
tone code work? Biochem Cell Biol 83, 468–476. 29 Shilatifard A (2006) Chromatin modifications by 45 Lan F & Shi Y (2009) Epigenetic regulation: methyla- tion of histone and non-histone proteins. Sci China C Life Sci 52, 311–322. 46 Krogan NJ, Dover J, Khorrami S, Greenblatt JF,
methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem 75, 243–269.
Schneider J, Johnston M & Shilatifard A (2002) COM- PASS, a histone H3 (lysine 4) methyltransferase required for telomeric silencing of gene expression. J Biol Chem 277, 10753–10755. 47 Santos-Rosa H, Bannister AJ, Dehe PM, Geli V & Ko- 30 Bhaumik SR, Smith E & Shilatifard A (2007) Covalent modifications of histones during development and dis- ease pathogenesis. Nat Struct Mol Biol 14, 1008–1016. 31 Kouzarides T (2007) Chromatin modifications and their function. Cell 128, 693–705. uzarides T (2004) Methylation of H3 lysine 4 at euchromatin promotes Sir3p association with hetero- chromatin. J Biol Chem 279, 47506–47512.
32 Kusch T & Workman JL (2007) Histone variants and complexes involved in their exchange. Subcell Biochem 41, 91–109.
48 Miller T, Krogan NJ, Dover J, Erdjument-Bromage H, Tempst P, Johnston M, Greenblatt JF & Shilatifard A (2001) COMPASS: a complex of proteins associated with a trithorax-related SET domain protein. Proc Natl Acad Sci USA 98, 12902–12907. 33 Shukla A, Chaurasia P & Bhaumik SR (2009) Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability. Cell Mol Life Sci 66, 1419–1433.
49 Shilatifard A (2008) Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr Opin Cell Biol 20, 341–348. 50 Schneider J, Wood A, Lee JS, Schuster R, Dueker J, 34 Zhang Y (2003) Transcriptional regulation by histone ubiquitination and deubiquitination. Genes Dev 17, 2733–2740. 35 Ng HH, Feng Q, Wang H, Erdjument-Bromage H,
Maguire C, Swanson SK, Florens L, Washburn MP & Shilatifard A (2005) Molecular regulation of his- tone H3 trimethylation by COMPASS and the regula- tion of gene expression. Mol Cell 19, 849–856. Tempst P, Zhang Y & Struhl K (2002) Lysine methyla- tion within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Genes Dev 16, 1518–1527.
36 Schneider J & Shilatifard A (2006) Histone demethyla- tion by hydroxylation: chemistry in action. ACS Chem Biol 1, 75–81.
51 Krogan NJ, Dover J, Wood A, Schneider J, Heidt J, Boateng MA, Dean K, Ryan OW, Golshani A, John- ston M et al. (2003) The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methyla- tion. Mol Cell 11, 721–729. 37 Schneider R, Bannister AJ & Kouzarides T (2002) Unsafe SETs: histone lysine methyltransferases and cancer. Trends Biochem Sci 27, 396–402. 38 Wang GG, Allis CD & Chi P (2007) Chromatin
remodeling and cancer, Part I: covalent histone modifi- cations. Trends Mol Med 13, 363–372. 52 Wood A, Schneider J, Dover J, Johnston M & Shilatif- ard A (2003) The Paf1 complex is essential for histone monoubiquitination by the Rad6–Bre1 complex, which signals for histone methylation by COMPASS and Dot1p. J Biol Chem 278, 34739–34742.
39 Hake SB, Xiao A & Allis CD (2004) Linking the epige- netic ‘language’ of covalent histone modifications to cancer. Br J Cancer 90, 761–769. 40 Sims RJ III & Reinberg D (2006) Histone H3 Lys 4 53 Gerber M & Shilatifard A (2003) Transcriptional elon- gation by RNA polymerase II and histone methylation. J Biol Chem 278, 26303–26306. methylation: caught in a bind? Genes Dev 20, 2779–2786. 41 Zhang K & Dent SY (2005) Histone modifying
enzymes and cancer: going beyond histones. J Cell Bio- chem 96, 1137–1148.
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1816
54 Ng HH, Robert F, Young RA & Struhl K (2003) Tar- geted recruitment of Set1 histone methylase by elongat- ing Pol II provides a localized mark and memory of recent transcriptional activity. Mol Cell 11, 709–719. 55 Lee JS, Shukla A, Schneider J, Swanson SK, Washburn MP, Florens L, Bhaumik SR & Shilatifard A (2007) 42 Pasini D, Bracken AP, Agger K, Christensen J, Hansen K, Cloos PA & Helin K (2008) Regulation of stem cell
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
69 Noma K & Grewal SI (2002) Histone H3 lysine 4
Histone crosstalk between H2B monoubiquitination and H3 methylation mediated by COMPASS. Cell 131, 1084–1096.
methylation is mediated by Set1 and promotes mainte- nance of active chromatin states in fission yeast. Proc Natl Acad Sci USA 99(Suppl 4), 16438–16445. 70 Roguev A, Schaft D, Shevchenko A, Aasland R &
56 Wood A, Shukla A, Schneider J, Lee JS, Stanton JD, Dzuiba T, Swanson SK, Florens L, Washburn MP, Wyrick J et al. (2007) Ctk complex-mediated regulation of histone methylation by COMPASS. Mol Cell Biol 27, 709–720. Stewart AF (2003) High conservation of the Set1 ⁄ Rad6 axis of histone 3 lysine 4 methylation in budding and fission yeasts. J Biol Chem 278, 8487–8493. 71 Roguev A, Schaft D, Shevchenko A, Pijnappel WW,
Wilm M, Aasland R & Stewart AF (2001) The Saccha- romyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. EMBO J 20, 7137–7148. 57 Shukla A, Stanojevic N, Duan Z, Sen P & Bhaumik SR (2006) Ubp8p, a histone deubiquitinase whose association with SAGA is mediated by Sgf11p, differ- entially regulates lysine 4 methylation of histone H3 in vivo. Mol Cell Biol 26, 3339–3352.
72 Roguev A, Shevchenko A, Schaft D, Thomas H, Stew- art AF & Shevchenko A (2004) A comparative analysis of an orthologous proteomic environment in the yeasts Saccharomyces cerevisiae and Schizosaccharomy- ces pombe. Mol Cell Proteomics 3, 125–132. 58 Shukla A, Stanojevic N, Duan Z, Shadle T & Bhaumik SR (2006) Functional analysis of H2B-Lys-123 ubiqui- tination in regulation of H3-Lys-4 methylation and recruitment of RNA polymerase II at the coding sequences of several active genes in vivo. J Biol Chem 281, 19045–19054.
59 Latham JA & Dent SY (2007) Cross-regulation of his- tone modifications. Nat Struct Mol Biol 14, 1017–1024. 60 Sun ZW & Allis CD (2002) Ubiquitination of his-
tone H2B regulates H3 methylation and gene silencing in yeast. Nature 418, 104–108.
73 Opel M, Lando D, Bonilla C, Trewick SC, Boukaba A, Walfridsson J, Cauwood J, Werler PJ, Carr AM, Kouzarides T et al. (2007) Genome-wide studies of his- tone demethylation catalysed by the fission yeast ho- mologues of mammalian LSD1. PLoS ONE 2, e386. 74 Nicolas E, Lee MG, Hakimi MA, Cam HP, Grewal SI & Shiekhattar R (2006) Fission yeast homologs of human histone H3 lysine 4 demethylase regulate a common set of genes with diverse functions. J Biol Chem 281, 35983–35988. 75 Schaner CE & Kelly WG (2006) Germline chromatin. 61 Dover J, Schneider J, Tawiah-Boateng MA, Wood A, Dean K, Johnston M & Shilatifard A (2002) Methyla- tion of histone H3 by COMPASS requires ubiquitina- tion of histone H2B by Rad6. J Biol Chem 277, 28368– 28371.
In WormBook (WormBook ed.). The C. elegans Research Community, WormBook, doi:10.1895/wormbook.1.73.1 76 Seydoux G & Dunn MA (1997) Transcriptionally 62 Shahbazian MD, Zhang K & Grunstein M (2005) His- tone H2B ubiquitylation controls processive methyla- tion but not monomethylation by Dot1 and Set1. Mol Cell 19, 271–277.
63 Weake VM & Workman JL (2008) Histone ubiquitina- tion: triggering gene activity. Mol Cell 29, 653–663. 64 Dehe PM, Pamblanco M, Luciano P, Lebrun R, repressed germ cells lack a subpopulation of phosphor- ylated RNA polymerase II in early embryos of Caenor- habditis elegans and Drosophila melanogaster. Development 124, 2191–2201. 77 Schaner CE, Deshpande G, Schedl PD & Kelly WG
Moinier D, Sendra R, Verreault A, Tordera V & Geli V (2005) Histone H3 lysine 4 mono-methylation does not require ubiquitination of histone H2B. J Mol Biol 353, 477–484. 65 Liang G, Klose RJ, Gardner KE & Zhang Y (2007) (2003) A conserved chromatin architecture marks and maintains the restricted germ cell lineage in worms and flies. Dev Cell 5, 747–757.
Yeast Jhd2p is a histone H3 Lys4 trimethyl demethy- lase. Nat Struct Mol Biol 14, 243–245.
78 Simonet T, Dulermo R, Schott S & Palladino F (2007) Antagonistic functions of SET-2 ⁄ SET1 and HPL ⁄ HP1 proteins in C. elegans development. Dev Biol 312, 367– 383.
79 Hsu DR & Meyer BJ (1994) The dpy-30 gene encodes an essential component of the Caenorhabditis elegans dosage compensation machinery. Genetics 137, 999– 1018. 80 Katz DJ, Edwards TM, Reinke V & Kelly WG (2009)
A C. elegans LSD1 demethylase contributes to germ- line immortality by reprogramming epigenetic memory. Cell 137, 308–320.
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1817
81 Eimer S, Lakowski B, Donhauser R & Baumeister R (2002) Loss of spr-5 bypasses the requirement for the 66 Briggs SD, Bryk M, Strahl BD, Cheung WL, Davie JK, Dent SY, Winston F & Allis CD (2001) Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. Genes Dev 15, 3286–3295. 67 Noma K, Allis CD & Grewal SI (2001) Transitions in distinct histone H3 methylation patterns at the hetero- chromatin domain boundaries. Science 293, 1150–1155. 68 Litt MD, Simpson M, Gaszner M, Allis CD & Felsen- feld G (2001) Correlation between histone lysine meth- ylation and developmental changes at the chicken beta- globin locus. Science 293, 2453–2455.
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
C. elegans presenilin sel-12 by derepressing hop-1. EMBO J 21, 5787–5796.
97 Randsholt NB, Maschat F & Santamaria P (2000) Polyhomeotic controls engrailed expression and the hedgehog signaling pathway in imaginal discs. Mech Dev 95, 89–99.
82 Jarriault S & Greenwald I (2002) Suppressors of the egg-laying defective phenotype of sel-12 presenilin mutants implicate the CoREST corepressor complex in LIN-12 ⁄ Notch signaling in C. elegans. Genes Dev 16, 2713–2728.
83 Lakowski B, Roelens I & Jacob S (2006) CoREST-like complexes regulate chromatin modification and neuro- nal gene expression. J Mol Neurosci 29, 227–239. 84 Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR,
98 Kuzin B, Tillib S, Sedkov Y, Mizrokhi L & Mazo A (1994) The Drosophila trithorax gene encodes a chro- mosomal protein and directly regulates the region-spe- cific homeotic gene fork head. Genes Dev 8, 2478–2490. 99 Netter S, Fauvarque MO, Diez del Corral R, Dura JM & Coen D (1998) white+ transgene insertions present- ing a dorsal ⁄ ventral pattern define a single cluster of homeobox genes that is silenced by the polycomb- group proteins in Drosophila melanogaster. Genetics 149, 257–275. Cole PA, Casero RA & Shi Y (2004) Histone demethy- lation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953.
85 McColl G, Killilea DW, Hubbard AE, Vantipalli MC, Melov S & Lithgow GJ (2008) Pharmacogenetic analy- sis of lithium-induced delayed aging in Caenorhabd- itis elegans. J Biol Chem 283, 350–357.
100 Grimaud C, Negre N & Cavalli G (2006) From genet- ics to epigenetics: the tale of Polycomb group and tri- thorax group genes. Chromosome Res 14, 363–375. 101 Ingham PW (1984) A gene that regulates the bithorax complex differentially in larval and adult cells of Dro- sophila. Cell 37, 815–823. 102 Kennison JA (1995) The Polycomb and trithorax 86 Sulston JE (1983) Neuronal cell lineages in the nema- tode Caenorhabditis elegans. Cold Spring Harb Symp Quant Biol 48(Pt 2), 443–452. 87 Pirrotta V (1998) Polycombing the genome: PcG, trxG, and chromatin silencing. Cell 93, 333–336.
88 Mahmoudi T & Verrijzer CP (2001) Chromatin silenc- ing and activation by Polycomb and trithorax group proteins. Oncogene 20, 3055–3066. 89 Dejardin J & Cavalli G (2005) Epigenetic inheritance group proteins of Drosophila: trans-regulators of home- otic gene function. Annu Rev Genet 29, 289–303. 103 LaJeunesse D & Shearn A (1995) Trans-regulation of thoracic homeotic selector genes of the Antennapedia and bithorax complexes by the trithorax group genes: absent, small, and homeotic discs 1 and 2. Mech Dev 53, 123–139. 104 Petruk S, Sedkov Y, Smith S, Tillib S, Kraevski V, of chromatin states mediated by Polycomb and tritho- rax group proteins in Drosophila. Prog Mol Subcell Biol 38, 31–63. 90 Orlando V (2003) Polycomb, epigenomes, and control of cell identity. Cell 112, 599–606. Nakamura T, Canaani E, Croce CM & Mazo A (2001) Trithorax and dCBP acting in a complex to maintain expression of a homeotic gene. Science 294, 1331–1334. 105 Sanchez-Elsner T & Sauer F (2004) The heat is on with 91 Ringrose L & Paro R (2004) Epigenetic regulation of TAC1. Nat Cell Biol 6, 92–93. 106 Beisel C, Imhof A, Greene J, Kremmer E & Sauer F cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet 38, 413–443.
(2002) Histone methylation by the Drosophila epigenetic transcriptional regulator Ash1. Nature 419, 857–862. 107 Byrd KN & Shearn A (2003) ASH1, a Drosophila
92 Beltran S, Blanco E, Serras F, Perez-Villamil B, Guigo R, Artavanis-Tsakonas S & Corominas M (2003) Tran- scriptional network controlled by the trithorax-group gene ash2 in Drosophila melanogaster. Proc Natl Acad Sci USA 100, 3293–3298. trithorax group protein, is required for methylation of lysine 4 residues on histone H3. Proc Natl Acad Sci USA 100, 11535–11540. 108 Adamson AL & Shearn A (1996) Molecular genetic
93 Collins RT & Treisman JE (2000) Osa-containing Bra- hma chromatin remodeling complexes are required for the repression of wingless target genes. Genes Dev 14, 3140–3152. analysis of Drosophila ash2, a member of the trithorax group required for imaginal disc pattern formation. Genetics 144, 621–633.
109 Angulo M, Corominas M & Serras F (2004) Activation and repression activities of ash2 in Drosophila wing imaginal discs. Development 131, 4943–4953. 94 Smith ST, Petruk S, Sedkov Y, Cho E, Tillib S, Cana- ani E & Mazo A (2004) Modulation of heat shock gene expression by the TAC1 chromatin-modifying complex. Nat Cell Biol 6, 162–167. 110 Tripoulas NA, Hersperger E, La Jeunesse D & Shearn
95 Moazed D & O’Farrell PH (1992) Maintenance of the engrailed expression pattern by Polycomb group genes in Drosophila. Development 116, 805–810. 96 Brizuela BJ & Kennison JA (1997) The Drosophila A (1994) Molecular genetic analysis of the Drosoph- ila melanogaster gene absent, small or homeotic discs1 (ash1). Genetics 137, 1027–1038.
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1818
homeotic gene moira regulates expression of engrailed and HOM genes in imaginal tissues. Mech Dev 65, 209–220. 111 Tripoulas N, LaJeunesse D, Gildea J & Shearn A (1996) The Drosophila ash1 gene product, which is localized at specific sites on polytene chromosomes,
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
contains a SET domain and a PHD finger. Genetics 143, 913–928.
scriptional basis of wing phenotypes and reveals con- served protein interactions. Genome Biol 8, R67. 123 Schwartz YB & Pirrotta V (2007) Polycomb silencing mechanisms and the management of genomic pro- grammes. Nat Rev Genet 8, 9–22. 124 Sedkov Y, Cho E, Petruk S, Cherbas L, Smith ST, 112 Papoulas O, Beek SJ, Moseley SL, McCallum CM, Sarte M, Shearn A & Tamkun JW (1998) The Dro- sophila trithorax group proteins BRM, ASH1 and ASH2 are subunits of distinct protein complexes. Development 125, 3955–3966.
113 Tanaka Y, Katagiri Z, Kawahashi K, Kioussis D & Kitajima S (2007) Trithorax-group protein ASH1 methylates histone H3 lysine 36. Gene 397, 161–168. Jones RS, Cherbas P, Canaani E, Jaynes JB & Mazo A (2003) Methylation at lysine 4 of histone H3 in ecdy- sone-dependent development of Drosophila. Nature 426, 78–83.
125 Thomas JO & Travers AA (2001) HMG1 and 2, and related ‘architectural’ DNA-binding proteins. Trends Biochem Sci 26, 167–174.
114 Bantignies F, Goodman RH & Smolik SM (2000) Functional interaction between the coactivator Drosophila CREB-binding protein and ASH1, a member of the trithorax group of chromatin modifiers. Mol Cell Biol 20, 9317–9330. 115 Nagy PL, Griesenbeck J, Kornberg RD & Cleary ML
126 Papoulas O, Daubresse G, Armstrong JA, Jin J, Scott MP & Tamkun JW (2001) The HMG-domain protein BAP111 is important for the function of the BRM chromatin-remodeling complex in vivo. Proc Natl Acad Sci USA 98, 5728–5733.
127 Elfring LK, Daniel C, Papoulas O, Deuring R, Sarte M, Moseley S, Beek SJ, Waldrip WR, Daubresse G, DePace A et al. (1998) Genetic analysis of brahma: the Drosophila homolog of the yeast chromatin remodel- ing factor SWI2 ⁄ SNF2. Genetics 148, 251–265. 128 Rozenblatt-Rosen O, Rozovskaia T, Burakov D, (2002) A trithorax-group complex purified from Sac- charomyces cerevisiae is required for methylation of histone H3. Proc Natl Acad Sci USA 99, 90–94. 116 Wysocka J, Myers MP, Laherty CD, Eisenman RN & Herr W (2003) Human Sin3 deacetylase and trithorax- related Set1 ⁄ Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev 17, 896–911. 117 Lee JH & Skalnik DG (2005) CpG-binding protein
(CXXC finger protein 1) is a component of the mam- malian Set1 histone H3-Lys4 methyltransferase com- plex, the analogue of the yeast Set1 ⁄ COMPASS complex. J Biol Chem 280, 41725–41731. Sedkov Y, Tillib S, Blechman J, Nakamura T, Croce CM, Mazo A & Canaani E (1998) The C-terminal SET domains of ALL-1 and TRITHORAX interact with the INI1 and SNR1 proteins, components of the SWI ⁄ SNF complex. Proc Natl Acad Sci USA 95, 4152–4157. 129 Lee N, Zhang J, Klose RJ, Erdjument-Bromage H, 118 Goo YH, Sohn YC, Kim DH, Kim SW, Kang MJ,
Tempst P, Jones RS & Zhang Y (2007) The trithorax- group protein Lid is a histone H3 trimethyl-Lys4 demethylase. Nat Struct Mol Biol 14, 341–343. 130 Secombe J, Li L, Carlos L & Eisenman RN (2007) The Jung DJ, Kwak E, Barlev NA, Berger SL, Chow VT et al. (2003) Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins. Mol Cell Biol 23, 140–149.
Trithorax group protein Lid is a trimethyl his- tone H3K4 demethylase required for dMyc-induced cell growth. Genes Dev 21, 537–551. 131 Schneider R, Bannister AJ, Myers FA, Thorne AW,
Crane-Robinson C & Kouzarides T (2004) Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nat Cell Biol 6, 73–77. 119 Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, Hayes DN, Shanmugam KS, Bhattacharjee A, Biondi CA et al. (2004) Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 13, 587–597. 120 Yokoyama A, Wang Z, Wysocka J, Sanyal M,
132 Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ, McMahon S, Karlsson EK, Kulbokas EJ III, Gingeras TR et al. (2005) Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181. 133 Ruthenburg AJ, Allis CD & Wysocka J (2007) Aufiero DJ, Kitabayashi I, Herr W & Cleary ML (2004) Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol 24, 5639–5649. 121 Steward MM, Lee JS, O’Donovan A, Wyatt M,
Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell 25, 15–30. 134 Campos EI & Reinberg D (2009) Histones: annotating Bernstein BE & Shilatifard A (2006) Molecular regu- lation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nat Struct Mol Biol 13, 852–854. chromatin. Annu Rev Genet 43, 559–599. 135 Wang H, Cao R, Xia L, Erdjument-Bromage H,
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1819
Borchers C, Tempst P & Zhang Y (2001) Purification and functional characterization of a 122 Beltran S, Angulo M, Pignatelli M, Serras F & Corom- inas M (2007) Functional dissection of the ash2 and ash1 transcriptomes provides insights into the tran-
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
histone H3-lysine 4-specific methyltransferase. Mol Cell 8, 1207–1217.
148 Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L & Shiekhattar R (2007) Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318, 447–450. 149 Suganuma T & Workman JL (2008) Crosstalk among histone modifications. Cell 135, 604–607. 136 Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y, Chuikov S, Valenzuela P, Tempst P, Steward R et al. (2002) PR-Set7 is a nucleo- some-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol Cell 9, 1201–1213. 137 Hamamoto R, Furukawa Y, Morita M, Iimura Y,
150 Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Hue- bert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K et al. (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326. Silva FP, Li M, Yagyu R & Nakamura Y (2004) SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol 6, 731–740. 138 Hayashi K, Yoshida K & Matsui Y (2005) A his-
tone H3 methyltransferase controls epigenetic events required for meiotic prophase. Nature 438, 374–378. 139 Milne TA, Dou Y, Martin ME, Brock HW, Roeder 151 Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mo¨ nch K, Minucci S, Porse BT, Marine JC et al. (2007) The Polycomb group proteins bind throughout the INK4A- ARF locus and are disassociated in senescent cells. Genes Dev 21, 525–530. 152 Agherbi H, Gaussmann-Wenger A, Verthuy C, RG & Hess JL (2005) MLL associates specifically with a subset of transcriptionally active target genes. Proc Natl Acad Sci USA 102, 14765–14770.
Chasson L, Serrano M & Djabali M (2009) Polycomb mediated epigenetic silencing and replication timing at the INK4a ⁄ ARF locus during senescence. PLoS ONE 4, e5622. 140 Ernst P, Mabon M, Davidson AJ, Zon LI & Korsmey- er SJ (2004) An Mll-dependent Hox program drives hematopoietic progenitor expansion. Curr Biol 14, 2063–2069.
153 Ansari KI, Mishra BP & Mandal SS (2009) MLL his- tone methylases in gene expression, hormone signaling and cell cycle. Front Biosci 14, 3483–3495.
141 Terranova R, Agherbi H, Boned A, Meresse S & Djabali M (2006) Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll. Proc Natl Acad Sci USA 103, 6629–6634.
154 Wang J, Scully K, Zhu X, Cai L, Zhang J, Prefontaine GG, Krones A, Ohgi KA, Zhu P, Garcia-Bassets I et al. (2007) Opposing LSD1 complexes function in developmental gene activation and repression pro- grammes. Nature 446, 882–887.
155 Shi Y & Whetstine JR (2007) Dynamic regulation of histone lysine methylation by demethylases. Mol Cell 25, 1–14. 156 Huang Y, Greene E, Murray Stewart T, Goodwin 142 Yu BD, Hess JL, Horning SE, Brown GA & Korsmey- er SJ (1995) Altered Hox expression and segmental identity in Mll-mutant mice. Nature 378, 505–508. 143 Lee S, Lee DK, Dou Y, Lee J, Lee B, Kwak E, Kong YY, Lee SK, Roeder RG & Lee JW (2006) Coactiva- tor as a target gene specificity determinant for his- tone H3 lysine 4 methyltransferases. Proc Natl Acad Sci USA 103, 15392–15397.
AC, Baylin SB, Woster PM & Casero RA Jr (2007) Inhibition of lysine-specific demethylase 1 by poly- amine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci USA 104, 8023– 8028. 144 Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD & Hess JL (2002) MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 10, 1107–1117. 145 Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, 157 Issa JP (2007) DNA methylation as a therapeutic target in cancer. Clin Cancer Res 13, 1634–1637.
158 Issa JP & Kantarjian HM (2009) Targeting DNA methylation. Clin Cancer Res 15, 3938–3946. 159 Batty N, Malouf GG & Issa JP (2009) Histone deacet- Verdine GL, Allis CD & Roeder RG (2006) Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol 13, 713–719.
ylase inhibitors as anti-neoplastic agents. Cancer Lett 280, 192–200.
160 Issa JP (2008) Cancer prevention: epigenetics steps up to the plate. Cancer Prev Res (Phila Pa) 1, 219–222. 146 Wysocka J, Swigut T, Milne TA, Dou Y, Zhang X, Burlingame AL, Roeder RG, Brivanlou AH & Allis CD (2005) WDR5 associates with histone H3 methy- lated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121, 859–872.
161 Oki Y & Issa JP (2006) Review: recent clinical trials in epigenetic therapy. Rev Recent Clin Trials 1, 169– 182.
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1820
162 Ansari KI & Mandal SS (2010) Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS J doi:10.1111/j.1742-4658.2010.07606.x. 147 Dou Y, Milne TA, Tackett AJ, Smith ER, Fukuda A, Wysocka J, Allis CD, Chait BT, Hess JL & Roeder RG (2005) Physical association and coordinate func- tion of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyl transferase MOF. Cell 121, 873–885.
S. Malik and S. R. Bhaumik
H3K4 methyltransferases from yeast to human
163 Marschalek R (2010) Mixed lineage leukemia: roles in
human malignancies and potential therapy. FEBS J doi:10.1111/j.1742-4658.2010.07608.x. Histone H3-Lys4 methyltransferase complex to transcription start sites of transcribed human genes. Mol Cell Biol 28, 609–618. 166 Ansari KI, Mishra BP & Mandal SS (2008) Human 164 Cosgrove MS & Patel A (2010) Mixed lineage leuke-
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
1821
mia: a structure-function perspective of the MLL1 pro- tein. FEBS J doi:10.1111/j.1742-4658.2010.07609.x. CpG binding protein interacts with MLL1, MLL2 and hSet1 and regulates Hox gene expression. Biochim Biophys Acta 1779, 66–73. 165 Lee JH & Skalnik DG (2008) Wdr82 is a C-terminal domain-binding protein that recruits the Setd1A
