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

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

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

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-

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

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

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

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

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

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-

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

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

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

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

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-

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-

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

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

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