Chromatin remodeling, development and disease

Mutation Research 647 (2008) 59–67

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Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis journal homepage: www.elsevier.com/locate/molmut Community address: www.elsevier.com/locate/mutres

Review

Chromatin remodeling, development and disease Myunggon Ko a , Dong H. Sohn a , Heekyoung Chung b , Rho H. Seong a,∗ a Department of Biological Sciences, Institute of Molecular Biology and Genetics, Research Center for Functional Cellulomics, Seoul National University, Seoul 151-742, Republic of Korea b Department of Pathology, College of Medicine, Hanyang University, Seoul 133-791, Republic of Korea

a r t i c l e

i n f o

Article history: Received 15 May 2008 Received in revised form 30 July 2008 Accepted 7 August 2008 Available online 20 August 2008 Keywords: Chromatin remodeling SWI/SNF Development Embryo T-cell Tumor suppression

a b s t r a c t Development is a stepwise process in which multi-potent progenitor cells undergo lineage commitment, differentiation, proliferation and maturation to produce mature cells with restricted developmental potentials. This process is directed by spatiotemporally distinct gene expression programs that allow cells to stringently orchestrate intricate transcriptional activation or silencing events. In eukaryotes, chromatin structure contributes to developmental progression as a blueprint for coordinated gene expression by actively participating in the regulation of gene expression. Changes in higher order chromatin structure or covalent modification of its components are considered to be critical events in dictating lineage-specific gene expression during development. Mammalian cells utilize multi-subunit nuclear complexes to alter chromatin structure. Histone-modifying complex catalyzes covalent modifications of histone tails including acetylation, methylation, phosphorylation and ubiquitination. ATP-dependent chromatin remodeling complex, which disrupts histone-DNA contacts and induces nucleosome mobilization, requires energy from ATP hydrolysis for its catalytic activity. Here, we discuss the diverse functions of ATP-dependent chromatin remodeling complexes during mammalian development. In particular, the roles of these complexes during embryonic and hematopoietic development are reviewed in depth. In addition, pathological conditions such as tumor development that are induced by mutation of several key subunits of the chromatin remodeling complex are discussed, together with possible mechanisms that underlie tumor suppression by the complex. © 2008 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The SWI/SNF complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SWI/SNF remodeling complex during embryonic development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SWI/SNF remodeling complex during T-cell development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SWI/SNF remodeling complex in the pathogenesis of tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction In mammals, there are at least three different families of ATP-dependent chromatin remodeling complexes: the SWI/SNF

∗ Corresponding author at: Institute of Molecular Biology and Genetics, Kwanakgu Kwanak-ro 599, Bldg 105, Rm 221, Seoul National University, Seoul 151-742, Republic of Korea. Tel.: +82 2 880 7567; fax: +82 2 887 9984. E-mail address: [email protected] (R.H. Seong). 0027-5107/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2008.08.004

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(switching-defective-sucrose non-fermenting), ISWI (imitationswitch), and Mi-2/NuRD (nucleosome remodeling and histone deacetylation) complexes [1,2]. Each complex can be distinguished by its catalytic ATPase subunit, which has a SNF2 family helicaselike ATPase domain. The best characterized complex is the SWI/SNF complex. The SWI/SNF complex consists of between 9 and 11 subunits that are highly conserved from yeast to human, and exhibits a high degree of diversity in the number and composition of its subunits depending on the cell contexts [2,3]. Although human SWI/SNF complexes have been shown to exist in two major

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forms, BRG1/hBRM-associated (BAF) and polybromo-associated BAF (PBAF) factors, many other forms contain tissue-specific subunits or additional sub-complexes [3]. Therefore, functional specificity of the SWI/SNF complex to ensure spatial and temporal gene regulation can be accomplished by combinatorial assembly of diverse tissue- or developmental stage-specific subunits. The ISWI complex consists of two to four subunits. Mammalian cells contain two highly homologous ATPase subunits of the ISWI complex: SNF2H and SNF2L [1,2]. ISWI complexes containing SNF2H include ACF (ATP-utilizing chromatin assembly and remodeling factor) and RSF (remodeling and spacing factor). Complexes containing SNF2L include NuRF (nucleosome-remodeling factor) and CERF (CECR2-containing remodeling factor). The third class of ATP-dependent chromatin remodeling complex Mi-2/NuRD simultaneously harbors nucleosome remodeling and histone-modifying activities [1,2]. Chromodomain and helicase-like domain (CHD) proteins such as CHD3 (Mi-2␣) and CHD4 (Mi-2␤) contain an ATPase domain and paired chromodomains that retain the ability to interact with methylated histone tails [2]. In general, the Mi-2/NuRD complex is implicated in transcriptional repression due to the presence of histone deacetylase 1 (HDAC1) and 2 (HDAC2) enzymes as integral subunits [4–6]. Many studies have demonstrated fundamental roles of chromatin remodeling complexes in development [1,7–9]. Instead of functioning similarly, each complex exhibits unique and contextdependent roles in various aspects of mammalian development. Sequential or cooperative action of chromatin remodeling complex classes, interaction with distinct partners, and spatiotemporal regulation of these physical associations contribute to specificity of the complexes and allow cells to determine which genes should be turned on or off. In this review, we describe the functions of ATPdependent chromatin remodeling complex, mainly those of the SWI/SNF complex, in development of embryo and hematopoietic

cell lineages that have been unraveled by studying in vivo mouse models. We also describe several issues concerning tumorigenesis induced by mutations that lead to loss or perturbations of chromatin remodeling activities, highlighting proposed mechanisms for tumor suppression by the chromatin remodeling complex. 2. The SWI/SNF complex The SWI/SNF complex contains two mutually exclusive ATPase subunits, either brahma (BRM) or Brm-related gene 1 (BRG1), both of which contain a bromo domain that allows these complexes to recognize acetylated histones [10]. Several mechanisms by which the SWI/SNF complex influences gene transcription have been suggested [1–3]. This complex has been shown to catalyze either nucleosomal changes that promote the binding of activator proteins, or large scale genomic reorganization. The SWI/SNF complex associates with various transcription factors or histone-modifying enzymes to regulate gene transcription (Fig. 1). The complex also functions by either promoting assembly of the RNA polymerase II pre-initiation complex or by stimulating transcriptional elongation. In vitro, the complex containing only four subunits, BRG1 or BRM, BAF155 (murine homolog: SRG3 in this review), BAF170, and BAF47 (SNF5/INI1) (SNF5 in this review) efficiently induces nucleosome remodeling at a rate comparable to the entire complex [11,12]. Thus, these subunits are considered to be core components of the mammalian SWI/SNF complex. Several lines of evidence show that SRG3 (a murine homologue of yeast SWI3, Drosophila MOIRA, and human BAF155) and its homologues function as scaffold proteins that play a key role in the assembly and stability of the SWI/SNF complex. SRG3 interacts directly with core components of the SWI/SNF complex [13] and physically associates with SNF5 or BRG1 through the SWIRM or SANT domain, respectively [13]. MOIRA interacts with BRM through the SANT domain, and BAF155 interacts with BAF57

Fig. 1. Proteins identified to interact directly or coimmunoprecipitate with the SWI/SNF complex.

M. Ko et al. / Mutation Research 647 (2008) 59–67

through the leucine-zipper motif [14,15]. RSC8, one of the yeast homologues of SRG3, interacts directly with STH1 and RSC6, yeast homologues of BRG1 and BAF60a, respectively [16,17]. SRG3 also functions as a key regulator of protein stability in the SWI/SNF complex because direct interaction of SRG3 with other components of the complex protects them from proteasomal degradation [13,15].

3. SWI/SNF remodeling complex during embryonic development Mouse embryonic development begins with fertilization in the oviduct [18]. Haploid sperm cells bind to and penetrate the zona pellucida to fuse with oocytes, which eventually restores a normal diploid set of chromosomes and triggers completion of meiotic division [19]. The fertilized egg, also called zygote, makes its way to the uterus while undergoing cleavage, which is a coordinated cell division with no significant growth to produce blastomeres. The first cleavage produces two identical cells and then divides continuously to produce 4 cells, 8 cells, 16 cells and so on. The first few divisions mainly rely on maternal gene products in the zygote cytoplasm, which are synthesized during oogenesis [20,21]. After several cleavages, the zygotic genome becomes transcriptionally competent and regulates subsequent embryonic development [20,21]. In mouse, this zygotic genome activation (ZGA) is initiated during the S-G2 transition in one-cell embryos, followed by a major ZGA during the two-cell stage [20,22–25]. At embryonic day 3 (E3.0), the 8cell embryo goes through compaction, when blastomeres flatten and become tightly interconnected by developing gap junctions to increase their contact with each other [26]. At the 16-cell stage, cells in the compacted embryo, termed a morula, undergo the first differentiation events as their blastomeres eventually become polarized into two distinct lineages: polar cells on the outside and apolar cells on the inside [27,28]. The outer polar cells, called trophectoderm cells, secrete fluid to form a blastocoel cavity and generate trophoblast cells of chorion that contribute to placenta formation [29]. The inner apolar cells adhere to one side of the cavity to form the inner cell mass (ICM) that will contribute to all the tissues of the embryo and some extraembryonic membranes such as yolk sac, allantois and amnion. The cleavage events are terminated at this stage of blastocyst. As the outer cell mass invades the endometrium of the uterine wall after implantation, the ICM splits into two layers: the epiblast (primitive ectoderm) and hypoblast [30]. Therefore, three differentiated tissue types exist in the mouse at E6.0: the trophoblast, epiblast and hypoblast. The hypoblast lies next to the blastocoel and gives rise to the primitive endoderm that forms the outer layer of the yolk sac [29]. The mouse epiblast at about E6.5 is a pluripotent tissue that undergoes gastrulation to give rise to all the cells of the embryo body. As a result of gastrulation, three primary germ layers that include endoderm, mesoderm and ectoderm are produced [30,31]. During gastrulation, a dramatic change in embryonic structure occurs through rapid cell proliferation and dynamic cell migration [31]. Since gastrulation has occurred, the neural plate begins to differentiate [32]. At around E8.5, the development of each of major organ systems is initiated. The mesoderm segments and neural folds start to form at the anterior end on the dorsal side of the embryo. In the final stage of gastrulation, the embryonic endoderm internalizes to form the gut, and the heart and liver move into their final positions relative to the gut. The head becomes distinct at this stage. At around E9.5, gastrulation is complete and the embryo has a distinct head. Forelimb buds also start to develop. Blood islands (where hematopoiesis occurs) and blood vessels are developing and organogenesis proceeds. After organogenesis, the embryo grows in size during the remaining days before birth (E18.5).

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The SWI/SNF complex is essential for mouse development (Table 1). Targeted disruption of the core complex components such as BRG1, SRG3 and SNF5, results in embryonic death during implantation stage [33–36]. On the other hand, BRM deficiency does not impair normal mouse development, presumably because BRG1 proteins functionally compensate for the loss of BRM [37]. The SWI/SNF complex is also required prior to the blastocyst stage. The complex is expressed in oocytes [33,38] and plays a critical role in ZGA, a process essential for the initial transcription of most genes in early embryos [39]. This process is a prerequisite for future cell lineage commitment and differentiation that underlie pattern formation and organogenesis. BRG1-disrupted oocytes are meiotically competent and capable of being fertilized, but embryos conceived from the depleted eggs show a defect in ZGA and are arrested at the two- to four-cell stage [39]. Notably, the expression of transcriptionrequiring complex (a marker of ZGA), and various genes activated during ZGA for transcription, RNA processing, and cell cycle regulation is affected. Early embryonic lethality due to the targeted disruption of the SWI/SNF complex poses a problem to analyze function of the SWI/SNF complex during mammalian development. Many alternative strategies to circumvent the barrier have been used such as tissue-specific gene deletion using the Cre-loxP system [40–42], tissue-specific expression of dominant-negative mutant protein [43], rescue from embryonic lethality by re-introducing transgenes [44], and induction of hypomorph mutations using N-ethyl-Nnitrosourea (ENU) [45]. Using these approaches, the SWI/SNF complex has been shown to be involved in the organogenesis and tissue formation during mouse development. The SWI/SNF complex is required for normal heart development. Tissue-specific deletion of BRG1 in the endocardium leads to embryonic lethality at E10.5–E11.5 due to impaired ventricular trabeculation during cardiogenesis [46]. Trabeculation defects are due to de-repression of a secreted matrix metalloproteinase, ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motif 1), which normally increases in expression later in development to prevent excessive trabeculation. BRG1 directly associates with ADAMTS1 regulatory sequences to repress its expression in the endocardium. Increased ADAMTS1 in the absence of endocardial BRG1 causes premature termination of trabeculation, resulting in heart malformation. BAF180, a specific subunit of the PBAF form of the SWI/SNF complex, also regulates cardiac chamber maturation [47]. BAF60c, a 60 kDa subunit of BAF complexes, is expressed specifically in the heart and somites in the early mouse embryo [48]. BAF60c silencing by RNA interference in mouse embryos causes defects in heart morphogenesis [48]. BAF60c promotes the interaction of the SWI/SNF complex with specific cardiac transcription factors including Tbx5, Nkx2.5, GATA4, and ␤-catenin, thereby potentiating the activation of heart-specific genes. BAF60c is also crucial for the determination of left-right (LR) asymmetry during vertebrate embryogenesis [49]. Knockdown of BAF60c in mice and zebrafish causes defects in LR axis specification. In BAF60c-depleted embryos, node morphogenesis is impaired and Notch1 expression as well as its ability to form a complex with BRG1 and RBP-J is significantly inhibited, repressing the expression of Nodal, a key LR regulator induced by Notch activation [49]. The SWI/SNF complex is critical for embryonic brain development. A subset of mutant mice that are haploinsufficient for BRG1 or SRG3 display brain malformations known as exencephaly due to defects in neural tube closure that may result from abnormal proliferation and differentiation of neural cells [33,34]. Studies using Xenopus and P19 embryonic carcinoma cells showed that BRG1 could promote vertebrate neurogenesis by associating with proneural basic helix-loop-helix (bHLH) proteins including Neurogenin-related-1 (Ngnr1) and NeuroD [50]. Loss of BRG1

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Table 1 In vivo functions of the SWI/SNF components in mouse development Subunit

Genetic modification

Phenotype

Reference(s)

BRG1

Gene knockout

Peri-implantation lethality; defects in brain development (exencephaly); enhanced tumorigenesis (mammary tumors, no loss-of-heterozygosity) Embryonic lethality at E11.5–E14.5; defects in erythropoiesis due to impaired ␤-globin transcription T-cell developmental arrest at DN stage; defects in CD4 repression and CD8 activation; impaired pre-TCR signaling Normal meiosis, ovulation and fertilization; developmental block at two- to four-cell stage; defects in zygotic genome activation Embryonic lethality at E10.5–E11.5; defects in heart development Defects in neural stem/progenitor cell maintenance; impaired gliogenesis; defects in brain development (exencephaly) Defects in embryonic vascular development; impaired erythropoiesis

[33,43,85]

Normal mouse development; slight increase in body weight; increased cellular proliferation; defects in DNA damage-induced cell cycle arrest Peri-implantation lethality; defects in brain development (exencephaly) Increased sensitivities to glucocorticoid- and stress-induced apoptosis

[37]

Defects in TCR signaling; enhanced SWI/SNF activity in vivo; impaired positive and negative selections Embryonic lethality at E10.5–E11.5; defects in embryonic angiogenesis

[61,65]

Peri-implantation lethality; enhanced tumorigenesis (rhabdoid tumors; loss-of-heterozygosity) Impaired hematopoiesis; enhanced tumorigenesis (lymphoma, rhabdoid tumors) Defects in CD4 repression and CD8 activation

[35,36,78]

Embryonic lethality at E10–E11; defects in heart development; defects in neural tube closure; defects in left-right asymmetry determination in embryos Embryonic lethality at E12.5–E15.5; defects in heart development; abnormal placenta

[48,49]

Hypomorphic mutation T-cell-specific deletion Oocyte-specific deletion Endocardial cell-specific deletion Brain-specific deletion Endothelial cell-specific deletion BRM

Gene knockout

SRG3 (BAF155)

Gene knockout Constitutive expression in mature T-cells Constitutive expression in immature T-cells Transgenic rescue of knockout mice

SNF5 (BAF47/INI1)

Gene knockout Reversible conditional inactivation

BAF57 BAF60c

Constitutive expression of dominant-negative mutant in T-cells Knockdown by RNA interference

BAF180

Gene knockout

blocks neuronal differentiation but leads to an increase in proliferating neural progenitors. In addition, conditional inactivation of BRG1 by Cre recombinase under control of the Nestin promoter has revealed essential roles of BRG1 in maintaining neural stem cells (NSCs) [51,52]. Interestingly, a critical switch in the accessory subunit composition of the SWI/SNF complex can determine whether NSCs continue to proliferate or differentiate [51]. BAF45a and BAF53a are assembled into the complex in the proliferating NSCs. However, as neural progenitors exit cell cycle to be committed into neuronal lineages, these subunits are replaced by BAF45b, BAF45c and BAF53b to drive neuronal differentiation. Therefore, the SWI/SNF complex is an essential regulator of neuronal differentiation and combinatorial assembly of mutually exclusive accessory subunits produces complexes with distinct functions, which are crucial for cell fate determination during neurogenesis. The SWI/SNF complex also plays a primary role in vascular development during murine embryogenesis [44,53]. Ectopic expression of the SRG3 transgene on a SRG3 null background rescues embryos from peri-implantation lethality and allows them to further develop [44]. Although rescued SRG3−/− embryos at E10.5 undergo normal vasculogenesis, vascular remodeling during subsequent angiogenesis in the yolk sac is severely impaired due to insufficient restoration of SRG3 expression. Similarly, conditional deletion of BRG1 in developing hematopoietic and endothelial cells leads to lethality at midgestation, and vascular development in the yolk sac is also impaired [53]. Gene expression analysis shows that this abnormal vascular development is due to altered expression of various genes involved in angiogenesis such as Angiopoietin1, Tie2, EphrinB2, Ihh and Notch1. However, the expression of VEGF and its receptors is not affected in the yolk [44]. These observations reveal a very interesting aspect in the function of the SWI/SNF chromatin remodeling complex that it regulates angiogenesis-related gene expression but not that involved in vasculogenesis during embryonic blood vessel formation.

[45] [40,41] [39] [46] [51,52] [53]

[34] [66]

[44]

[79] [43]

[47]

BRG1-containing SWI/SNF-like complex is required for both embryonic and adult ␤-globin transcription and erythropoiesis [45,53]. ENU-induced BRG1 mutant protein assembles into the SWI/SNF complex, but its nucleosome remodeling activity is diminished. Mutant embryos develop normally until midgestation, but then exhibit a block in development of the erythroid lineage, leading to anemia and death at E14.5 [45]. These mutant embryos fail to transcribe adult ␤-globin genes, despite successful recruitment of the mutant BRG1-containing complex to the ␤-globin locus control region (LCR). In addition, mice carrying a conditional deletion of BRG1 in developing hematopoietic and endothelial cells display reduced embryonic ␣-globin (␨) and ␤-globin transcription during primitive erythropoiesis [53]. In vitro studies revealed that the SWI/SNF-related complex physically interacts with erythroid Krüppel-like factor (EKLF), a zinc finger transcription factor that activates ␤-globin gene expression by binding to the CACCC element in the ␤-globin promoter [54–56]. The multi-protein complex, called E-RC1 (EKLF coactivator-remodeling complex 1) interacts with EKLF to facilitate transcription from reconstituted chromatin templates containing the human ␤-globin promoter [55,56]. The E-RC1 complex isolated from mouse erythroleukemia (MEL) cells includes various SWI/SNF components BRG1, BAF170, SRG3, SNF5, and BAF57. However, the E-RC1 complex is distinct from the SWI/SNF complex because the purified SWI/SNF complex cannot substitute for E-RC1 to activate EKLF-mediated ␤-globin transcription. The E-RC1 complex is specifically recruited to the ␤-globin promoter by associating with EKLF, which is further enhanced by the presence of ␤-globin LCR sequences, and remodels the chromatin structure into a transcriptionally active state [55]. Another complex, called PYR complex, is implicated in ␥- to ␤-globin gene switching during erythroid development [57–59]. The complex is similar but not identical to E-RC1 in that it contains SWI/SNF subunits such as SNF5, BAF57, BAF60a, SRG3 and

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Fig. 2. Transcriptional control of SRG3 and its roles in T-cell development. In immature thymocytes, E-protein family members, E2A and HEB, bind to the E-box element in the SRG3 promoter and thereby SRG3 is highly expressed. Then, SRG3 efficiently associates with GR to render thymocytes susceptible to GC- or stress-induced apoptosis. On the other hand, TCR or Notch signals repress the SRG3 transcription by inhibiting transactivating functions of the E2A/HEB complex. TCR signals block the binding of E2A/HEB complex to the SRG3 promoter by rapidly inducing Id3 proteins. Notch signals allow for the complex formation in the E-box element but prevent the recruitment of p300 to the E2A/HEB complex by inducing Deltex-1. Transrepression of SRG3 in activated thymocytes results in GC resistance and allows cells to undergo further development including positive and negative selections.

BAF170, but does not contain BRG1 protein [58,59]. The PYR complex also includes subunits of NuRD complex (Mi-2␤ and HDAC2) as a repressor component, and Ikaros (also known as LyF-1) as a sequence-specific DNA-binding factor [59]. The PYR complex appears to bind to the intergenic boundary sequences between fetal (␥) and adult (␤) ␤-globin-like genes and induces chromatin remodeling of these regulatory sequences, leading to specific activation of ␤-globin and repression of ␥-globin expression. Although in vivo function of the complex remains to be confirmed, deletion of PYR-binding sequences from a human ␤-globin mini-locus construct in transgenic mice leads to delayed human ␥- to ␤-globin switching, suggesting its in vivo role during erythroid development [58]. Many exquisite in vivo models have been established to understand the role of the SWI/SNF complex during T-cell development. Because its role during development has been most extensively investigated during T-cell development and understood in the context of T-cell receptor signaling, a separate section is devoted for this discussion.

4. SWI/SNF remodeling complex during T-cell development Useful insights into the genetic control of T-cell development by ATP-dependent chromatin remodeling complexes were provided by examining mice carrying either conditional inactivation or lymphoid-specific overexpression of SWI/SNF components [8]. The SWI/SNF complex modulates CD4 and CD8 co-receptor expression. Transgenic expression of BAF57N mutant protein (a dominantnegative form of the BAF57 subunit whose amino-terminal high mobility group (HMG) domain is deleted), and conditional inactivation of BRG1 in a T-cell-specific manner impair CD4 repression and

CD8 activation in thymocytes [40,41]. BRG1 is specifically targeted to the CD4 silencer element, which is important for CD4 suppression, but its association with the enhancer III or IV regions of CD8 has not been observed. BRG1 ablation leads to a developmental block at CD4− CD8− double negative (DN) to CD4+ CD8+ double positive (DP) transition and reduces cell viability. The BRG1-deleted thymus is predominantly comprised of DN cells and also harbors a few CD4+ CD8− cells whose CD4 is inappropriately de-repressed in a small fraction of DN thymocytes. In addition, total thymocyte cellularity is dramatically reduced, and almost no DP or mature CD4+ CD8− or CD4− CD8+ single positive (SP) cells are observed in BRG1 mutant mice. It is thought that developmental defects in BRG1-deficient thymocytes are due to an inability of BRG1-deleted cells to properly respond to signals emanating from pre-TCR, which are essential for cell proliferation and developmental transition [40]. BRG1 deficiency impairs the expression of some genes associated with cell cycle progression and cell viability. For example, BRG1 is required for the expression of some Wnt signaling target genes such as c-Kit, c-Myc, and NPM [40]. The expression of components of the SWI/SNF complex is finely controlled in response to TCR signals, and this affects the survival, positive or negative selection, and gene expression in developing thymocytes (Fig. 2). SRG3 expression is dynamically controlled during T-cell development [60,61]. SRG3 and BRG1 transcripts are downregulated by TCR signaling during positive selection, while SNF5 or BAF60a transcripts remain unchanged [61]. The E protein transcription factor family, E2A and HEB, specifically bind to the E-box element in the SRG3 promoter, maintaining high SRG3 expression in immature DP thymocytes [62–64]. However, TCR signaling represses SRG3 transcription by antagonizing the binding of E2A/HEB complex to the SRG3 promoter via induction of Id3, a dominant-negative inhibitor of E protein activity [64]. Alteration

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of SRG3 expression changes the level and, therefore, the activity of SWI/SNF chromatin remodeling complex in thymocytes [61]. Regulation of the SWI/SNF complex by TCR signaling causes a few changes in developing thymocytes. The level of SRG3 expression regulates the sensitivity of developing thymocytes to glucocorticoid (GC)-induced apoptosis [60,62–66]. Immature DP thymocytes are relatively more sensitive to GC-induced apoptosis than mature SP T-cells. By physically associating with GC receptor (GR) in T-cells, SRG3 upregulates its transcriptional activity, thereby enhancing GC- and stress-induced apoptosis [60,64,66]. BRG1 also activates the transcriptional activity of GR through physical interaction [67]. Alteration of the SRG3 expression in transgenic mice alters the GC sensitivity of developing T-cells [66]. TCR signaling-mediated repression of SRG3 transcription decreases the SRG3-GR complex, and probably SWI/SNF-GR complex, and confers activated thymocytes a GC resistance. Therefore, GC sensitivity of thymocytes is dynamically controlled by TCR signaling via regulation of the SWI/SNF remodeling complex during T-cell development. It is likely that Notch1-mediated signals also regulate the SWI/SNF chromatin remodeling complex. Notch1 signal, which antagonizes GC-induced apoptosis in T-cells, also inhibits SRG3 transcription [62,65,68]. In this process, Notch1-activated RBP-J or Deltex1 represses SRG3 transcription through N-box or E-box motifs in the SRG3 promoter, respectively [62,65]. In particular, Deltex1 represses the transactivating function of the E2A/HEB complex bound to the E-box element by inhibiting recruitment of p300 to the complex [62]. Therefore, Notch1 also controls the GC sensitivity of developing thymocytes by regulating the SWI/SNF complex. It is not clear yet whether regulation of the SWI/SNF complex by Notch1-mediated signals plays any role in the differentiation of other tissues and cells. Constitutive expression of SRG3 in transgenic mice leads to increased chromatin remodeling activity of the SWI/SNF complex in vivo, and inhibits TCR-mediated repression of SRG3 and BRG1 expression [61]. De-regulated activity of the SWI/SNF complex by constitutive SRG3 expression disrupts TCR-triggered signal transduction and changes the expression of several genes such as Lat and Cbl, which are important for TCR-mediated signaling [61,69,70]. Positive and negative selections are impaired in these mice due to partial defects in downregulation of SRG3 expression [61]. Thus, chromatin remodeling activity of the SWI/SNF complex is tightly regulated by TCR- and/or Notch-mediated transcriptional control and this is important for proper execution of developmental programs in the thymus.

5. SWI/SNF remodeling complex in the pathogenesis of tumors Increasing pieces of evidence suggest that several subunits of the SWI/SNF complex are implicated in tumor development and that they display intrinsic tumor suppressor activity. Loss of SNF5 is observed in a majority of human malignant rhabdoid tumors (MRTs), a highly aggressive pediatric cancer [71–73]. SNF5 inactivation has also been frequently observed in other tumor types that are histologically distinct from MRT [74–77]. In addition, mice heterozygous for SNF5 are predisposed to tumors with features similar to the human MRTs, which are frequently metastatic to the lung and/or lymph node. SNF5-deficient tumors undergo loss of heterozygosity (LOH), which results in SNF5 depletion [35,78,79]. BRG1 and BRM mutations are also frequently observed in various tumor cell lines including pancreatic, breast, lung and prostate cancer cells [80–83]. In addition, BRG1 and BRM proteins are not detected in ∼30% of human non-small lung cancer cell lines and ∼10% of primary lung cancer cells lose BRG1 or BRM expression

[84]. Consistently, mice heterozygous for BRG1 are prone to tumorigenesis, albeit at a low incidence [33,85]. Unlike SNF5-deficient tumors, BRG1-deficient tumors occur at different locations such as the neck or inguinal regions, display different features of epitheloid origin, and appear not to undergo LOH [33]. The SWI/SNF complex physically associates with Rb [86] and this interaction is involved in Rb-mediated cell cycle arrest by repressing the E2F-responsive promoters [87–89]. At G1 phase of the cell cycle, repressor complex containing HDAC, Rb and SWI/SNF is assembled to inhibit the expression of cyclins E and A, thereby arresting cell cycle progression [87]. BRG1 loss renders cells resistant to Rb-mediated cell cycle arrest to promote oncogenesis. Re-introduction of BRG1 into BRG1-deficient cancer cell lines restores Rb function to repress E2F target genes such as cyclin E and induces expression of the cyclin-dependent kinase (Cdk) inhibitors p21 and p15 [88]. Similarly, ectopic overexpression of SNF5 in SNF5-deficient rhabdoid tumor cells leads to G1 cell cycle arrest, which may be caused by induction of p16Ink4a and activation of Rb function [90–92]. In addition, SNF5 represses cyclin D1 expression by directly recruiting HDAC complex to the cyclin D1 promoter, thereby leading to cell cycle arrest [93]. Overexpression of cyclin D1 abrogates SNF5-induced cell cycle arrest in rhabdoid tumor cells and cyclin D1 is frequently overexpressed in various human rhabdoid tumors. Furthermore, cyclin D1 deficiency on a SNF5 heterozygous background inhibits rhabdoid tumor development in mice, suggesting that cyclin D1 may be a critical mediator of SNF5 tumor suppressor activity in vivo [94]. The SWI/SNF complex associates directly with cancer-related molecules such as BRCA1 and c-Myc [95]. BRCA1 activates p53-dependent transcription, which is abrogated by a dominantnegative mutant form of BRG1 [96]. SNF5 also interacts directly with c-Myc and this interaction is important for transactivating the function of c-Myc [97]. Most cancers display defects in controlling p53 activities due to mutations of the p53 tumor suppressor gene itself, or de-regulation of molecules that modulate the expression or function of p53. Therefore, the effects of p53 loss on the development of tumors in SNF5 heterozygous mice were assessed in several studies [42,98]. As a result, it has been suggested that genetic ablation of p53 accelerates tumor formation in mice haploinsufficient for SNF5 [98]. The phenotypic profile and anatomical locations of all tumors observed in the double knockout mice are almost identical to those of SNF5 heterozygous mice (CD8+ mature T-cell lymphoma), suggesting that developmental features of tumors is initially determined by SNF5 loss and then p53 deficiency dramatically increases the rate of tumor onset. However, inactivation of p16Ink4a or Rb does not influence the latency of tumor development in SNF5 conditional knockout mice [98]. The SWI/SNF complex is also involved in various cellular processes that are potentially associated with tumor formation including DNA synthesis, virus integration, DNA repair, and mitotic gene regulation. Numerous studies to dissect the connection between these activities and tumor formation are currently in progress. Nonetheless, it remains unresolved whether BRG1 or SNF5 exhibit tumor suppressing activities as a component of the SWI/SNF complex, or function independently of the complex. The intact SWI/SNF complex is assembled even in the absence of SNF5 and the expression of some BRG1 target genes is not affected upon SNF5 loss, suggesting that SWI/SNF functions independently of SNF5 in malignant transformation [99]. Furthermore, the molecular mechanisms underlying tumor development in mice with inactivation of BRG1 or SNF5 are still unclear. Paradoxical observations that phenotypes induced by BRG1 or SNF5 deficiency in mouse embryonic fibroblasts (MEFs) are very similar to those of cancer cells whose BRG1 or SNF5 are ectopically overexpressed are noteworthy.

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Both cell lines undergo cell cycle arrest, cell death, or senescence. At the molecular level, p21 expression is upregulated upon either overexpression or inactivation of BRG1 or SNF5 [42,88,98,100,101]. The SWI/SNF complex also harbors a co-activator function for p53mediated transcription in vitro [102]. On the other hand, the level of p53 protein is upregulated in SNF5-deficient MEFs, thereby enhancing p53-mediated transcription. Further studies are required to resolve these issues. Nevertheless, these indicate that the SWI/SNF complex needs to be finely controlled for normal cell growth and activities. 6. Perspectives The exquisite regulation of gene expression is essential for normal cellular and tissue development. Dynamic chromatin restructuring by chromatin remodeling complex is integral for spatial and temporal regulation of transcriptional programs. Progress is being made in understanding the roles of the SWI/SNF chromatin remodeling complex in developmental or pathological processes. However, many questions regarding their roles in fundamental features of development, cellular physiology and diseases still remain to be answered. It will be particularly important to address how functional specificity of the SWI/SNF chromatin remodeling complex is determined. It is not clear which genes require the complex for their proper expression and how the complex modulates the expression of particular genes, but not the others, as observed in the case of embryonic angiogenesis and vasculogenesis. Therefore, uncovering the mechanisms that regulate chromatin remodeling activity and targeting of the complex to specific gene loci to control cellular and tissue development is an important subject of future investigation. In addition, activity and specificity of the complex may be altered in response to developmental signals. Investigations on the signaling pathways and the ways that it operates during development are also required. Genome-wide mapping of SWI/SNF binding sites and their changes during particular developmental processes will be critically instrumental to answer these questions. In addition, even though the SWI/SNF complex has been implicated in tumor suppression, the mechanisms by which the complex performs this function remain to be elucidated. The SWI/SNF complex is also involved in various physiological processes such as cell cycle progression, DNA replication, viral integration and DNA repair. Elucidation of the molecular mechanisms that modulate chromatin remodeling and concomitant gene expression during physiological and pathological processes will help to devise efficient therapeutic tools to overcome pathological conditions induced by defects in chromatin remodeling. Conflict of interest The authors declare that there are no conflicts of interest. Acknowledgement This work was supported by a grant from Korea Science and Engineering Foundation (KOSEF), through the Research Center for Functional Cellulomics to R.H.S. References [1] A. Saha, J. Wittmeyer, B.R. Cairns, Chromatin remodelling: the industrial revolution of DNA around histones, Nat. Rev. Mol. Cell Biol. 7 (2006) 437–447. [2] M. Vignali, A.H. Hassan, K.E. Neely, J.L. Workman, ATP-dependent chromatinremodeling complexes, Mol. Cell. Biol. 20 (2000) 1899–1910. [3] V.K. Gangaraju, B. Bartholomew, Mechanisms of ATP dependent chromatin remodeling, Mutat. Res. 618 (2007) 3–17.

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