Hongpeng He and
Norbert Lehming
are members of the
Department of Microbiology,
Faculty of Medicine, National
University of Singapore. Their
research interests include the
regulation of gene transcription
in yeasts and higher eukaryotic
organisms, chromatin
structure, signal transduction,
as well as molecular
mechanisms underlying
protein–DNA and protein–
protein interactions.
Keywords: chromatin,
methylation, acetylation,
phosphorylation,
ubiquitination, transcription
Global effects of
histone modifications
Hongpeng He and Norbert Lehming
Date received (in revised form): 1st August, 2003
Abstract
The relationship between chromatin structure and transcriptional regulation has been the
focus of many research publications over the past few years. A lot of progress has been made
in understanding the role of histone modifications. The interdependence of histone
methylation and DNA methylation has been revealed. Methylation, acetylation,
phosphorylation and ubiquitination of specific histone residues are all able to affect the DNA
binding of transcription factors and to change the structure of chromatin on a genome-wide
scale. This review aims to summarise some of the experiments that demonstrated the global
effects of the modifications of the five histone proteins, H1, H2A, H2B, H3 and H4.
THE NUCLEOSOME
DNA does not exist naked in the nucleus
of the eukaryotic cell but is associated
with histone proteins in the form of
chromatin. The DNA is wrapped around
the histone octamer, which consists of
two copies each of H2A, H2B, H3 and
H4. This protein–DNA complex is called
the nucleosome, the smallest unit of
chromatin (Figure 1). The precise
structure of the nucleosome has been
determined.1 Histone H1 is believed to
link the nucleosomes together, facilitating
the formation of higher-order structures
of chromatin.2
HISTONE H1
Hongpeng He and
Norbert Lehming,
Department of Microbiology,
Faculty of Medicine,
National University of Singapore,
Block MD4,
5 Science Drive 2,
Singapore 117597
Tel: +65 6874 3499
Fax: +65 6776 6872
E-mail: [email protected]
Histone H1 is called the linker histone;
however, it has been shown that this
histone is not essential for viability. The
deletion or over-expression of histone H1
has no global effect on chromatin
condensation and gene expression, as has
been observed in tobacco,3 mice,4
tetrahymena5,6 and fungi.7 Rather, H1
seems to act as a positive or negative
gene-specific regulator of transcription in
vivo. In Ascobolus immerses, the deletion of
histone H1 did not change methylationassociated gene silencing.7 In Xenopus
oocytes, an increase in histone H1
specifically restricted TFIIIA-activated
transcription, while a decrease in histone
H1 facilitated the activation of the oocyte
5S rRNA genes by TFIIIA.8 Saccharomyces
cerevisiae histone Hho1p is homologous to
histone H1 of other organisms and was
shown to have similar biochemical and
biological properties.9,10 A strain deleted
for the HHO1 gene was found to be
viable and had no growth or mating
defects.11 Hho1p was not required for
telomeric silencing, basal transcriptional
repression, nor for efficient sporulation.11
Unlike core histone mutations, the
HHO1-deleted strain did not show a Sin
or Spt phenotype.11 The absence of
Hho1p did not lead to a change in the
nucleosome repeat length nor in the
global positioning of the
nucleosomes.11,12 Using DNA array
technology, however, it has been shown
that the HHO1 disruption did have a
transcriptional effect on a subset of
genes.13 There is approximately one
Hho1p molecule for every 37
nucleosomes.13 Chromatin
immunoprecipitation experiments have
shown that Hho1p is localised to rDNA
sequences.13 Therefore, Hho1p might
play a similar role as the linker histones
but it is restricted to specific chromosomal
locations.13
In Tetrahymena thermophyla histone H1,
five phosphorylation sites have been
identified, all positioned within a single
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Global effects of histone modifications
Figure 1: The nucleosome. (A) The nucleosome consists of two copies of each of H2A, H2B, H3 and H4, as well as 146
base pairs of double-stranded DNA wrapped around the histone octamer approximately 1.75 times. The N-termini of all
the core-histones extend from the nucleosome. Histone H1 binds to linker DNA and stabilises the nucleosome. (B and C)
A speculative model for the dynamic role of the nucleosome in transcription. (B) The non-acetylated and methylated
histone tails carry a high positive net charge and interact so strongly with the negatively charged DNA that the DNA
strands become inaccessible to the transcription machinery. (C) Acetylation or phosphorylation of the histone tails reduces
the positive net charge, decreasing the interaction with the DNA. This exposes the promoter to the transcription
machinery. The modified histone tails may also create an interface for the recruitment of transcription factors
Phosphorylation is the
main modification of
H1, the linker histone
cluster: S42, S44, T46, T34 and T53.14
The substitution of all of these residues by
alanine had little effect on viability.14 The
replacement of all of these residues by
glutamic acid, which is thought to mimic
the phosphorylation status, phenocopied
H1 removal with respect to the basal
activation of one gene (ngoA) and the
repression of the induced expression of
another gene (CyP1).15 Consistent with
previous reports, the global gene
expression was not detectably changed in
either strain.16 Phosphorylation of the
linker histone H1(S)-3 was elevated in
mouse fibroblasts transformed with
oncogenic Ras or constitutively active
mitogen-activated protein kinase.17
Incorporation of histone H1 into mouse
mammary tumour virus (MMTV)
minichromosomes improved nucleosome
stability and decreased basal transcription
from the MMTV promoter. Activated
transcription, however, was enhanced in
H1-containing minichromosomes.18
Taf(II)250 specifically ubiquitinates the
linker histone H1 and not the four core
histones. Mutations in Taf(II)250 that
reduced the enzymatic ubiquitination
function reduced the expression of
specific genes as well.19
HISTONE H2A
Histone H2A is the unique histone that
extends both its N- and its C-terminal
ends into the extranucleosomal space.
Both ends are necessary for telomere
position effect on transcription (TPE, or
telomeric silencing), as the deletion of
either end caused a significant reduction
in TPE.20 N-terminal point mutation of
K4R/K7R reduced telomeric silencing as
well, whereas K4M/K7M, which mimics
the acetylated state, enhanced the TPE
phenotype.20 H2A.Z, a variant of H2A,
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He and Lehming
Acetylation of H2A and
its variant H2A.Z affects
TPE. Ubiquitination of
H2A influences the
recruitment of
transcription factors
Acetylated H2A-H2B is
removed from the
nucleosome by
cromation remodelling
factors
acted synergistically with boundary
elements, preventing the spread of
heterochromatin and antagonising
telomeric silencing.21
There are five possible ubiquitinated
residues in H2A (K4, K119, K120, K123
and K126); however, their function
remains unclear. Recent work with
ubiquitinated H2A indicated that this
histone modification did not affect the
nucleosome nor the chromatin
structure.22 This suggested that the
modification itself could function as a
marker for transcription factors interacting
with histones.23
In Tetrahymena, H2A.Z is essential for
cell survival. Lysines 4, 7, 10, 13, 16 and
21 are the only acetylated residues in
H2A.Z. Mutation of these six lysines to
arginine is lethal. Retention of one
acetylated lysine is sufficient to provide
the essential function of H2A.Z.24
HISTONE H2B
H2B ubiquitination at
K123 is genetically
upstream of H3
methylation at K4/K79
and telomere silencing
H2B-K123 is a conserved ubiquitination
site. Its mutation is shown to confer
defects in mitotic cell growth and meiosis.
Ub-H2B was not detected in RAD6
mutants, identifying Rad6 as the major
cellular activity that ubiquitinates H2B in
yeast.25 Methylation of H3-K4 (lysine 4
of histone H3) required the preubiquitination of H2B-K123. Deletion of
Rad6, but not Gcn5 or Rpd6, had a
negative effect on H3-K4 methylation.26
In an H2B-K123R mutant, the H3-K4
methylation was abolished, and the
silencing at the telomeres (which is
mediated by H3-K4 methylation) was
damaged. H3-K4R had no effect on H2B
ubiquitination, however, indicating that
ubiquitination at H2B is upstream of
methylation at H3-K4.27–29 Rad6mediated ubiquitination of H2B-K123 is
important for efficient methylation of
H3-K79, while methylation of H3-K79 is
not required for ubiquitination of H2BK123. Methylation of H3-K79 is
necessary for telomeric silencing.30
Tup1p is recruited to, and represses,
genes that regulate mating, glucose and
oxygen utilisation, stress response and
DNA damage. Hda1p specifically
deacetylates histones H3 and H2B. Tup1p
interacts with Hda1 in vitro and is thought
to mediate localised histone deacetylation
through Hda1.31 Transcriptional
activators, like Gal4-VP16, and chromatin
remodelling complexes, like ATPdependent chromatin assembly and remodelling factor (ACF), induce
chromatin remodelling in the absence of
histone acetylation. Transcriptional
activators recruit histone acetyltransferases
like p300 to promoters after chromatin
remodelling has occurred. Histone
acetylation is an important step for
subsequent chromatin remodelling and
results in the transfer of histone H2AH2B dimers from nucleosomes to histone
chaperones like NAP-1.32
Histone phosphorylation might be
connected with chromatin condensation.
H2B-S14 is phosphorylated by the Mist1
kinase in human HL-60 cells during
apoptosis.33
The presence of N,N-dimethylproline
at the N-terminus of H2B from Sipunculus
nudus was established by mass
spectrometry and nuclear magnetic
resonance spectroscopy. This unusual
post-translational modification of histone
H2B generates a stable positive charge
which could strengthen the interaction
with the linker DNA.34
Chemical treatment of hepatoma
AH7974 cells leads to a marked
accumulation of mono-ADP-ribosylated
H1 and H2B. The modification of
histones by a single ADP-ribose group
may represent an independent process to
modulate DNA–histone interactions.35
HISTONE H3
Histone H3 is one of the core histones. Its
post-translational modification is
important for the regulation of
transcription and chromatin
condensation. Histone H3 from chicken
erythrocytes has been analysed with the
help of mass spectroscopy. The results
showed that lysines 4, 9, 14, 27, 36 and
79 were methylated and lysines 14, 18 and
23 were acetylated.36
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Global effects of histone modifications
H3 tri-methylation at
K4 is an epigenetic
marker. At the mDNA
locus, it serves as a
marker for activation,
while at the rDNA
locus, it serves as a
marker for repression
H3 tri-methylation at
K9 is genetically
upstream of DNA
methylation. They are
connected via HP1 and
MeCP2
Besides the lysine residues mentioned
above, arginines 2, 17 and 26 can be
methylated. Histone H3 methylation can
have a positive (H3-K4 or H3-R17) or
negative (H3-K9) influence on
transcription. The methylation status of a
specific residue can affect the status of
other residues, including those on
neighbouring histones. Different
methylation patterns are thought to cause
different biological consequences, which
is referred to as the ‘histone code’.37
H3-K4 methylation is a marker for
transcriptionally active genes. Methylation
of H3-K4 occurs in three states: mono-, diand tri-methylated. The di-methylated
state is associated with both
transcriptionally active and inactive genes,
whereas the tri-methylated state occurs
exclusively at transcriptionally active
protein-coding genes.38 At the rDNA
locus, however, H3-K4 is a marker for
repression. Set1-dependent H3-K4
methylation is required for rDNA
silencing. The mutant H3-K4R, which
prevents K4 methylation, impairs rDNA
silencing.39 Targeted recruitment of the
Set1 histone methyltransferase by RNA
polymerase II provides a localised mark and
memory of recent transcriptional activity.40
H3-K9 methylation is involved in gene
silencing in many organisms, but in S.
cerevisiae, H3-K9 is not methylated. In
Neurospora crassa, it was shown that Dim5, which contains a SET domain,
methylates H3-K9.41 This methylation
was necessary for DNA methylationinduced gene silencing. Furthermore, the
histone methylation was found to be
genetically upstream of DNA
methylation, suggesting that methylated
nucleosomes can serve as markers for
imprinting at times when the DNA is demethylated during embryogenesis. In
Arabidopsis, it was shown that the link
between histone methylation at H3-K9
and DNA methylation at position 5 of
cytosine is made by the heterochromatinbinding protein HP1. Kryptonite, a SET
domain-containing histone
methyltransferase, methylates H3-K9 at
the SUPERMAN locus. HP1, which
binds specifically to tri-methylated H3K9, recruits CMT3, a DNA
methyltransferase.42 Moreover, in human
cells, methylation of H3-K9 is a marker
for gene silencing. MeCP2, a
transcriptional repressor which binds
methylated DNA, is associated with both
histone deacetylase and H3-K9
methyltransferase activity.
Chromatin-IP experiments have shown
that the promoter of the repressed gene
H19, for example, is associated with both
methylated H3-K9 and MeCP2.43 Thus,
DNA methylation and histone
methylation appear to be tightly
connected. Furthermore, H3-K9
methylation, as well as H3-K9
hypoacetylation, serves as a marker for Xchromosome inactivation.44 Also, on the
active X-chromosome, methylation at
H3-K9 is associated with inactive genes,
while methylation at H3-K4 is associated
with active genes.45 Su(var)3-9, a SET
domain-containing histone
methyltransferase, is responsible for
methylating H3-K9. Su(var)3-9 is
associated with HP1, which in turn binds
trimethylated H3-K9, suggesting a
mechanism for the spreading of
heterochromatin.46
H3-K79 is the unique non-N-terminal
residue being post-translationally
modified. Dot1p affects telomeric
silencing and methylates histone H3 at
K79. Deletion of DOT1 caused total loss
of H3-K79 methylation. In an H3-K79A
mutant background, telomeric silencing
was lost.47
Coactivators of the nuclear receptor
p160 locally modify chromatin structure
and help to recruit RNA polymerase II to
the gene promoter. In a yeast two-hybrid
screen, one member of the p160
coactivator complex associated with the
coactivator-associated arginine
methyltransferase (CARM1). CARM1
preferentially methylated histone H3, and
mutant derivatives of CARM1 reduced
both methyltransferase and coactivator
activities.48 Upon stimulation with
oestrogen, H3-R17 was methylated by
CARM1. Furthermore, CARM1 was
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In pancreatic cells, the
combination of histone
acetylation and
methylation contributes
to the activation of the
insulin promoter
H3 phosphorylation at
S10 is important for
gene regulation by
TNF-alpha and heat
shock
found to be associated with the S2 gene
promoter, which is regulated by the
oestrogen receptor.49
Lysine residues can be either
methylated or acetylated. There are
several lysine residues within the Nterminal tail of histone H3. So far, only
K14, K18 and K23 have been observed to
be acetylated; however, further
modifications possibly exist, and the
specific recognition of different enzymes
might be affected by the amino acid
sequence around the lysine residue. In
pancreatic B cells, the proximal insulin
promoter is hyperacetylated at histone H3
by HAT p300, compared with non-B
cells. The same promoter is
hypermethylated at H3-K4 by the histone
methyltransferase Set7. Therefore, the
regulation of the insulin promoter is likely
to be regulated by a combination of
transcription factors.50
Histone H3 is phosphorylated at S10
and S28. This modification is related to
cell division and the regulation of
transcription. Histone S10
phosphorylation is involved in the
condensation of the mitotic chromosome,
and never in mitosis gene A (NIMA)
kinase is required for entry into meiosis.
NIMA can phosphorylate H3-S10 in vitro,
as identified by a H3-S10A mutant.51
EGF-induced phosphorylation of H3-S10
required RSK-2, a kinase involved in
growth control. In the presence of growth
factor, an RSK-2-containing complex
interacted with the transcriptional
coactivator, CREB binding protein
(CBP). As CBP is a histone
acetyltransferase, phosphorylation and
histone acetylation might act together to
facilitate gene expression of mitogenresponsive promoters.52 Furthermore,
stimulation of phosphorylation and
acetylation of H3 by epidermal growth
factor was found to be synergistic and
sequential, as the acetyltransferase Gcn5
preferentially bound phosphorylated H3S10.53 IKK-alpha phosphorylated H3-S10
directly in vitro. Upon stimulation with
tumour necrosis factor-alpha (TNFalpha), IKK-alpha was shown to be
recruited to the promoter region of
nuclear factor kappa B (NF-kB)-regulated
genes. In cells deleted for IKK-alpha, H3S10 phosphorylation was abolished and
TNF-alpha regulation of gene expression
was suppressed.54 During mitosis and
meiosis, Ipl1/aurora kinase and Glc7/PP1
phosphatase dynamically regulate H3
phosphorylation in yeast. With the help
of S10A and S28A mutants, it was shown
that H3 is phosphorylated at S10 and not
at S28. Ipl1 also phosphorylates histone
H2B, which contains several serines
within its N-terminus.55 In response to
heat shock, acetylation of H3-K4
appeared unchanged, but the H3-S10
phosphorylation was redistributed. The
global level of phosphorylation decreased
but, at the heat shock loci, the level of
phosphorylation increased. The result
indicated that H3 phosphorylation plays
an important role in the transcriptional
regulation of the heat shock loci.56
Ubiquitination might play a role in
loosening the nucleosome structure in
preparation for histone removal. In
meiotic cells, the level of ubiquitinated
histone changed at different stages. Using
anti-ubiquitin antibodies, ubiquitinated
histone species were detected specifically
in elongating spermatids.57
The modification of the N-terminal
tails of the histones leads to the binding of
specific proteins. The transcriptional
repressor complex NuRD binds to the Nterminal tail of histone H3, regardless of
whether K9 is methylated or
unmethylated; however, methylation of
H3-K4 prevents binding.58 The
acetylated forms of histones H3 and H4 in
the nucleosomes positioned at promoters
are used by Spt-Ada-Gcn5acetyltransferase (SAGA) and SWI/SNF
complexes to anchor the complexes to
these promoter regions. The anchoring
required the bromodomains of Swi2 and
Gcn5, respectively.59,60 Trimethylated
H3-K9 is specifically recognised by the
chromo domain of HP1, and this
recognition is mediated by the Rb
protein.61 The DNA methyltransferases
(Dnmts) associate with histone H3-K9
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Global effects of histone modifications
H4 is differentially
acetylated by different
SRC co-activators and
different HAT
complexes
methyltransferase SUV39H1 via the plant
homeodomain (PHD) finger-like motif.
HP1 was found to be associated with both
SUV39H1 and Dnmts.62
Site-specific H3 tail modifications are
functionally interdependent. Human
SUV39H1 encodes an H3-K9-specific
methyltransferase containing a SET
domain. Methylation of H3-K9 is
influenced negatively by phosphorylation
of H3-S10.63 In S. cerevisiae, Snf1
phosphorylates H3-S10, followed by
Gcn5 acetylating H3-K14.64 Upon
repression with unliganded thyroid
hormone receptor (TR), methylation of
H3-K9 increased, while methylation of
H3-K4 and H3-R17 decreased. A doublemodified form phosphorylated at H3-S10
and acetylated at H3-K14 was also found
to decrease. Addition of ligand activated
the TR-repressed genes. This coincided
with a decrease in the methylated forms of
H3-K4 and H3-K9, while the methylated
form of H3-R17 increased, as did the
double-modified form pS10/acK14. TR
was found to interact with the histone
methyltransferase SUV39H1.65
HISTONE H4
Acetylation and deacetylation are
dynamic processes, which are executed
by specific histone acetyltransferases
(HATs) and histone deacetylases.
Acetylation is often connected to active
gene loci, while deacetylation is linked to
repression. Histone H4 from HeLa cells
was analysed with mass spectroscopy.
Although there are 15 possible acetylation
sites, only four acetylated lysines (K5, K8,
K12 and K16) were detected.66 Steroid
receptors regulate transcription by
recruiting coactivator complexes to the
promoters of their target genes. These
coactivators include members of the
steroid receptor coactivator (SRC)
family, SRC-1, SRC-2 and SRC-3. The
receptor-interacting domains of the
SRCs determine the preference for
specific receptors, while their
transcriptional activation domains
mediate interaction with HAT.
Progesterone receptor interacts with
SRC-1, which recruits CBP and thus
enhances the acetylation of H4-K5.
Glucocorticoid receptor interacts with
SRC-2, which recruits p300/CBPassociated factor (pCAF) and thus
promotes the acetylation of H3-K14.67
K20 and R3 are two potential sites for
methylation of histone H4. Methylation
of H4-K20 is catalysed by the PR-Set7, a
SET domain-containing histone
Table 1: The effects of histone modifications. The table summarises the effects of the singular
histone modifications described in this review; however, there is interdependency and crosstalk between the different histone modifications that can alter their individual effects
Histone
Modification
Effect
H1
Phosphorylation
Chromatin condensation; gene-specific activation and
repression
Transcriptional activation
Tetrahymena survival
Elusive
Prerequisite of H3 methylation
Chromatin condensation
Chromatin remodelling
Chromatin stabilisation
Elusive
Transcriptional activation
Transcriptional repression
Transcriptional activation
Chromatin condensation; transcriptional activation
Nucleosome loosening
Transcriptional activation
Transcriptional repression
Transcriptional activation
H2A
H2B
H3
H4
Ubiquitination
Acetylation
Ubiquitination
Ubiquitination
Phosphorylation
Acetylation
Methylation
ADP-ribosylation
Methylation (H3-K4, R17)
Methylation (H3-K9, K79)
Acetylation
Phosphorylation
Ubiquitination
Acetylation
Methylation (H4-K20)
Methylation (H4-R3)
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PRMT1, recruited by
transcriptional
activators, can
methylate H4
methyltransferase. This modification is
involved in gene silencing. PR-Set7 is
located on mitotic chromosomes, and its
activity was found to be cell cycleregulated.68,69 H4-R3 is methylated by
protein arginine methyltransferase
(PRMT1), a nuclear receptor coactivator.
H4-R3 methylation facilitates
transcriptional activation, as shown by
mice deleted for PRMT1. The
transcriptional activator YY1 has been
shown to bind to and recruit PRMT1 to
its target promoters.70
5.
Shen, X., Yu, L., Weir, J. W. and Gorovsky,
M. A. (1995), ‘Linker histones are not essential
and affect chromatin condensation in vivo’,
Cell, Vol. 82, pp. 47–56.
6.
Shen, X. and Gorovsky, M. A. (1996), ‘Linker
histone H1 regulates specific gene expression
but not global transcription in vivo’, Cell, Vol.
86, pp. 475–483.
7.
Barra, J. L., Rhounim, L., Rossignol, J. L. and
Faugeron, G. (2000), ‘Histone H1 is
dispensable for methylation-associated gene
silencing in Ascobolus immersus and essential for
long life span’, Mol. Cell. Biol., Vol. 20, pp.
61–69.
8.
Bouvet, P., Dimitrov, S. and Wolffe, A. P.
(1994), ‘Specific regulation of Xenopus
chromosomal 5S rRNA gene transcription in
vivo by histone H1’, Genes Dev., Vol. 8, pp.
1147–1159.
9.
Ushinsky, S. C., Bussey, H., Ahmed, A.A.
et al. (1997), ‘Histone H1 in Saccharomyces
cerevisiae’, Yeast, Vol. 13, pp. 151–161.
CONCLUSION
All five histone proteins are modified
inside the nucleus of the cell (Table 1),
but, so far, only modifications at H3
have clearly been shown to affect
transcription on a global rather than on a
gene-specific scale. Future work will go
towards deciphering the histone code.
There are a huge number of possible
combinations of histone modifications.
There is also interdependency and crosstalk between the different histone
modifications. Histone modifications
have been shown to serve as epigenetic
markers. The understanding of how the
cell interprets all of these combinations is
a prerequisite to solving the mysteries of
epigenetics.
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