Tài liệu Báo cáo khoa học: Mixed lineage leukemia: histone H3 lysine 4 methyltransferases from yeast to human pptx

MINIREVIEW
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
Introduction
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
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.
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
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:
(Received 16 November 2009, revised
12 January 2010, accepted 22 January
2010)
doi:10.1111/j.1742-4658.2010.07607.x
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.
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
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].
H3
N-A R T K R K S T K R K K R K S K C
.
.

K
4
9
14 18 23 27 36
79
me
A
B
me
me me

me
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)
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)
MES-2 (Ce)
E (Z) (Dm)
G9a (Dm)
EZH2 (Hs)
EZH1 (Hs)
G9a (Hs)

Set2 (Sc)
Set2 (Sp)
Set2 (Dm)
ASH1 (Dm)
NSD1 (Hs)
SETD2/HYPB (Hs)
Dot1 (Sc)
Dot1 (Sp)
DOT1L (Hs)
Gene
activation,
telomeric
silencing
& DNA
repair
Hetero-
chromatin
formation
& silencing
Hetero-
chromatin
formation
& silencing
Inhibition
of intragenic
transcription
& hetero-
chromatin
spreading, &
regulation of

transcriptional
elongation
Gene
activation
& silencing,
splicing,
& DNA repair
Lysine
methylases
Functions
Lysine
methylases
Functions
H4
N-SGRGKGGKGLGKGGAKRHRKV C
5
8
12 16 20
me
Heterochromatin
formation & silencing
Set9 (Sp)
Pr-SET7 (Dm)
ASH1 (Dm)
SUV4-20 (Hs)
Pr-SET7/SET8 (Hs)
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.
H3K4 methyltransferases from yeast to human S. Malik and S. R. Bhaumik

1806 FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
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 (fission yeast), Caenorhabditis
elegans (roundworm), Drosophila melanogaster (fruit
fly), Mus musculus (mouse) and Homo sapiens (human).
H3K4 methylation and HMTs in
Saccharomyces cerevisiae
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, Cps25⁄ Sdc1 and Cps15 ⁄ Shg1)
(Tables 1–3) [29,33,48,49]. Set1 is essential for mono-,
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 factor 1 (Paf1) 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 [33,49,51,54,55], and the coding
sequences of the actively transcribing genes are there-

fore trimethylated at the K4 of histone H3 [33,51,54–
58].
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 cross-talk between histone H2B K123
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
COMPASS complex [33,55]. COMPASS without
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)
COMPASS ⁄ Set1C Set1C COMPASS-like complex TAC1
ASH1
ASH2
TRR
MLL1
MLL2
MLL3
MLL4
SET1A

SET1B
SET7 ⁄ 9
SMYD3
ASH1
Meisetz
S. Malik and S. R. Bhaumik H3K4 methyltransferases from yeast to human
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS 1807
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
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
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
⁄
Set1C
Set1
Cps60 ⁄ Bre2
Cps50 ⁄ Swd1
Cps40 ⁄ Spp1
Cps35 ⁄ Swd2
Cps30 ⁄ Swd3
Cps25 ⁄ Sdc1
Cps15 ⁄ Shg1
Set1C
Set1
Ash2
Swd1
Spp1
Swd2
Swd3
Sdc1
Shg1
COMPASS-like complex
SET-2 ⁄ SET1
ASH2 ⁄ Y17G7B.2
CFPL-1

SWD-3
SWD-2 ⁄ C33H5.6
SPP-1 ⁄ F52B11.1
DPY-30
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 ⁄ SWD2
a
CFP1 ⁄ CGBP
a
DPY-30
HCF1

a
Wdr82 and CFP1 ⁄ CGBP are present in human SET1A and SET1B complexes, but not in mouse [117,165,166].
H3K4 methyltransferases from yeast to human S. Malik and S. R. Bhaumik
1808 FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
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
N-terminal tail of histone H3 in vitro. By contrast,
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,
Cps60 ⁄ Bre2 (Table 3), in S. cerevisae does not [70].
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].
Table 4. Histone H3 lysine 4 demethylases in different eukaryotes (references are cited in the text). me
3
, trimethyl; me
2

, dimethyl; me
3 ⁄ 2
,
tri- and dimethyl; and me
2 ⁄ 1
, di- and monomethyl.
Saccharomyces cerevisae Schizosaccharomyces pombe Caenorhabditis elegans Drosophila Mammals (mouse and human)
Jhd2 (me
3
) Swm1 (me
2
)
Swm2 (me
2
)
SPR-5 (me
2
)
T08D10.2 (me
2
)
R13G10.2 (me
2
)
Lid (me
3
) LSD1 (me
2 ⁄ 1
)
JARID1A (me

3 ⁄ 2
)
JARID1B (me
3 ⁄ 2
)
JARID1C (me
3 ⁄ 2
)
JARID1D (me
3 ⁄ 2
)
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
Set1 Set1 SET-2 ⁄ SET1 TRX MLL1-4, SET1A ⁄ SET1B
Cps60 ⁄ Bre2 Ash2 ASH-2 ASH2 ASH2L ⁄ ASH2
Cps50 ⁄ Swd1 Swd1 CFPL-1 RBBP5
Cps30 ⁄ Swd3 Swd3 SWD-3 WDR5 WDR5
Cps35 ⁄ Swd2 Swd2 SWD-2 WDR82 ⁄ SWD2
Cps40 ⁄ Spp1 Spp1 SPP-1 CFP1
Cps25 ⁄ Sdc1 Sdc1 DPY-30 DPY-30
Cps15 ⁄ Shg1 Shg1
ASH1 ASH1L ⁄ ASH1
TRR
Menin; HCF1 ⁄ HCF2; NCOA6; PA1;
PTIP; UTX; MOF; SET7 ⁄ 9; SMYD3; Meisetz

S. Malik and S. R. Bhaumik H3K4 methyltransferases from yeast to human
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS 1809
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
(after SWIRM1 and SWIRM2), in Sch. pombe
(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.
H3K4 methylation and HMTs in
Caenorhabditis elegans
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 has an important role in 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].
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
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-

thermore, like in fission yeast, SET-2 ⁄ SET1 may be
hyperlinked to the complex that is homologus to
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 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
absence of Y17G7B.2 ⁄ ASH-2. Depletion of set-2,
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 residual level of 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.
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
SPR-5, two other proteins in C. elegans, namely
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].
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
H3K4 methyltransferases from yeast to human S. Malik and S. R. Bhaumik
1810 FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
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
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
number of developmental genes, including the Hox
(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].
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, called trithorax acetylation 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
[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-
somes, including Hox genes [104], and thus exist
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.
In addition to TRX, two other 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
S. Malik and S. R. Bhaumik H3K4 methyltransferases from yeast to human
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS 1811
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.
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].
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
methylation is also observed at the hh and BR-C
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.
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 three distinct complexes, 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 the BRM complex [128]. Together, these
results indicate that H3K4 methylation and ATP-
dependent chromatin remodeler, BRM, function in a

concerted manner to regulate transcription. Apart
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 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
functional domains found in mammalian Jumonji,
H3K4 methyltransferases from yeast to human S. Malik and S. R. Bhaumik
1812 FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
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
additional layer to gene regulation by the PcG and
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
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  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, significant H3K4 methylation is 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
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–
138]. Of these, six members containing the SET
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
have different phenotypes in mice [140–144]. For
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.
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.
In addition to its role in H3K4 methylation, MLL
complex interacts with a TATA-box binding protein
(TBP)-associated factor component of transcription
factor IID, components of E2F transcription factor 6
(E2F6) subcomplex, and MOF (a MYST family
S. Malik and S. R. Bhaumik H3K4 methyltransferases from yeast to human
FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS 1813
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
histone H3 at K27 through its UTX subunit
[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].
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.
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-
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
of LSD1 facilitates expression of the aberrantly
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-
natorial therapy targeting histone deacetylases and
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.
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-
H3K4 methyltransferases from yeast to human S. Malik and S. R. Bhaumik
1814 FEBS Journal 277 (2010) 1805–1821 ª 2010 The Authors Journal compilation ª 2010 FEBS
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.
Acknowledgements
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
Institutes of Health grant (1R15GM088798-01), a
National Scientist Development Grant (0635008N)
from American Heart Association, a Research Scholar
Grant (06-52) from American Cancer Society, a
Mallinckrodt Foundation award, and several internal
grants from Southern Illinois University.
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