Keywords: chromatin; chromatin remodeling; coactivators; corepressors; histone acetyltransferase; histone deacetylase; histone kinase; histone methyltransferase; nuclear receptor; transc
Trang 1M I N I R E V I E W
Nuclear receptor-dependent transcription with chromatin
Is it all about enzymes?
W Lee Kraus1,2and Jiemin Wong3
1
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA;2Department of Pharmacology, Weill Medical College of Cornell University, New York, USA;3Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza Houston, TX, USA
Nuclear receptors (NRs) are ligand-regulated,
DNA-bind-ing transcription factors that function in the chromatin
environment ofthe nucleus to alter the expression ofsubsets
ofhormone-responsive genes It is clear that chromatin,
rather than being a passive player, has a profound effect on
both transcriptional repression and activation mediated by
NRs NRs act in conjunction with at least three general
classes ofcofactors to regulate transcription in the context of
chromatin: (a) chromatin remodelers; (b) corepressors; and
(c) coactivators, many ofwhich have distinct enzymatic
activities that remodel nucleosomes or covalently modify
histones (e.g acetylases, deacetylases, methyltransferases, and kinases) In this paper, we will present a briefoverview of these enzymes, their activities, and how they assist NRs in the repression or activation oftranscription in the context of chromatin
Keywords: chromatin; chromatin remodeling; coactivators; corepressors; histone acetyltransferase; histone deacetylase; histone kinase; histone methyltransferase; nuclear receptor; transcription
I N T R O D U C T I O N
Nuclear receptors (NRs) comprise a large superfamily of
DNA-binding transcriptional regulatory proteins that
con-trol the expression ofdistinct subsets ofgenes in the
chromatin environment ofthe nucleus [1–3] In many cases,
the activities ofthe receptors are modulated by the binding
ofhormonal ligands (e.g steroids, retinoids, thyroid
hormone, and vitamin D3), which function as key regulators
in numerous physiological processes (e.g growth,
develop-ment, metabolism, homeostasis, and reproduction) [1,2]
Most nuclear receptors share a conserved structural and
functional organization, including a highly conserved
DNA-binding domain, a C-terminal ligand-binding
domain, and two transcriptional activation functions (an N-terminal AF-1 and a C-terminal AF-2) (Fig 1) [1,2] The two most widely studied classes ofNRs can be categorized based on their dimerization and DNA binding properties: (a) class I contains the steroid hormone receptors, which function primarily as homodimers, and (b) class II contains the vitamin and thyroid hormone receptors, which function primarily as heterodimers with RXR [2] The structural organization ofthe receptors makes them ideally suited for the transduction ofhormonal signals into gene-regulatory transcriptional responses
During the regulation ofhormone-responsive genes, NRs must gain access to their cognate receptor binding sites (hormone response elements, or HREs) in promoter DNA that is assembled into chromatin, the physiological template for transcription [3,4] The packaging of genomic DNA into nucleosomes (protein–DNA structures which are the repeat-ing units ofchromatin) restricts the access ofthe transcrip-tional machinery to the promoters ofhormone-regulated genes, thereby reducing the transcription ofthose genes [3–5] Although chromatin was at one time largely overlooked or considered a passive player in NR-dependent transcription,
it is now clear that it plays a critical role The importance ofchromatin in achieving a proper ligand-regulated, NR-dependent transcriptional response (i.e on/off switch-ing with/without hormone) has been demonstrated experi-mentally using both in vitro and cell-based assays [6,7] NRs make use ofchromatin to apply an exquisite level oftranscriptional control to the genes that they regulate (i.e repress or activate), but they do not carry out this alone NRs act in conjunction with at least three general classes of cofactors to regulate transcription in the context of chro-matin, namely: (a) chromatin remodelers; (b) corepressors; and (c) coactivators, many ofwhich have distinct enzymatic activities [4,8,9] For example, chromatin remodeling
Correspondence to W L Kraus, Department ofMolecular Biology
and Genetics, Cornell University, 465 Biotechnology Building, Ithaca,
NY 14853, USA.
Fax: + 1 607 255 6249, Tel.: + 1 607 255 6087,
E-mail: wlk5@cornell.edu,
Abbreviations: CARM, coactivator associated arginine
methyltrans-ferase; CBP, CREB-binding protein; HAT, histone acetyltransmethyltrans-ferase;
HDAC, histone deacetylase; HMT, histone methyltransferase; NCoR,
nuclear receptor corepressor; NR, nuclear receptor; PCAF, p300/
CBP-associated factor; PRMT, protein arginine methyltransferase;
SMRT, silencing mediator for retinoid and thyroid hormone
recep-tors; SRC, steroid receptor coactivator.
Note: a homepage for W L Kraus can be found at
http://www.mbg.cornell.edu/kraus/kraus.html The Cornell University
Department ofMBG homepage can be found at
http://www.mbg.cornell.edu.
Dedication: This Minireview Series is dedicated to Dr Alan Wolffe,
deceased 26 May 2001.
(Received 8 October 2001, accepted 7 December 2001)
Trang 2complexes contain ATPase subunits [10] Likewise,
corepressor and coactivator complexes contain histone
modifying enzymes (e.g acetylases, deacetylases,
methyl-transferases, and kinases) that covalently modify specific
lysine, arginine, or serine residues in the N-terminal tails of
the core histones [4,11–14] One consequence ofthese
post-translational modifications may be to specify a Ôhistone
codeÕ that directs the binding ofvarious regulatory factors,
via specific chromatin-binding domains (e.g bromodomains
and chromodomains), to the histone tails [13] The various
enzymatic activities listed above are recruited to
hormone-responsive promoters via direct or indirect interactions with
NRs and subsequently modify their chromatin substrates to
regulate transcription by RNA polymerase II (RNA pol II)
(Fig 2) [3,4,8]
In this paper, we will present a briefoverview ofthese
enzymes, their activities, and how they assist NRs in the
repression or activation oftranscription in the context of
chromatin Although the methods used to generate this
information will not be presented in detail, many of them
have recently been reviewed elsewhere [15]
C H R O M A T I N M O D I F Y I N G E N Z Y M E S
A N D T H E R E P R E S S I O N
O F T R A N S C R I P T I O N B Y N R s
Histone deacetylases (HDACs)
Many class II NRs, including thyroid hormone receptor
and retinoic acid receptor, have the capacity to actively
repress the transcription oftheir target genes in the absence
oftheir cognate ligands [3,4,9,16] Early competition
experiments indicated that NR-dependent transcriptional
repression requires cellular accessory proteins, termed
corepressors [17,18] Two closely related corepressors,
SMRT and NCoR, were subsequently identified in yeast
two-hybrid screens based on their ability to interact with
unliganded NRs [19,20] The requirement ofcorepressors
for repression by unliganded NRs is clearly illustrated by a
lack ofNR-dependent repression in isolated NCoR–/–
mouse embryo fibroblasts [21] Although transcriptional
repression can be mediated via direct targeting ofthe basal
transcription machinery by unliganded NRs and/or
core-pressors [22,23], strong evidence indicates that chromatin
structure plays a pivotal role in repression by unliganded
NRs [6,24,25] The importance ofchromatin in
NR-dependent repression was demonstrated in studies using
Xenopus oocytes showing that repression ofthe TRbA
promoter by unliganded TR/RXR heterodimers requires
the proper assembly ofthe promoter into chromatin [6]
Following the identification ofSMRT and NCoR as
corepressors for NRs, a number of studies were published
implicating histone deacetylase (HDAC) enzymes in
SMRT/NCoR-dependent transcriptional repression by unliganded NRs (reviewed in [4,9,11,12,16]) The identifi-cation ofHDACs as components ofNR corepressor complexes, in conjunction with a well documented correla-tion between hypoacetylated core histones and transcrip-tionally inactive chromatin [13,26], has led to a major effort
to clarify the roles of HDACs in repression by unliganded NRs Currently, three major classes ofHDACs have been identified Class I includes HDACs 1, 2, 3, and 8, which are related to the yeast transcriptional regulator Rpd3p, and class II includes HDACs 4, 5, 6, and 7, which are related to yeast Hda1p [27] The third class ofHDACs are the NAD+-dependent Sir2 family proteins [28] While it is clear that HDAC activity is essential for repression by unliganded nuclear receptors [24,25], questions remain regarding which HDACs are involved and how they are recruited by unliganded NRs
Class I HDACs, specifically HDACs 1 and 2, were the first to be implicated in NR-dependent transcriptional repression, as they were found to interact with mammalian Sin3 proteins (Sin3A and Sin3B), which in turn were found
to interact with both SMRT and NCoR [29,30] The observed interactions between Sin3 and the corepressors led
to a model where unliganded NRs could repress tran-scription, at least in part, through the recruitment of Sin3-HDAC1/2 complexes by SMRT or NCoR [29,30] However, the role ofSin3 proteins in repression mediated by SMRT and NCoR is not as straightforward as the model suggests Some reports indicate that purified native SMRT– NCoR complexes contain Sin3 [31,32], while others indicate that the purified repressor complexes contain none [31,33– 35] Whether this discrepancy reflects differences in the purification protocols used, the existence ofdistinct or heterogeneous SMRT–NCoR complexes, or variations in the strength ofassociation ofSin3 complexes with different corepressor complexes under different cellular conditions is presently unclear Further studies will be required to sort out these possibilities
Class II HDACs, including HDACs 4, 5, 6, and 7, have been shown to interact directly with SMRT and NCoR, thus representing a second possible mechanism by which HDAC activities can be recruited to unliganded NRs [36,37] However, the extent to which class II HDACs contribute to repression by unliganded NRs is an open question, as native SMRT and NCoR complexes purified from human cells or Xenopus oocytes have so far only been found to contain class I HDACs (primarily HDAC3, but also HDACs 1 and 2) [31–33,35] Thus, the relative importance ofclass I and class II HDACs in NR-dependent transcriptional repression remains undetermined Interest-ingly, the class I HDAC3 has also recently been shown to interact directly with SMRT and NCoR, leading to a stimulation ofHDAC activity [38] Such interactions that alter enzyme activity could provide an additional level of regulatory control
A third mechanism by which class I or II HDAC complexes might contribute to NR-dependent transcrip-tional repression is through a nontargeting mechanism In this scenario, interactions with histone-binding proteins such as RbAp46/48, which are found in HDAC com-plexes [11,12], could direct the HDACs to the chromatin template rather than HDAC-corepressor–NR interactions Whether this occurs in vivo has not been determined
Fig 1 NRs share a conserved structural and functional organization,
including a highly conserved DNA-binding domain (DBD), a C-terminal
ligand-binding domain (LBD), and two transcriptional activation
func-tions (AF-1 and AF-2).
Trang 3Regardless ofhow the HDACs are brought to the
chromatin template, it is clear that they play an important
role in transcriptional repression by unliganded NRs in
the context ofchromatin Although HDACs have also
been shown to deacetylate nonhistone substrates,
inclu-ding acetylated p53 and NF-jB [39–41], a role for factor
deacetylase activity in NR-dependent transcription has not
been demonstrated
HDAC complexes containing chromatin remodelers
At least two types ofHDAC complexes containing
ATP-dependent chromatin remodeling activities have been
iden-tified The first includes variations ofthe Mi-2/NURD
complex [42–48], which in its most complete form contains
HDACs 1 and 2, the histone-binding proteins RbAp46/48,
the Snf2-related ATPase Mi-2, and methyl-DNA binding
proteins such as MBD2 and MeCP1 [49] The second is the
NCoR-1 complex, which contains NCoR, HDAC3, and
several subunits ofthe SWI/SNF complex, including the
Snf2-related ATPase Brg1 [32] Of the two types of
complexes, only the Mi-2/NURD complex has been shown
to repress transcription in biochemical assays, which it does
through remodeling and histone deacetylation
ofnucleo-somes assembled from methylated DNA [49] The role of
HDAC/chromatin remodeler complexes in NR-dependent
transcriptional repression has not been investigated
exten-sively However, one study has shown that microinjection of
neutralizing antibodies against Mi-2 (also known as CHD4)
partially relieves TR-dependent transcriptional repression in
Xenopus oocytes [46] These results suggest a role for
HDAC–chromatin remodeler complexes in NR-dependent
repression However, further studies in this area are clearly
needed Interestingly, the expression ofgenes encoding a
number ofNRs (including estrogen receptor and retinoic
acid receptor b) has been shown to be inhibited through CpG
methylation ofthe NR gene promoter DNA in some cancer
cell lines [50] Thus, methylation-targeted Mi-2/NURD
complexes might play a role in regulating NR activity by
altering NR expression in some pathological states
Histone methyltransferases (HMTs)
In addition to acetylation, core histones, especially H3 and H4, are also targets for methylation A number of histone methyltransferases (HMTs) have been identified, including: (a) the H3 lysine 9 (H3-K9)-specific HMTs Suv39H1 and G9a, which are involved in transcriptional repression or silencing [51,52]; (b) the H3 lysine 4 (H3-K4)-specific HMT Set 9 (also known as Set7), which is involved in transcrip-tional activation [53,54]; and (c) members ofthe protein arginine methyltransferase (PRMT) family, such as PRMT1 and CARM1, which are also involved in transcriptional activation [55–58] While no specific methyltransferase has been reported to participate in transcriptional repression by unliganded NRs, it is worth mentioning these enzymes because they may indirectly reduce the transcriptional activity ofNRs For example, Suv39H1 is a heterochroma-tin-associated, SET domain-containing protein with intrin-sic H3 lysine 9-specific HMT activity [51] The methylation ofH3 lysine 9 in nucleosomes generates a binding motiffor the chromodomain ofthe heterochromatin-associated pro-tein HP1, which can promote the formation of higher order chromatin structures that are repressive to transcription [59,60] Previous studies have shown that the incorporation oflinker histones into chromatin, which also promotes the formation of higher order chromatin structures, reduces NR-dependent transcription [61–63] Thus, it is possible that a similar effect will be observed with HP1 Whether unliganded NRs use lysine-specific HMTs to actively repress transcription, however, remains to be determined
C H R O M A T I N M O D I F Y I N G E N Z Y M E S
A N D T H E A C T I V A T I O N
O F T R A N S C R I P T I O N B Y N R s ATP-dependent chromatin remodelers
As mentioned above, the packaging ofgenomic DNA into nucleosomes restricts the receptor-dependent assembly of transcription complexes at the promoters ofhormone-regulated genes Unlike many DNA-binding transcriptional regulators, NRs bind stably and with reasonably high affinity to DNA even when their cognate HREs are assembled into chromatin [3] Thus, the relevant issue seems
to be how the receptors promote the formation of an open chromatin architecture at the promoter One way is through the ligand-dependent recruitment ofchromatin remodeling complexes, which are multipolypeptide enzymes categorized
by the type ofATPase subunit that they contain, including yeast Snf2-like (e.g SWI/SNF) or Drosophila ISWI-like (e.g RSF, CHRAC, ACF) [10] Human SWI/SNF (hSWI/ SNF) represents a family of related complexes usually containing eight or nine subunits, with either hBrg1 or hBrm as the ySnf2-related ATPase subunit; however, the exact composition ofthe complexes can vary from one cell type to the next [10] Chromatin remodeling complexes use the energy stored in ATP to mobilize or structurally alter nucleosomes, allowing greater access ofthe transcriptional machinery to promoter DNA, thus facilitating transcrip-tional activation [3,4,8,10,64]
The involvement ofSWI–SNF complexes in NR-dependent transcription was originally suggested by studies
in yeast and mammalian cells showing a stimulatory effect
Fig 2 Multiple proteins with chromatin remodeling or histone
modify-ing activities facilitate transcriptional regulation (repression and
activa-tion) by NRs See the text for abbreviations and details.
Trang 4ofSWI–SNF components on NR-dependent activity [65–
68] Since then, additional cell-based approaches have
supported these results, including experiments showing a
requirement for hBrg1-receptor interactions in estrogen
receptor and glucocorticoid receptor gene regulatory
activ-ity [69,70] and chromatin immunoprecipitation (ChIP)
experiments showing the recruitment ofhBrg1 to an
estrogen-regulated promoter upon hormonal stimulation
[70] Recently, a direct demonstration ofthe requirement for
the hSWI/SNF complex in receptor-dependent
transcrip-tion was made using the purified complex and an in vitro
chromatin assembly and transcription system with retinoic
acid receptor/RXR heterodimers [71] Additional in vitro
transcription experiments have shown that recombinant
ISWI can support progesterone receptor-dependent
trans-cription with chromatin templates [72] These in vitro
studies, in conjunction with previous cell-based studies,
make the important point that although ATP-dependent
chromatin remodeling is required for NR-dependent
trans-cription, it is not sufficient [71,73,74] Chromatin
remode-ling may set the stage for subsequent actions by coactivators
with histone modifying activities, such as histone
acetyl-transferases [8,71,74,75]
Histone acetyltransferases (HATs)
Numerous studies in yeast and higher eukaryotic organisms
have demonstrated a link between the acetylation ofspecific
lysine residues in the N-terminal tails ofcore histones (e.g
histone H3 lysine 14) and the activation oftranscription
[26,76] An intriguing connection between NRs and
chro-matin was made when some nuclear receptor coactivators,
including p300 and CBP (two closely related factors
commonly referred to collectively as p300/CBP), as well as
PCAF (p300/CBP-associated factor), were found to possess
intrinsic nucleosomal HAT activity [77–79] Although initial
studies suggested that both p300/CBP and PCAF bind
directly to NRs [80,81], more recent results indicate that the
interaction ofp300/CBP with many NRs is mainly indirect,
and mediated by the SRC (steroid receptor coactivator)
family of bridging factors [82–85] Interestingly, some
reports [86,87], but not others [84,88], have suggested that
members ofthe SRC family also possess a weak intrinsic
HAT activity Recent biochemical experiments indicate that
a critical function of ligand-activated, DNA-bound NRs is
to serve as nucleation sites for the recruitment of HAT
enzymes to promoters in chromatin [83], a conclusion
consistent with ChIP assays showing ligand-dependent
recruitment ofHATs to hormone-regulated promoters
in vivo[89,90]
The link between histone acetylation and transcriptional
activation is, by now, well-established, yet the exact
mechanism ofhow histone acetylation leads to enhanced
activation is not clear Although histone acetylation was
originally thought to facilitate chromatin remodeling by
ÔlooseningÕ the association ofthe histone octamer with DNA
through the neutralization ofpositive charges in the histone
tails, more recent results suggest that histone acetylation
may require prior chromatin remodeling or may occur at a
post-remodeling step [8,71,74,75] The results ofone study
suggest that post-remodeling histone acetylation by p300
may direct the transfer of histone H2A–H2B dimers from
nucleosomes to a histone chaperone [75] Such an effect may
help to establish and maintain an open chromatin confi-guration conducive to transcription The differences observed in the order ofaction ofchromatin remodelers and HATs in different experimental systems have not been adequately explained, but may represent promoter-specific types ofregulation [8] Recent results suggest another role for histone acetylation, namely to create binding sites on the amino-terminal tails ofcore histones for acetylated lysine binding domains, such as the bromodomain (reviewed in [91]), similar to the way that methylated H3-K9 serves as a binding site for chromodomain-containing proteins (des-cribed above) A mechanism like this may allow for the recruitment ofbromodomain-containing factors (e.g the HAT TAFII250) to promoters that have nucleosomal histones with specific patterns ofacetylation [91] Another question related to histone acetylation is why a number of different HATs are required by NRs to activate the transcription ofgenes in chromatin The fact that p300/ CBP and PCAF have different histones [77–79,92] and nonhistones (see, for example [93–95]), substrate specificities may provide the answer, as each can acetylate a distinct set oftargets, possibly directing a distinct set ofoutcomes Although HAT activity is critical for NR-dependent transcription, it is important to note that coactivators such as PCAF (which is found in a large multipolypep-tide complex with a number ofother transcription-related factors [96]) and p300/CBP contribute other activities to the transcription process For example, p300/CBP inter-acts with RNA pol II complexes [97] and possesses a glutamine-rich C-terminal region similar to the gluta-mine-rich activation domains found in some transcrip-tional activators, suggesting that p300/CBP may also function as ÔclassicalÕ coactivator by interacting with RNA pol II [98] Furthermore, both PCAF and p300/ CBP can acetylate nonhistone, transcription-related fac-tors, which in many cases has been shown to alter the activity ofthose factors (reviewed in [99]) For example, the acetylation ofSRC3 (also known as ACTR, an SRC family member) by p300 was shown to cause a disruption ofreceptor–coactivator complexes, leading to
a decrease in receptor-mediated gene activation [90] Estrogen receptor alpha has been shown to be a target for p300-mediated acetylation, which may alter the transcriptional activity ofthe receptor [100] Thus some HATs, such as p300/CBP and PCAF, serve as multi-functional coactivators for NR-dependent transcription, contributing multiple activities to the process
HMTs Although some HMTs, such as Suv39H1 described above, are involved in gene silencing, other HMTs are involved in gene activation In a recent collection ofexperiments, two PRMT (protein arginine methyltransferase) family mem-bers, CARM1 (coactivator-associated arginine methyl-transferase) and PRMT1, were shown to interact with SRC2 (also known as GRIP1, an SRC family member) and enhance the activity ofa variety ofnuclear receptors in mammalian cell-based reporter gene assays [55,56], as well
as Xenopus microinjection experiments [57] The stimulation ofreceptor activity by CARM1 and PRMT1 was shown to
be dependent on the presence ofthe SRC protein and require the intrinsic methyltransferase activities of CARM1
Trang 5and PRMT1 [55–57] Both CARM1 and PRMT1 can
methylate histones in vitro [56,57], and recent studies suggest
that both do so in vivo as well [57,58,101] Interestingly,
CARM1 and PRMT1 exhibit different HMT specificities;
CARM1 primarily methylates arginines 17 and 26 of
histone H3 (H3-R17 and R26) [102], whereas PRMT1
methylates arginine 3 ofhistone H4 (H4-R3) [57] The fact
that these two methyltransferases have distinct, rather than
overlapping, HMT specificities may underlie the synergism
that has been observed between them during the stimulation
ofNR activity [55] Like the HATs mentioned above,
CARM1 and PRMT have also been shown to methylate
nonhistone substrates (e.g p300/CBP by CARM1; STAT1
by PRMT1), thereby regulating the transcriptional activity
ofthe target proteins [103,104] However, the role offactor
methylation in NR-dependent transcription has not yet
been explored in detail
Interestingly, cooperative functional interactions between
HMTs and HATs have been observed during the
stimula-tion ofNR activity (e.g synergism between CARM1 and
p300 with estrogen receptor) [105] The interplay between
HMTs and HATs can be observed at the enzymatic level, as
well For example, methylation ofH4-R3 by PRMT1 was
shown to increase acetylation ofH4-K8 and K12 by p300
[57] In contrast, preacetylation ofH4 reduced subsequent
H4-R3 methylation by PRMT1 [57] Although not
demon-strated in the context ofNR-dependent transcription,
H3-K4 methylation by Set9 (also known as Set7) has been
shown to antagonize H3-K9 methylation by Suv39H1, and
vice versa[53,54] Furthermore, pre-methylation by Set9 and
Suv39H1 ofH3 in a core histone mixture had different
effects on the subsequent acetylation of H3 and H4 by p300,
with Set9 stimulating and Suv39H1 inhibiting the
p300-mediated acetylation [54] These results illustrate the
com-plex interactions that can occur between different factors
with histone modifying activities, generating interplay at the
level ofthe nucleosome that results in a Ôcombinatorial
histone codeÕ [91] Furthermore, they suggest that dissecting
the individual contributions ofparticular HMTs and HATs
in the context ofa large, NR-dependent transcriptional
regulatory complex may be difficult, as each effect may be
subtle and may influence the activity ofother factors in the
complex This will be an important area ofcontinued
investigation
Linker and core histone kinases
Linker histones, such as histone H1, bind to the linker
DNA flanking the nucleosome core In doing so, they
facilitate the compaction of chromatin into higher order
chromatin structures, which can lead to the repression of
transcription with a variety ofDNA-binding activators,
including NRs [61,106,107] Interestingly, the repression of
NR activity by histone H1 can be relieved by the
ligand-dependent phosphorylation ofH1 by cdk2 (and possibly
other kinases, as well), which leads to the removal ofH1
from the promoter region [62,108,109] Thus,
post-trans-lational modification oflinker histones must be considered
when evaluating the transcriptional activity ofNRs with
chromatin Interestingly, recent studies suggest that
another post-translational modification ofH1, namely
ubiquitination, may also play a role in regulating the
repressive effects of H1 [110] However, this has not yet
been shown to play a role in modulating NR transcrip-tional activity
In addition to the phosphorylation oflinker histones, the phosphorylation ofthe core histone H3, specifically at serine
10, has also been shown to enhance the transcription of genes in chromatin (reviewed in [13]) The phosphorylation ofH3-S10 appears to be tied to intracellular protein kinase signaling pathways [111,112] and can enhance the subse-quent acetylation ofnearby lysine residues [111,113,114] Thus, as was observed for methylation and acetylation of H4 [57], phosphorylation and acetylation ofH3 are functionally linked Although H3 phosphorylation has not yet been demonstrated to play a role in NR-dependent transcription with chromatin, it seems likely to play a role
In this regard, it is interesting to note that some ofthe same signaling pathways that enhance H3-S10 phosphorylation (e.g MAP kinase) [111,112] have been shown to enhance
NR transcriptional activity [115,116]
C O N C L U S I O N S
In closing, we should ask, ÔIs NR-dependent transcription with chromatin really all about enzymes?Õ Given the fact that NRs rely on coactivators that target the basal transcriptional machinery (e.g the mediator complexes) [117] in addition to enzymes involved in chromatin remodeling and histone modification, the answer is no Nonetheless, it is clear that the enzymes described herein play critical roles in the process ofNR-stimulated tran-scription by RNA pol II, which is itselfa complex and fascinating enzyme As noted above, gaps remain in our understanding ofwhich specific enzymes regulate the transcriptional activity ofNRs with chromatin, how they
do it, and how they are regulated These questions will be important avenues ofinvestigation in the future
A C K N O W L E D G E M E N T S
The research ofW L K is supported by grants from the NIH, the Burroughs Wellcome Fund, and the Susan G Komen Breast Cancer Foundation The research ofJ W is supported by grants from the NIH and US Army Medical Research.
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