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EMBO reports 4, 10, 944–947 (2003)
doi:10.1038/sj.embor.embor941
Regulating histone acetyltransferases and deacetylases
Gaëlle Legube & Didier Trouche
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Laboratoire de Biologie Moléculaire des Eucaryotes,
UMR 5099 Centre National de la Recherche Scientifique, 118 Route
de Narbonne, 31062 Toulouse Cedex,
France
To whom correspondence should be addressed
Didier Trouche Tel: +33 5 61 33 59 15; Fax: +33 5 61 33 58 868;
trouche@ibcg.biotoul.fr
Received 16 June 2003; Accepted 1 August 2003.
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Abstract
Histone acetyltransferases and histone deacetylases regulate the
acetylation of histones and transcription factors, and in doing so have major
roles in the control of cell fate. Many recent results have indicated that
their function is strictly regulated in cells through the modulation of their
levels, activity and availability for interaction with specific transcription
factors. In this review, we present the various molecular mechanisms that bring
about this tight regulation and discuss how these regulatory events influence
cellular responses to environmental changes.
EMBO reports 4, 10, 944–947 (2003)
doi:10.1038/sj.embor.embor941
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Introduction
In eukaryotes, the packaging of DNA in chromatin interferes with DNA
metabolic processes such as transcription, replication and DNA repair.
Chromatin structure and function can be affected by various post-translational
modifications of the amino-terminal tails of nucleosomal histones, of which
lysine acetylation is the best characterized. Acetylation is thought to
increase DNA accessibility through the neutralization of the positive charge of
lysine residues. This modification correlates largely with transcriptional
activation, but it is also involved in DNA replication, histone deposition and
DNA repair. Histone acetylation also regulates protein–protein
interactions, as some acetylated lysines are recognized by bromodomains, which
are found in many proteins that regulate chromatin function (Strahl & Allis, 2000).
Histone acetylation is catalysed by histone acetyl transferases
(HATs), whereas the reverse reaction is performed by histone deacetylases
(HDACs). HATs and HDACs are classified into many families that are often
conserved from yeast to humans (Marmorstein & Roth,
2001; Thiagalingam et al., 2003).
For example, human class I, class II and class III HDACs are homologous to the
yeast Rpd3, Hda1 and Sir2 HDACs, respectively. HATs and HDACs are usually
embedded in large multimolecular complexes (Fig. 1), in
which the other subunits function as cofactors for the enzyme, and they have a
strict specificity for acetylation sites. HATs and HDACs participate in the
genome-wide turnover of acetyl groups on histones and, in addition, some also
modify other factors. Through their physical interaction with sequence-specific
transcription factors, they are also targeted to specific promoters (Fig. 1), where they locally modify histones or transcription
factors and thus regulate gene transcription.
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Figure 1
Model of local action of histone acetyltransferases and histone
deacetylases. Histone acetyltransferases (HATs) and histone deacetylases
(HDACs) are recruited to their target promoters through a physical interaction
with a sequence-specific transcription factor (TF). They usually function
within a multimolecular complex ('enzymatic complex'), in which the other
subunits are necessary for them to modify nucleosomes around the binding site.
These enzymes can also modify factors other than histones (protein X) to
regulate transcription. Note that the position of the modified nucleosome that
is shown has been chosen at random for this figure.
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Because of the importance of histone acetylation in chromatin
function, HATs and HDACs have major roles in the control of cell fate and their
misregulation is involved in the development of some human tumours (Timmermann et al., 2001). Moreover, they are
targeted by many viral proteins, which often affect their activity (Caron et al., 2003). Consistent with the importance
of HATs and HDACs, they are tightly regulated in living cells and their
activity is modulated by signalling pathways.
Although many reviews have focused on the various HAT and HDAC
families and their roles in chromatin function, transcriptional regulation or
cell fate (for example, see Marmorstein & Roth,
2001; Thiagalingam et al., 2003),
none has extensively explored how their function can be regulated. Here, we
describe the various mechanisms by which mammalian cells control HAT and HDAC
activity, grouping them into three main classes that regulate the amount of
enzyme, their enzymatic activity, or their availability for interaction with
specific transcription factors.
Regulating enzyme quantity
As for all other proteins, an obvious way to regulate the activity
of HATs and HDACs is to regulate their expression, and indeed the transcription
of some of these enzymes is known to be tightly regulated during development.
Although the molecular mechanisms of this regulation and the signals involved
have, in most cases, not been defined, some interesting insights into the
transcriptional regulation of the Hdac1 gene promoter have been
obtained. For example, Hdac1 messenger RNA expression is induced by
histone hyperacetylation, which suggests that a feedback loop controls histone
acetylation levels in vivo (Hauser et al.,
2002). In addition, Hdac1 mRNAs levels increase in a mouse
lymphocyte cell line that has been stimulated with growth factors (for example,
interleukin-2 (IL-2); Bartl et al., 1997),
and in Swiss 3T3 cells that have been stimulated by serum (Hauser et al., 2002). This induction might be of
crucial importance for cell growth, as the inactivation of Hdac1 causes
proliferation defects in mice (Lagger et al.,
2002).
The intracellular level of a protein depends on the rate of its
translation and its half-life, and so far, one example of the regulation of HAT
stability has been described. Tip60, a HAT that is involved in apoptosis and
DNA repair after double-stranded breaks, is degraded by the proteasome after
ubiquitylation by the ubiquitin ligase Mdm2 (Legube et
al., 2002). Interestingly, DNA-damage-induced signalling leads to
Tip60 accumulation, which suggests that the response to DNA damage involves the
precise control of Tip60 expression. Similarly, Wiper-Bergeron and
collaborators found that Hdac1 is also subject to proteasome-dependent
degradation and that this process is important for glucocorticoid-induced
preadipocyte differentiation (Wiper-Bergeron et al.,
2003).
Regulating enzyme activity
Two main mechanisms that regulate the enzymatic activity of HATs and
HDACs have been described: post-translational modifications (see
supplementary information online for
a more complete list of HAT and HDAC post-translational modifications) and
protein–protein interactions. In addition, the availability of metabolic
cofactors might also influence acetylation levels.
Post-translational modifications. The activities of many HATs
and HDACs have been shown to be regulated through phosphorylation. For example,
the HAT activity of CREB-binding protein (CBP) is stimulated on phosphorylation
by cyclin E/cyclin-dependent kinase 2 (Ait-Si-Ali et
al., 1998). This event could be important for cell-cycle
progression, as the HAT activity of CBP is required for progression to S
phase.
The cellular response to DNA damage also involves changes in the HAT
activity of some enzymes as a result of their phosphorylation. For example,
activating transcription factor 2 (ATF2) is a sequence-specific transcription
factor that has HAT activity and is phosphorylated in response to irradiation
with ultraviolet light (Kawasaki et al.,
2000). This phosphorylation increases ATF2's HAT activity, which
leads to the transcriptional activation of promoters containing cAMP-responsive
elements, the DNA elements recognized by ATF2.
The enzymatic activities of HATs and HDACs can also be regulated by
other modifications; for example, HDAC4 has been shown to be sumoylated by the
SUMO (small ubiquitin-related modifier) E3 ligase RANBP2 (Kirsh et al., 2002). This seems to be important for
enzyme function, as a point mutation in the sumoylated residue reduces HDAC4
activity.
Protein–protein interactions. Both HATs and HDACs are
usually part of large, multimolecular complexes, which contain other components
that are often required for enzyme activity. However, the modulation of this
activity through the regulation of complex assembly has not been seen so far.
By contrast, many examples of the control of HAT activity by factors that are
not bona fide components of the complex have been described.
The activity of CBP or the closely related p300 HAT has been shown
to be stimulated in cis by a variety of sequence-specific transcription
factors such, as HNF1- , HNF4, Sp1, Zta, NF-E2, C/EBP- and
phosphorylated Elk1 (Chen et al., 2001;
Li et al., 2003; Soutoglou et al., 2001). Through this stimulation,
these sequence-specific transcription factors are thought to increase the
acetylation of histones (or other transcription factors) at their target
promoters. By contrast, other transcription factors, such as Msx3, Hox proteins
and Twist, block HAT activity (Hamamori et al.,
1999; Mehra-Chaudhary et al.,
2001; Shen et al., 2001), and
this property is shared by the Rsk2 kinase (Merienne et
al., 2001). Interestingly, some members of this latter class have
been shown to exert an effect in trans: for example, Twist can repress
the activity of many transcription factors that function through CBP or
p300/CBP-associated factor (pCAF; Hamamori et al.,
1999). Thus, binding of a transcription factor to a HAT can affect
gene expression through other transcription factors.
The activity of acetylation-controlling enzymes can also be
modulated through the recruitment to the complex of an enzyme that catalyses
the reverse reaction. Indeed, some complexes containing both HAT and HDAC
activities have been characterized. For example, sumoylated p300 can interact
with HDAC6, and this interaction brings about transcriptional repression
(Girdwood et al., 2003).
Availability of metabolic cofactors. The activity of enzymes
can also be regulated by the availability of cofactors. HAT activity is
dependent on the presence of acetyl-coenzyme A and it is therefore possible
that intracellular levels of this cofactor might be used to control acetylation
levels. However, this has not been described so far. The deacetylation reaction
catalysed by class I as well as class II HDACs does not require any cofactors,
whereas deacetylation by HDACs of the Sir2 family is dependent on the presence
of NAD+ (Denu, 2003). Interestingly,
a genetic link has been established between Sir2 and some enzymes belonging to
the NAD+ metabolic pathways, which suggests that metabolic
networks and acetylation levels are coupled.
Regulating enzyme availability
Many transcription factors regulate transcription by physically
recruiting HATs and HDACs to promoters (Fig. 1), and the
modulation of this interaction by signalling pathways has been widely
documented. In many cases, this regulation is achieved by post-translational
modifications of the transcription factors, but this is outside the scope of
this review. However, some examples have been described in which the enzyme
itself is directly targeted. The availability of HATs or HDACs can be regulated
by changing either their subcellular localization or their capacity to interact
with specific transcription factors.
The former is an attractive way to control acetylation levels, as
cytoplasmic enzymes cannot modify chromatin-incorporated histones. The
best-characterized example of such a mode of regulation is that of the class II
HDACs (see below). Another example is HDAC3, which can be relocated to the
cytoplasm by its physical interaction with the adaptor TAB2 protein in the
presence of IL-1 (Baek et al.,
2002).
The availability of HATs and HDACs for a given signalling event can
also be modulated in a more specific manner by changing their ability to be
recruited by specific transcription factors. For example, CBP is phosphorylated
in its GF box, and this phosphorylation is required for the recruitment of CBP
by the AP1 transcription factor (Zanger et al.,
2001). The methylation of CBP within its CREB-binding KIX domain by
coactivator arginine methyltransferase 1 (CARM1) decreases its affinity for
phosphorylated CREB, so that it is then available to interact with other
transcription factors (Xu et al., 2001).
Together, these results suggest that the range of transcription factors that
can recruit CBP is affected significantly by its post-translational
modifications.
What happens during signalling?
In general, the extent to which the molecular events described above
affect histone or protein acetylation levels in response to a signal is still
poorly understood. However, recent studies have described in detail some
molecular mechanisms that might represent paradigms of what happens during
signalling.
One example is the phosphorylation of class II HDACs that occurs
during muscle differentiation. Some type II HDACs, such as HDAC5, can bind to
and repress the activity of the myocyte enhancer factor 2 (MEF2) transcription
factor, which is important for muscle differentiation (McKinsey et al., 2001). On induction of muscle
differentiation, these class II enzymes are phosphorylated by
Ca2+/calmodulin-dependent protein kinases (CaMKs) and are
thereby relocalized to the cytoplasm. This regulation is of crucial importance
for muscle differentiation. Indeed, an HDAC5 that is mutated in its
phosphorylation site is constitutively localized to the nucleus and is a potent
inhibitor of myogenesis. Conversely, an HDAC5 mutant that is retained in the
cytoplasm is unable to inhibit muscle differentiation. These results have led
to a model in which muscle-specific genes are repressed in proliferating
myoblasts through the actions of class II HDACs associated with MEF2 (McKinsey et al., 2001). On the signal to
differentiate, phosphorylation of these HDACs creates a binding site for the
14-3-3 chaperone proteins, which leads to their nuclear export, and
muscle-specific genes are expressed. Consistent with this model, an increase in
histone acetylation of MEF2-dependent muscle-specific genes can be detected
during myogen-esis (Lu et al., 2000). Thus,
during the process of muscle differentiation, phosphorylation of class II HDACs
at the endpoints of signal transduction pathways seems to be directly
responsible for the regulation of histone acetylation on specific
promoters.
Another interesting example is the activation of immediate-early
genes after the stimulation of resting cells to proliferate. On growth factor
treatment, the signal is transduced through the mitogen-activated protein
kinase (MAPK) pathway to the nucleus. Activation of some immediate-early genes,
such as cIL8, relies on the phosphorylation of the transcription factor
Elk1 by Mapk. The involvement of p300 or CBP in immediate-early gene
transactivation has been widely documented, but the molecular mechanisms
underlying their action have remained largely unknown. Li and colleagues
recently reported that p300 was constantly present on the cIL8 promoter,
probably through its interaction with unphosphorylated Elk1 (Li et al., 2003). After signalling, Elk1
phosphorylation changes the Elk1/p300 contacts and p300 HAT activity is
induced. Thus, in this case, signal-induced gene transactivation is likely to
be due to the stimulation of p300 HAT activity after changes in its
interactions with a transcription factor.
Perspectives
Besides the regulatory events described above, HATs and HDACs are
subject to a variety of post-translational modifications, the molecular roles
of which remain largely uncharacterized (see
supplementary information online).
In some cases, these modifications are likely to have an important role, as
they affect the transcriptional activity of HATs and HDACs. For example,
phosphorylation of p300 at its carboxy terminus increases its ability to
coactivate the CEBP- transcription factor (Schwartz
et al., 2003), whereas phosphorylation of CBP by CaMK favours
its ability to mediate CREB transcriptional activation (Impey et al., 2002). In addtition, CBP methylation
by CARM1 outside the KIX domain is important for its ability to function as a
coactivator for the oestrogen receptor (Chevillard-Briet
et al., 2002). In all these cases, it would be interesting to
investigate whether these modifications affect the acetylation status of
specific promoters.
All of the studies described in this review have focused on the
molecular events that target the HATs and HDACs themselves. However, bona
fide enzymes are usually multimolecular complexes in which cofactors are
required for the catalytic subunit to modify nucleosomes. It will be
informative to investigate to what extent these cofactors are subject to
regulation, and whether signalling can affect their activity. In addition,
according to the 'histone code' hypothesis (Strahl &
Allis, 2000), which states that the various histone modifications act
interdependently to specify a given function for chromatin, acetylation is
linked to other histone modifications. Furthermore, HATs and HDACs function in
a concerted way with ATP-dependent chromatin-remodelling complexes. Regulation
of any of these enzymes, therefore, could add another layer of complexity to
the acetylation status of specific promoters.
Finally, a striking proportion of the molecular events described above
lead to the regulation of the CBP/p300 enzymes (see
supplementary information online;
Fig. 2). CBP and p300 have important roles in opposing
processes such as cell proliferation and terminal differentiation (Goodman
& Smolik, 2000). Moreover, they can co-activate many different
transcription factors. Their levels are thought to be limiting in cells, and so
their activity and availability are likely to be tightly regulated.
Post-translational modifications of these proteins might act in concert to
specify a functional state and, as already suggested (Gamble
& Freedman, 2002), this could establish the 'CBP/p300 code' in a
manner reminiscent of the popular histone code. The binding of proteins that
affect CBP/p300 functions (see above) could also be involved in the
establishment of the code. It will be interesting to determine whether such a
code is restricted to CBP/p300 or applies more generally to the other HATs or
HDACs that are important for cell fate.
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Figure 2
Functional 'code' of CREB-binding protein/p300 post-translational
modifications. Representation of the CREB-binding protein (CBP) and p300
histone acetyl transferases including their functional domains
(cysteine/histidine-rich domains (CH1 and CH3); CREB-binding domain (KIX);
bromodomain (Br); and acetyl transferase domain (AT)) and some of their
post-translational modifications (phosphorylation (P); methylation (Met); and
sumoylation (Sumo)). The post-translational modifications activating (in green)
or inhibiting (in red) CBP or p300 enzymatic activity (filled circles) or
transcriptional activity (empty circles) are shown. The transcription factors
for which binding to CBP or p300 is affected by CBP/p300 modifications are also
shown. Note that some modifications have only been documented for CBP or for
p300. The lines below some modifications indicate the region in which the
modification occurs for sites that have not been fully characterized. NR,
nuclear receptor superfamily.
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Supplementary
information is available at EMBO reports online
(http://www.emboreports.org).
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Acknowledgements
We thank L. Vandel and V. Régnier for critical reading of the
manuscript. We apologize to our colleagues for important studies that have not
been cited due to space limitations. D.T. is supported by a grant from the
Ligue Nationale Contre le Cancer as an Equipe Labellisée. G.L. is the
recipient of a studentship from the Ligue Nationale Contre le Cancer.
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