The BRG1 transcriptional coregulator
Kevin W.Trotter and Trevor K. Archer
Corresponding Author: firstname.lastname@example.org
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park,
North Carolina, USA
The packaging of genomic DNA into chromatin, often viewed as an impediment to the transcription process,
plays a fundamental role in the regulation of gene expression. Chromatin remodeling proteins have been
shown to alter local chromatin structure and facilitate recruitment of essential factors required for transcription.
Brahma-related gene-1 (BRG1), the central catalytic subunit of numerous chromatin-modifying enzymatic
complexes, uses the energy derived from ATP-hydrolysis to disrupt the chromatin architecture of target
promoters. In this review, we examine BRG1 as a major coregulator of transcription. BRG1 has been implicated
in the activation and repression of gene expression through the modulation of chromatin in various tissues
and physiological conditions. Outstanding examples are studies demonstrating that BRG1 is a necessary
component for nuclear receptor-mediated transcriptional activation.The remodeling protein is also associated
with transcriptional corepressor complexes which recruit remodeling activity to target promoters for gene
silencing.Taken together, BRG1 appears to be a critical modulator of transcriptional regulation in cellular
processes including transcriptional regulation, replication, DNA repair and recombination.
Received September 21st, 2007; Accepted January 23rd, 2008; Published February 1st, 2008 | Abbreviations: AR: androgen receptor; ARID:
AT-rich interaction domain; BAF:BRG1/hBrm-associated factors; BRG1:brahma-related gene-1; BRK:BRM and KIS; CARM1:coactivator-associated
arginine methyltransferase-1; CDK:cyclin-dependent kinase; DBD:DNA-binding domain; ER:estrogen receptor; GR:glucocorticoid receptor; hBrm:
human brahma; HDAC: histone deacetylase; HDAC3: histone deacetyltransferase 3; HMT: histone methyltransferase; HP-1: heterochromatin
protein-1; HRE: hormone response element; HSA: helicase/SANT-associated; KAP-1: Krab associated protein 1; LTR: long terminal repeat; MBD:
methyl CpG-binding protein; MMTV: mouse mammary tumor virus; N-CoR-1: nuclear receptor corepressors-1; NF1: nuclear factor-1; NLS: nuclear
localization signal; NR: nuclear receptor; NUMAC: nucleosomal methylation activation complex; OTF: octamer transcription factor; PBAF:
polybromo-associated BAF; PIC: preinitiation complex; PPARγ: peroxisome proliferator-activated receptor γ; PR: progesterone receptor; QLQ:
Glutamine-Leucine-Glutamine; RAR: retinoic acid receptor; Rb: retinoblastoma tumor suppressor; REST: repressor element 1-silencing transcription
factor; RSC:remodeling the structure of chromatin; SMARCA4:SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily
a, member 4; SWI/SNF: mating-type switching and sucrose non-fermenting; TAT: tyrosine aminotransferase; TBP: TATA binding protein; TO:
tryptophan oxygenase; VDR: vitamin-D receptor; WINAC: WSTF including nucleosome assembly complex; WSTF: Williams syndrome transcription
factor; ZFP: zinc finger proteins | Copyright © 2008, Trotter and Archer.This is an open-access article distributed under the terms of the Creative
Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use distribution and reproduction in any medium, provided
the original work is properly cited.
Cite this article: Nuclear Receptor Signaling (2008) 6, e004
The packaging of genomic DNA into nucleosomes, the
fundamental unit of chromatin, creates a barrier to nuclear
processes, such as transcription, by obstructing the
association of essential factors and gene-specific
regulators to recognition sequences within target
promoters.The regulation of genetic information from a
highly organized chromatin structure is essential for
normal cellular growth, development, differentiation and
genomic stability [Chen et al., 2006; Hansen, 2002;
Workman and Kingston, 1998].The basic unit of
chromatin structure is the nucleosome, which consists of
146 bp of genomic DNA wrapped around two copies each
of core histone proteins H2A, H2B, H3 and H4 [Wolffe,
2001]. Regions of DNA between adjacent nucleosomes
are occupied with a molecule of linker histone protein,
H1 [Aoyagi et al., 2005; Hayes and Hansen, 2001].The
association of H1 facilitates condensation of the chromatin
structure into 30-nm fibers which in turn self-assembles
and organizes into a higher ordered architecture resulting
in the formation of the chromosome [Tremethick, 2007;
Mammalian genes, assembled into chromatin using a
combination of histone and non-histone proteins, can
adopt a multilayered chromatin structure that can be
spatially divided into transcriptionally “active” or “inducible”
euchromatic, or into mostly “silent” or “inactive”
heterochromatic conformations, according to different
cellular circumstances [Horn and Peterson, 2006].These
modulations of chromatin structure, that often accompany
transcriptional regulation, frequently require the enzymatic
activity of multi-protein complexes to alter the
nucleosomal arrangement [Felsenfeld and Groudine,
2003; Kinyamu and Archer, 2004]. At least two highly
conserved chromosome-modifying enzymatic activities
have been described that alter chromatin structure
through disruption of histone-DNA contacts by
ATP-dependent chromatin remodeling complexes, or by
covalent modification of histone tails by means of
acetylation, methylation, phosphorylation, ubiquitination,
sumoylation and/or ADP ribosylation [Kouzarides, 2007;
Trotter and Archer, 2007].
Alteration of the chromatin architecture by ATP-dependent
remodeling complexes is considered a significant step in
transcriptional regulation of many eukaryotic genes.
These chromatin-modifying enzymes use energy derived
from ATP hydrolysis to actively alter the nucleosomal
structure [Johnson et al., 2005]. A number of chromatin
remodeling complexes have been identified that modulate
the arrangement and stability of nucleosomes in a
non-covalent manner. Generally, these ATP-dependent
remodeling machines are divided into four major
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Nuclear Receptor Signaling | The Open Access Journal of the Nuclear Receptor Signaling Atlas
subfamilies, characterized by the identity of their central
catalytic subunit, which include BRG1 (or hBrm), ISWI,
Mi-2 and Ino80 of their respective complexes SWI/SNF,
ISWI, NuRD and INO80 [Eberharter and Becker, 2004;
Human SWI/SNF contains either BRG1 or hBRM
(Brahma) as the central ATPase subunit.The paralogous
catalytic subunits share a high degree of sequence
identity (74%) and display similar biochemical activities
in vitro [Khavari et al., 1993; Phelan et al., 1999;
Randazzo et al., 1994]. Despite their similarities, the two
ATPase subunits can play different roles in various
cellular processes including proliferation and
differentiation [Bultman et al., 2000; Kadam and Emerson,
2003; Reyes et al., 1998].This review will focus on BRG1,
the proteins with which it associates, its recruitment and
dynamic interactions with chromatin and the physiological
pathways which it participates in as a transcriptional
The BRG1 (or hBRM) protein is the central catalytic
ATPase of the SWI/SNF chromatin-remodeling complex.
The BRG1 homologue, Swi2, was first identified in yeast
by genetic screens searching for proteins important for
mating-type switching (SWI) and sucrose non-fermenting
(SNF) [Neigeborn and Carlson, 1984; Stern et al., 1984;
Winston and Carlson, 1992]. Further analysis identified
suppressors of these SWI and SNF mutations which
included genes encoding histones and other
chromatin-associated proteins, suggesting these products
may be involved in transcriptional regulation through
modulation of chromatin structure [Sif, 2004;Winston and
Carlson, 1992].These yeast proteins were later found to
assemble into a multi-subunit complex, designated
SWI/SNF, which was shown in vitro to alter nucleosomal
structure, in an ATP-dependent manner, resulting in an
open and accessible chromatin conformation conducive
for transcription factor binding [Cairns et al., 1994;
Peterson et al., 1994].The catalytic ATPase activity of
the yeast SWI/SNF chromatin remodeling complex is
provided by the Swi2 or Snf2 protein [Pazin and
Kadonaga, 1997; Peterson and Tamkun, 1995]. In S.
cerevisiae, a second, more abundant SWI/SNF-like
complex exists, designated RSC (Rsc1 and Rsc2) [Cairns
et al., 1996]. Although RSC complexes contain
Swi2/Snf2-like ATPase activity, derived from the Sth1
subunit, and demonstrate similar biological activities on
chromatin, biochemical studies suggest the SWI/SNF
and RSC complexes regulate expression of distinct sets
of genes [Lorch et al., 2001; Mohrmann and Verrijzer,
2005]. Homologues of yeast SWI2/SNF2 have been
identified in humans, Drosophila and mice [Dingwall et
al., 1995; Khavari et al., 1993; Kwon et al., 1994; Laurent
et al., 1993; Muchardt and Yaniv, 1993; Randazzo et al.,
1994;Tamkun et al., 1992;Wang et al., 1996a].
The BRG1 and hBrm proteins share a high degree of
sequence identity (74%) and display similar biochemical
activities in vitro [Khavari et al., 1993; Phelan et al., 1999;
Randazzo et al., 1994]. Despite their similarities, the two
ATPase subunits of SWI/SNF play different roles in
various cellular processes including proliferation and
differentiation using mechanisms of specificity that are
currently undefined [Bultman et al., 2000; Kadam and
Emerson, 2003; Reyes et al., 1998]. BRG1 is composed
of multiple domains, most of which have been identified
by primary sequence analysis and include an
evolutionarily conserved catalytic ATPase domain, as
well as a conserved C-terminal bromodomain, AT-hook
motif and the less characterized N-terminal region housing
QLQ, HSA and BRK domains [Fan et al., 2005; Khavari
et al., 1993] (Figure 1).
The bromodomain of BRG1 has been implicated in the
recognition of acetylated lysines within histone H3 and
H4 tails [Chandrasekaran and Thompson, 2007; Shen et
al., 2007]. Such modifications within target promoters
may serve as an interaction surface for the assembly
and/or recruitment of bromodomain-containing coregulator
complexes, including SWI/SNF. In conjunction with the
C-terminal bromodomain, BRG1 also contains an AT-hook
sequence motif which may aid in DNA binding or
recruitment of SWI/SNF to acetylated lysines within
histone tails [Singh et al., 2006].
The N-terminus of BRG1 encompasses several regions
of interest which could prove essential for BRG1 function.
A glutamine-leucine-glutamine motif (QLQ) was identified
within amino acids 172-208. Although the functional
relevance of this motif remains unclear, QLQ domains
are often implicated in protein-protein interactions or may
contribute to the conformational structure of the protein
[Kim et al., 2003;Williamson, 1994]. Also identified were
HSA and BRK domains located between amino acid
475-532 and 612-656, respectively. HSA domains are
regions of unknown function found in helicases and other
DNA-binding proteins of eukaryotes [Doerks et al., 2002].
BRK domains, also referred to as the TCH domain, are
small protein modules of unknown function associated
with transcription and CHROMO domain helicases and
in DEAD/DEAH box helicase domains [Allen et al., 2007;
Doerks et al., 2002].
Taken together, BRG1 is composed of numerous putative
domains and motifs, many of which appear to be
evolutionarily conserved [Khavari et al., 1993]. Found
outside the catalytic ATPase domain, within both the N-
and C-terminus, are regions which may serve as potential
protein interaction modules.These domains may be
utilized in the recognition of modified histone proteins
and/or recruit the chromatin remodeling activity of BRG1
to genomic targets.
BRG1 complexes and interacting
In cells, BRG1 is found within the context of various
multi-protein complexes, usually as the central enzymatic
subunit, with roles in transcriptional regulation, DNA
replication, repair and recombination. Among the various
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BRG1 coregulator activity
as domains found within the N- and C-terminus.The conserved domain identification and predictions were performed using the NCBI specialized
BLAST conserved domains database (http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi).
Domain architecture of BRG1. The BRG1 chromatin remodeling protein contains an evolutionarily conserved ATPase region, as well
BRG1-containing complexes, the SWI/SNF family has
been best characterized regarding structure, function and
enzymatic activity. Human SWI/SNF contains one of two
mutually exclusive ATPase-containing subunits, BRG1
or hBrm, and numerous BAFs (BRG1-associated factors),
most of which are orthologous to those found in yeast
SWI/SNF and RSC [Nie et al., 2000;Wang et al., 1996b;
Xue et al., 2000]. Mammalian BRG1 is usually associated
with approximately 10-12 BAF subunits or other proteins
involved in regulation of gene expression, as well as
nucleosome assembly, genomic stability and
maintenance. Human SWI/SNF includes a heterogeneous
mixture of proteins, where most purified complexes
contain core subunits BRG1 (or hBrm), BAF170, BAF155
and BAF47/INI1, as well as BAF60, BAF57, BAF53 and
actin [Wang et al., 1996a]. Human SWI/SNF can be
further subdivided into the BAF and PBAF
(Polybromo-associated BAF) complexes.These
complexes are distinguished only by the presence of
specific subunits, BAF250a/b or BAF180, found in BAF
or PBAF, respectively [Lemon et al., 2001; Nie et al.,
2000;Yan et al., 2005].This differential makeup of the
various BRG1/Brm-based complexes suggests the BAF
subunits may play important roles in promoter-specific
targeting or to convey a stabilized nucleosomal
conformation favorable for SWI/SNF activity. Interestingly,
BRG1 protein alone is capable of inducing a remodeled
nucleosomal state in vitro; however, addition of the core
SWI/SNF subunits, BAF170, BAF155 and BAF47
reconstitutes chromatin remodeling to near optimal levels
[Phelan et al., 1999].
The BRG1 protein can also be found assembled with
transcription factor and histone-modifying enzyme
complexes to activate or repress nuclear processes
including transcription, elongation and DNA replication
(Figure 2). For example, the WINAC (WSTF including
nucleosome assembly complex), which shares subunits
with both SWI/SNF- and ISWI-based chromatin
remodeling complexes, consists of at least 13
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BRG1 coregulator activity
components, BRG1 and hBrm, as well as member
subunits of the SWI/SWI-BAF including BAF250, BAF170,
BAF155, BAF60a, BAF57, BAF53 and BAF47, and WSTF
(Williams syndrome transcription factor), a reported
member of the SNF2h-based remodeling complex [Aoyagi
et al., 2005; Kitagawa et al., 2003]. Interestingly, WINAC
includes proteins associated with DNA replication, TopoIIβ
and CAF-1p150, and transcription elongation factor
FACTp140, which are not present in other
SWI/SNF-based complexes [Belandia and Parker, 2003].
WINAC promotes both the assembly and disruption of
nucleosomal structure, in an ATP-dependent manner, via
BRG1 and hBrm ATPase and contributes to the assembly
of replicated DNA into chromatin.The WSTF component
of WINAC is able to interact with vitamin-D receptor, in
a ligand-independent manner, to both activate and
repress gene transcription by inducing a remodeled
chromatin state and allowing transcription or condensing
the nucleosomal architecture to repress gene expression
[Kitagawa et al., 2003].
Histone-modifying enzymes such as
coactivator-associated arginine methyltransferase-1
(CARM1) associate with BRG1 in the NUMAC complex
(nucleosomal methylation activation complex) [Xu et al.,
2004].This complex harbors multiple
SWI/SNF-associated proteins including BRG1, BAF250,
BAF170, BAF155, BAF57, BAF47 and β-actin, and was
found to display increased activity for histone methylation
via CARM1 activity. In the NUMAC complex, BRG1 and
CARM1 directly associate and assemble on estrogen
receptor (ER)-responsive target promoters to
cooperatively activate transcription [Xu et al., 2004].
BRG1 can also be found associated with other
histone-modifying enzymes such as histone
deacetylases-3 (HDAC3) and the transcriptional
corepressors KAP-1 (Krab associated protein 1) within
the NCoR-1 (Nuclear receptor corepressors-1) complex.
Four core SWI/SNF proteins, BRG1, BAF170, BAF155
and BAF47, were identified by mass spectrometry or
immunoblotting as members of the NCoR-1 complex
[Underhill et al., 2000]. Also associated with this complex
is KAP-1, which interacts with proteins containing KRAB
domains, a common motif found in DNA-binding
transcriptional repressors. KAP-1 has also been observed
to interact in vivo with HP-1 (heterochromatin protein-1)
proteins which are important for gene silencing [Nielsen
et al., 1999; Ryan et al., 1999].Taken together, the
presence of BRG1 in NCoR-1 strongly suggests the
complex possesses chromatin modifying function which
may be required for transcriptional repression. An exciting
possibility is that chromatin remodeling activity within
NCoR-1 may be necessary to facilitate the binding of
specific corepressors with nucleosomal targets to induce
Various studies have identified BRG1-interacting proteins
using methods such as immunoaffinity selection,
chromatographic purifications and mass spectrometric
peptide sequencing, as well as protein-protein interaction
assays including yeast two-hybrid cDNA library screens,
GST-pull down, immunoblotting and
immunoprecipitations. Searching the Myriad ProNet
protein-protein interaction database, we identified proteins
which have been reported to interact either directly of
indirectly with BRG1 [Wixon, 2001]. Figure 3 summarizes
these BRG1-associating proteins and classifies the
putative interaction according to the transcriptional
outcome. Interestingly, BRG1 interacts with a diverse
group of nuclear proteins involved in a wide range of
processes and include nuclear receptors, members of
the transcriptional machinery, chromatin-modifying
enzymes and tumor suppressors, as well as core
SWI/SNF subunits and proteins critical for genomic
stability and maintenance [Chen et al., 2006;Trotter and
Archer, 2007].The number of putative biochemical
associations involving BRG1 suggests this evolutionarily
conserved DNA-dependent ATPase containing protein
may be critical for numerous biological activities. Although
these studies demonstrate BRG1 has the potential to
associate with vast numbers and types of proteins, the
mechanistic consequences in vivo of many of these
interactions remain to be determined.
Role of BRG1 in transcription control
Recruitment to target genes
The SWI/SNF enzymatic complexes are large multimeric
assemblies which are thought to be recruited to specific
gene targets through association with DNA-binding
transcription factors, coregulators, or by members of the
general transcriptional machinery.These BRG1
assemblies contain a multitude of distinct DNA-binding
motifs which are thought to play vital roles in targeting
SWI/SNF activity to gene-specific promoters. It has been
suggested that these DNA-binding motifs do not direct
the complex to specific genomic sequences, but rather
work in concert with gene-specific activation domains
within transcriptional or histone-binding factors to allow
efficient binding and chromatin remodeling [Peterson and
Multiple interactions are probably involved in the recruiting
and stabilization of BRG1-containing SWI/SNF to
hormone responsive promoters. Depending on the stage
of transcription, nucleosomal composition, and promoter
architecture, one or more subunits may play leading roles
in SWI/SNF binding. Several SWI/SNF components
including BRG1, BAF250, BAF60a/c and BAF57 have
been shown to mediate critical interactions between
several Type-I NRs, including glucocorticoid receptor
(GR), estrogen receptor (ER), progesterone receptor
[Roopra et al., 2004] and androgen receptor (AR) [Link
et al., 2005], as well as Type-II NRs, retinoic acid receptor
(RAR), vitamin D3 receptor (VDR) and the peroxisome
proliferator-activated receptor γ (PPARγ) [Aoyagi et al.,
2005; Chen et al., 2006; Debril et al., 2004; Dilworth et
al., 2000; Ichinose et al., 1997; Lemon et al., 2001; Link
et al., 2005;Trotter and Archer, 2004;Trotter and Archer,
Components of SWI/SNF with bromodomains such as
BRG1, hBrm and BAF180 are thought to target acetylated
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BRG1 coregulator activity
chromatin-modifying complexes including transcription coactivators and corepressors. BRG1 (or hBrm) is the central catalytic subunit of SWI/SNF-BAF
or -PBAF chromatin remodeling complexes, which have been implicated in the transcriptional activation or repression of a variety of genes. Nuclear
receptors can associate with many of these complexes through direct interaction with BAF subunits such as BAF250, BAF60a and BAF57. BRG1 can
be found in complexes with transcription coactivators and histone modifying enzymes such as WINAC and NUMAC. Conversely, BRG1 can be assembled
in complexes known to repress transcription and induce gene silencing including NCoR and mSin3A/HDAC complexes.
BRG1-containing chromatin-modifying complexes. The BRG1 chromatin remodeling protein can associate with numerous
histone tails [Singh et al., 2007]. In addition, SWI/SNF
subunits, including BRG1, BAF250, BAF60a and BAF57,
have been reported to mediate critical interactions with
NRs.These associations are thought to be important
mediators for recruiting the remodeling complex to
genomic targets [Belandia et al., 2002; Garcia-Pedrero
et al., 2006; Hsiao et al., 2003; Inoue et al., 2002].
Consequently, it is likely that multiple interactions mediate
recruitment and stabilization of the SWI/SNF remodeling
complex to gene-specific promoters through direct or
indirect interactions involving one or more BAF proteins.
The interaction between GR and BRG1 can occur through
BAF250 and/or BAF60a.The BAF250 subunit, which
contains intrinsic DNA-binding capabilities through an
ARID (AT-rich interaction domain) motif, directs SWI/SNF
activity to GR-responsive promoters using both
DNA-binding and protein-protein interactions in
combination to confer specificity of action [Trotter and
Archer, 2007]. Interestingly, BAF60a utilizes distinct
protein-binding surfaces, one each for interaction with
GR and BRG1, to specifically regulate GR-responsive
promoters. Glucocorticoid receptor binding of BAF60a
has been shown to take place in a ligand-independent
manner, but is required for efficient GR-mediated
transcriptional activation and remodeling of the mouse
mammary tumor virus (MMTV) promoter or endogenous
promoters in vivo [Hsiao et al., 2003]. By contrast, the
interaction between GR and BAF250a is dependent on
the presence of ligand [Nie et al., 2000].
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The BAF57 subunit has been shown to be a critical
subunit by which SWI/SNF interfaces with various NRs
including GR, ER and AR [Garcia-Pedrero et al., 2006;
Hsiao et al., 2003; Link et al., 2005]. BAF57 interacts with
both ER and p160 coactivators to recruit SWI/SNF, in a
ligand-dependent manner, to estrogen-responsive
promoters for transcriptional activation [Belandia et al.,
2002]. Additionally, BAF57 has been shown to associate
directly with AR to recruit BRG1-based complexes to
AR-responsive promoters to alter transcriptional activity
[Link et al., 2005; Marshall et al., 2003].
have been conducted using various techniques which have identified
BRG1-interacting proteins. For the purpose of this review, these
BRG1-associating proteins have been grouped into two categories
according to their transcriptional consequence: activation or repression.
BRG1 has been reported to associate with numerous proteins implicated
in transcriptional activation including various NRs such as AR (Marshall
et al., 2003), ERα (Ichinose et al., 1997), GR (Fryer and Archer, 1998),
PPARγ (Debril et al., 2004), PR (Vicent et al., 2006) and VDR (Kitagawa
et al., 2003).Tumor suppressor proteins have also been found associated
with BRG1, including BRCA1 (Bochar et al., 2000), p53 (Lee et al., 2002),
and FANCA (Otsuki et al., 2001). Other proteins which are reported to
interact with BRG1 include β-catenin (Barker et al., 2001), CARM1 (Xu
et al., 2004), EVI-1 (Chi et al., 2003), Mef2D (Ohkawa et al., 2006),
p130(RB2) (Giacinti and Giordano, 2006), Smad3 (Xi et al., 2007, 2008)
and STAT proteins (Ni and Bremner, 2007; Pattenden et al., 2002).
Proteins involved in transcriptional repression also interact with BRG1
and include GR (Bilodeau et al., 2006), HDACs (Underhill et al., 2000),
HP-1 (Nielsen et al., 1999), Mbd3 (Datta et al., 2005), Mi-2β (Shimono
et al., 2003), mSin3A (Sif et al., 2001), Rb (Giacinti and Giordano, 2006),
PRMT5 (Pal et al., 2003), REST (Ooi et al., 2006), SMRT (Jung et al.,
2001) and SYT-SSX (Ito et al., 2004; Perani et al., 2003).This list
highlights a number of BRG1-interacting proteins which are considered
transcription coactivators, corepressors or tumor suppressor proteins.
Reported BRG1-interacting proteins. Numerous studies
Recruitment of BRG1-containing complexes is also
thought to occur through association with zinc finger
proteins (ZFP), which represent a family of eukaryotic
regulatory factors that have been shown to control
numerous cellular processes such as differentiation,
proliferation, signaling and apoptosis.The association
between SWI/SNF and ZFPs were shown to take place
exclusively through specific DNA-binding domains (DBD)
and BRG1 to initiate ZFP-dependent transcription [Kadam
and Emerson, 2003].This enables BRG1-based
chromatin modifying complexes to selectively target
distinct sets of promoters.Taken together, BRG1
complexes can be recruited to target promoters through
association with BAF subunits or transcription factors
which display DNA-binding capabilities.
A role for BRG1 chromatin remodeling complexes in
transcriptional regulation by NRs was initially proposed
for GR in yeast studies and substantiated in vivo using
mammalian cell models [Fryer and Archer, 1998;
Muchardt and Yaniv, 1993;Trotter and Archer, 2004;
Yoshinaga et al., 1992]. Numerous studies suggest
ATP-dependent chromatin remodeling by BRG1
influences ligand-induced transcriptional activation by a
variety of NRs. Integrated hormone-responsive promoter
systems such as MMTV and the estrogen-dependent pS2
have been employed to investigate the molecular
mechanisms involved in NR-mediated chromatin
remodeling and transcriptional activation by BRG1 [Chen
et al., 2006].
The steroid hormone responsive MMTV promoter
acquires a phased array structure of six positioned
nucleosomes when stably integrated as chromatin.These
nucleosomes are highly organized over the long terminal
repeat (LTR), which encompasses several regulatory
elements including hormone response elements (HREs)
and binding sites for transcription factors, as well as for
TATA binding protein (TBP) [Archer et al., 1991;Trotter
and Archer, 2004].These transcriptional elements found
within MMTV allow for strong promoter activation by
glucocorticoids through mechanisms requiring chromatin
modifying proteins such as BRG1. Chromatin remodeling
proteins are thought to increase DNA accessibility, thus
permitting recruitment and binding of transcription factors
to site-specific sequences and allowing promoter
Using techniques such as ultrafast UV-laser crosslinking
have provided insight into the progression and possible
mechanism of GR-mediated chromatin remodeling by
SWI/SNF at the MMTV promoter. Using this assay, the
highly dynamic interactions between GR and MMTV were
found to be dependent on the GR-mediated activity of
SWI/SNF, suggesting the transient association of GR
occurs in concert with chromatin remodeling [McNally et
al., 2000; Nagaich et al., 2004]. Collectively, these studies
demonstrate rapid binding of GR to the chromatin followed
by active displacement during the remodeling process.
In the absence of GR, the BRG1 remodeling complex is
associated with random positions on the chromatin
template, but is recruited to specific regions in the
presence of ligand-bound receptor [Fletcher et al., 2002;
Georgel et al., 2003; Nagaich et al., 2004]. Studies using
a stably integrated MMTV reporter, in the BRG1/hBrm
null SW-13 cell line, also further establish the requirement
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BRG1 coregulator activity
for BRG1 in GR-dependent promoter activation.
Interestingly, non-BRG1-based ATP-dependent chromatin
remodeling complexes, such as ISWI or Mi-2, are unable
to substitute for BRG1 activity including chromatin
remodeling, transcription factor binding and transcriptional
activation of the stably integrated promoter. In this cell
model, a select number of endogenous GR-responsive
promoters were analyzed including p21, HSD-11β-type
2 and PLZF, each of which displays a similar
transcriptional dependence for BRG1 activity [Trotter and
Further insight into the molecular mechanism of BRG1
action was provided through the generation and
characterization of chimeric proteins constructed from
two of the best studied ATP-dependent chromatin
remodeling proteins, BRG1 and SNF2h [Fan et al., 2005].
Both BRG1 and SNF2h represent the central catalytic
subunit of the SWI/SNF- and ISWI-based chromatin
remodeling complexes, respectively, and genetic analyses
indicate these ATPase proteins can not complement each
other (27.8% homology between the two remodeling
proteins; 44.3% homology over ATPase domain).To
determine if ATPase activity provided from another
remodeling protein could function within the context of
SWI/SNF, a chimeric protein was generated by replacing
the BRG1 ATPase region with the ATPase domain
derived from SNF2h.The chimeric protein, designated
B-S-B, was evaluated using in vitro chromatin remodeling
assays which revealed the mechanism of remodeling is
specific to the ATPase present.In vivo, the BRG1/SNF2h
chimera induced expression from a subset of
BRG1-dependent genes when introduced into SW-13
cells. Interestingly, the chimeric protein was unable to
stimulate GR-mediated transcriptional activation or
chromatin remodeling of integrated MMTV, indicating the
ATPase activities of BRG1 and SNF2h are not functionally
interchangeable [Fan et al., 2005].Together, these data
suggest BRG1 activity is a critical component for
hormone-dependent transcriptional activation.
Numerous studies have utilized promoter reporter models
to analyze the role of BRG1 in NR-mediated transcription
regulation. Results from these reports reveal BRG1 is a
critical component required for transcriptional activation
involving NRs including PR, AR and ER [Chen et al.,
2006]. Studies using chromatin MMTV show PR competes
with GR for available BRG1 upon glucocorticoid
treatment, indicating the remodeling protein is a required
component of PR-mediated promoter activation [Fryer
and Archer, 1998; Li et al., 2003]. Examination of
AR-mediated transcriptional regulation suggests
recruitment of SWI/SNF has been established for
AR-dependent gene expression [Marshall et al., 2003].
Estrogen receptor has also been reported to require
BRG1 activity for activation of ER-responsive genes.
Interestingly, transcriptional activation from ER-dependent
promoters, within SW-13 cells, was significantly reduced
in the absence of BRG1; conversely, ER-mediated
transcription was restored upon expression of the
remodeling protein [Chen et al., 2006]. Additionally, BRG1
can associate with ligand-bound VDR within the WINAC
complex which is recruited to VDR-responsive promoters
activating transcription. Defects in this VDR-signaling
complex lead to the autosomal genetic disorder Williams
syndrome [Kitagawa et al., 2003].
In summary, chromatin remodeling is an essential
regulatory step where BRG1-containing complexes can
directly and indirectly support ligand-mediated
transcriptional activation by NRs. Given the functional
diversity of NR, it is thought that coactivators differentially
affect chromatin remodeling based on target gene and
its biological context.
The role of BRG1 has been widely associated with
transcriptional activation; however, studies indicate the
remodeling protein can play critical roles in gene silencing
through interactions with a variety of transcriptional
corepressors [Gaston and Jayaraman, 2003; Underhill
et al., 2000]. BRG1 has been shown to interact with
retinoblastoma tumor suppressor [Zhang et al., 2000] to
form a repressor complex which inhibits cell cycle proteins
such as cyclin A, D1 and E [Giacinti and Giordano, 2006;
Zhang et al., 2000]. Complexes purified from mammalian
extracts demonstrate BRG1 associates and is a member
of the mSin3A/HDAC complex that is implicated in
transcriptional repression of a variety of genes [Sif et al.,
2001].The chromatin remodeling protein was also found
in association with the NCoR corepressor complex, which
displays HDAC activity and includes the heterochromatin
protein-1 (HP1) interacting protein TIF1β [Underhill et al.,
Several studies have reported multisubunit complexes
possessing ATPase activity exist in combination with
histone deacetylases (HDACs), methyl CpG-binding
proteins (MBDs) and histone methyltransferases (HMTs)
in transcriptional repression complexes coupling
ATP-dependent chromatin remodeling with a wide variety
of mechanisms involved in gene silencing [Bilodeau et
al., 2006; Dacwag et al., 2007; Datta et al., 2005; Pal et
al., 2003; Xu et al., 2006]. Interestingly, subunits of the
mSin3A/HDAC corepressor complex associate with
BRG1, suggesting the SWI/SNF complex may be involved
in transcriptional repression and gene silencing [Sif,
2004]. Recent studies have shown the SWI/SNF complex
and their associated histone-modifying enzymes are
involved in the transcriptional repression of genes
important for various cellular processes such as cycle
regulation [Giacinti and Giordano, 2006]. BRG1 has
shown to associate with Rb proteins to induce cell cycle
arrest and this Rb-mediated transcriptional repression is
dependent on HDAC activity. Additionally,
BRG1/HDAC-containing complexes have been shown to
repress expression of genes involved in cell cycle
regulation including cdc2, cyclin A, D1, E and the
Myc/Max/Mad target cad [Pal et al., 2003; Zhang et al.,
2000].This repression is thought to occur through direct
interaction and recruitment of PRMT5 and the
mSin3A/HDAC2 corepressor complex to target promoters
for transcriptional inhibition [Pal et al., 2003].
www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06004 | Page 7 of 12
BRG1 coregulator activity
BRG1 also associates with the SYT oncoprotein
assembly, which has been reported to display corepressor
activity through interactions with mSin3A/HDAC
transcriptional regulatory complexes [Ito et al., 2004].
Taken together, these studies suggest BRG1 activity is
a critical component of the mSin3A/HDAC repression
complex, which acts on chromatin through transcriptional
regulators, corepressors and histone-modifying enzymes
and leads to gene silencing.
Promoter inhibition by BRG1 has been reported for a
number of genes using either the HDAC-dependent or
-independent pathways.The repressor element
1-silencing transcription factor (REST) is a transcriptional
regulator that has been shown to repress expression of
genes involved in neuronal function [Battaglioli et al.,
2002; Schoenherr and Anderson, 1995]. Interestingly,
REST function depends on its associations with a wide
variety of proteins including HDAC1, HDAC2 and core
SWI/SNF subunits BRG1, BAF170 and BAF57, as well
as histone demethylase LSD1 and histone
methyltransferase G9a [Battaglioli et al., 2002; Gu et al.,
2005; Roopra et al., 2004; Shi et al., 2004]. Although the
precise mechanism regarding BRG1-dependent
REST-mediated repression remains unclear, BRG1 is
thought to be involved in the establishment of an altered
promoter state which allows histone
acetylation-dependent binding of REST and results in
transcriptional inhibition [Ooi et al., 2006].
Nuclear hormone receptors have been shown to mediate
gene repression through association with BRG1.
Ligand-bound GR is critical for the expression of a variety
of proteins including tryptophan oxygenase (TO) and
tyrosine amino transferase [Tamkun et al., 1992] during
liver development [Danesch et al., 1987; Grange et al.,
2001]. Interestingly, SWI/SNF complexes containing
BRG1 were shown to significantly downregulate the
GR-mediated transcription of both genes in a
HDAC-independent manner.This observation suggests
BRG1 activity may induce a closed conformation, thus
restricting transcription factor binding and resulting in
attenuated gene expression [Inayoshi et al., 2005].
BRG1 has also been characterized as a coactivator and
corepressor at the same promoter, switching modes of
action by ligand-directed differential coordination with
various transcriptional regulators. For example, BRG1 is
recruited to the same ER-responsive promoters by
different cofactors in response to hormone or antagonists
to transcriptionally activate or repress gene expression,
respectively. SWI/SNF complexes recruited by
ligand-bound ER result in active gene transcription;
conversely, when BRG1 is recruited via HDAC1, p300
and prohibitin, in response to ER-bound antagonist, the
promoter activation was significantly diminished [Zhang
et al., 2007]. Although the mechanism underlying this
molecular switching remains unclear, it does provide
interesting insight into the role of BRG1 as a
transcriptional coregulator.Taken together, these studies
demonstrate the BRG1 chromatin remodeling protein can
associate with corepressor complexes and be recruited
by a variety of transcription factors to specific promoters
to inhibit transcription and induce gene silencing.
Biological role of BRG1 – deregulated
BRG1 and hBrm are highly conserved, mutually exclusive,
catalytic proteins found incorporated within the context
of numerous enzymatic complexes that modify chromatin
structure and alter gene expression patterns. In vitro,
these ATPase-containing proteins display similar
chromatin remodeling activities and studies indicate that
BRG1 and hBrm can regulate transcriptional activity at
distinct genes [Kadam and Emerson, 2003]. However, in
vivo studies suggest these proteins exhibit distinct
non-redundant biological functions. Interestingly, genetic
inactivation of BRG1 or hBrm in mice resulted in moderate
to severe deregulation of cellular processes such as
proliferation. BRG1-deficient mice die at the
pre-implantation stage, suggesting that BRG1 is essential
for early development. Moreover, BRG1 heterozygotes
were found to be predisposed to tumor development.
Conversely, hBrm null mice were found to be viable, fertile
and dispensable for cell growth, although these mice
showed increased expression of BRG1 in certain tissues
and displayed aberrant cell cycle regulation [Reyes et al.,
1998].Together, these knock-out studies show BRG1-
and hBrm-containing complexes are regulated and
targeted differently to alter gene expression patterns
during critical stages of cell proliferation and
The SWI/SNF chromatin remodeling complex has been
described as a key regulator of skeletal muscle
differentiation, where the ATPase of BRG1 is required
for gene expression at different stages of skeletal
myogenesis. Recent studies have shown that expression
of myogenic late genes requires BRG1 ATPase activity
in conjunction with myogenin and Mef2D [Ohkawa et al.,
2007]. Interestingly, BRG1 associates with both MyoD
and Mef2 which targets BRG1-based chromatin
remodeling activity to myogenic-specific gene promoters
to regulate protein expression at different stages of
skeletal muscle differentiation [Ohkawa et al., 2006].
Genetic and molecular evidence indicate BRG1 can act
as tumor suppressors in a variety of human cancers or
cell lines due to mutations or downregulation of protein
expression [Wong et al., 2000]. In BRG1-null cell lines,
reintroduction of exogenous BRG1 induces a growth
arrest phenotype by repression of E2F-genes and
activation of cyclin-dependent kinase (CDK) inhibitors
p21 and p15 [Hendricks et al., 2004]. BRG1 has also
been reported to interact with other tumor suppressors
including pRb, BRCA1, c-Myc, c-Fos and member
proteins of the Wnt signaling pathway [Barker et al., 2001;
Bochar et al., 2000; Eroglu et al., 2006; Murphy et al.,
1999; Pal et al., 2003].Therefore, due to the multitude of
transcriptional events which require SWI/SNF activity,
loss of BRG1 would tend to alter normal gene expression
patterns and possibly lead to oncogenic phenotypes.
www.nursa.org NRS | 2008 | Vol. 6 | DOI: 10.1621/nrs.06004 | Page 8 of 12
BRG1 coregulator activity
The role of BRG1 in transcriptional activation by
numerous Type-I and Type-II NRs or transcriptional
repression through association with mSin3A/HDAC
complexes has been firmly established. Among the
various BRG1-based complexes, the SWI/SNF family
has been the best characterized regarding function and
enzymatic activity in transcriptional activation with
chromatin remodeling. Activated receptors bound to target
DNA sequences recruit transcriptional coactivators, such
as BRG1, which are essential to modulate chromatin
structure, and initiate gene expression. Studies suggest
NRs recruit SWI/SNF activity to gene-specific promoters,
in a ligand-dependent manner, where BRG1 functions to
remodel the chromatin architecture.This remodeled
nucleosomal state allows access to and binding of
members of the preinitiation complex (PIC) [Trotter and
Archer, 2007]. Conversely, BRG1-mediated gene
silencing is also thought to involve manipulation of the
promoter structure, resulting in increased binding of
chromatin modifying enzymes and/or repressor
complexes, such as mSin3A/HDAC1/2, to inhibit
transcription.Targeting BRG1 activity is thought to be
mediated through interactions with various members of
the enzymatic complex, including BAF subunits, which
have been shown to associate with numerous
transcriptional coactivator or corepressor proteins.Taken
together, these observations imply BRG1 is an essential
component of a diverse group of chromatin-modifying
complexes which alter chromatin structure to regulate
transcription.To this end, clear mechanistic insights
gained from the functional interactions between BRG1
and nuclear receptors may provide a better understanding
regarding the precise role the remodeling protein plays
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