SWI/SNF-Brg1 Regulates Self-Renewal and Occupies Core Pluripotency-Related Genes in Embryonic Stem Cells

Kidder, Benjamin L.; Palmer, Stephen; Knott, Jack H.

doi:10.1634/stemcells.2008-0710

Cited by 223 publications

(250 citation statements)

References 59 publications

(83 reference statements)

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“…The requirement for Brg in ES cell maintenance and in blastocysts was reported recently by Knott and coworkers (39), confirming earlier results with gene deletion and studies reported here. In addition, we show that Brg acts in the context of a specialized complex, esBAF.…”

Section: Discussionsupporting

confidence: 93%

An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency

Ronan²,

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

521

658

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Mammalian SWI/SNF [also called BAF (Brg/Brahma-associated factors)] ATP-dependent chromatin remodeling complexes are essential for formation of the totipotent and pluripotent cells of the early embryo. In addition, subunits of this complex have been recovered in screens for genes required for nuclear reprogramming in Xenopus and mouse embryonic stem cell (ES) morphology. However, the mechanism underlying the roles of these complexes is unclear. Here, we show that BAF complexes are required for the self-renewal and pluripotency of mouse ES cells but not for the proliferation of fibroblasts or other cells. Proteomic studies reveal that ES cells express distinctive complexes (esBAF) defined by the presence of Brg (Brahma-related gene), BAF155, and BAF60A, and the absence of Brm (Brahma), BAF170, and BAF60C. We show that this specialized subunit composition is required for ES cell maintenance and pluripotency. Our proteomic analysis also reveals that esBAF complexes interact directly with key regulators of pluripotency, suggesting that esBAF complexes are specialized to interact with ES cell-specific regulators, providing a potential explanation for the requirement of BAF complexes in pluripotency.BAF complexes ͉ BAF155 ͉ Brg E S cells are pluripotent cells capable of both limitless selfrenewal and differentiation into all embryonic lineages. These abilities are conferred by various mechanisms, including transcription factors (1-3), possibly Polycomb complexes (4, 5), microRNAs (6), and histone modification enzymes (7) that work in coordination to maintain the expression of pluripotency genes while repressing lineage-determinant genes. The involvement of such mechanisms in pluripotency has been investigated extensively in recent years (reviewed in ref. 8), but the role of chromatin remodeling enzymes remains unclear.The mammalian genome encodes about 30 SWI2/SNF2-like ATPases, which are assembled into SWI/SNF-like complexes with ATP-dependent chromatin remodeling activity. Of these, Brg and Brm are alternative ATPases of a family of 2-MDa multisubunit SWI/SNF or BAF complexes and make up the prototypic mammalian SWI/SNF-like chromatin remodeling complexes (9, 10). BAF complexes have been shown to be essential for many aspects of mammalian development (11-13). A role of BAF complexes in pluripotency is suggested by observations that deletion of Brg, BAF155 (or Srg3), and BAF47 (or hSNF5) all lead to peri-implantation lethality and failure of the totipotent cells that give rise to both the inner cell mass and trophoblast to survive and grow (14-16). The catalytic ATPase subunit, Brg, also was recovered in screens for factors essential for nuclear reprogramming (17) and to ES cell morphology (18). In addition, ES cells lacking BAF250 have defects in ES cell maintenance and differentiation (19,20). However, the mechanism by which BAF complexes help to establish and maintain pluripotency is not understood.In vitro, BAF complexes use energy generated from ATP hydrolysis to alter DNA-nucleosome contacts (21) and can also e...

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Section: Discussionsupporting

confidence: 93%

An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency

Ronan²,

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

521

658

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“…Our data are consistent with the research of Kidder et al (2009), who showed that RNA interferencemediated knockdown of BRG1 in embryonic stem cells resulted in a loss of pluripotency and self-renewal.…”

Section: Discussionsupporting

confidence: 93%

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

et al. 2010

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We focused our attention on brahma-related gene 1 (BRG1), the ATPase subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, and analyzed its role in mesenchymal stem cell (MSC) biology. We hypothesized that deviation from the correct concentration of these proteins, which act at the highest level of gene regulation, may be deleterious for cells. We wanted to know what would happen if a cell had to cope with altered regulation of gene expression, either by upregulation or downregulation of BRG1. We assumed that cells would try to restore homeostasis or, alternatively, that the event could trigger senescence/apoptosis phenomena. To this end, in MSCs, we silenced BRG1gene. Knockdown of BRG1 expression induced a significant increase in senescent cells and decrease in apoptotic cells. It is interesting that BRG1 downregulation also induced an increase in heterochromatin. At the molecular level, these phenomena were associated with activation of retinoblastoma-like protein 2 (RB2)/P130-and P53-related pathways. Senescence was accompanied by reduced expression of some stemness-related genes. This is consistent with our previous research, which showed that BRG1 upregulation by ectopic expression also induced senescence processes. Together, these data suggest that BRG1 belongs to a class of genes whose expression is tightly regulated; hence, subtle alterations in BRG1 activity seem to negatively affect mechanisms regulating chromatin status and, in turn, impair cellular physiology.

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“…Previous studies have shown that Ezh2 is required for GC formation and the SWI/SNF complex synergistically regulates several genes together with the Ezh2-PRC2 complex (36)(37)(38)(39). MTA3, a subunit of the NuRD complex, is also known to interact with Bcl-6 and to inhibit Blimp-1 expression (40).…”

Section: Discussionmentioning

confidence: 99%

The SWI/SNF chromatin remodeling complex regulates germinal center formation by repressing Blimp-1 expression

Choi

Jeon

Choi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Germinal center (GC) reaction is crucial in adaptive immune responses. The formation of GC is coordinated by the expression of specific genes including Blimp-1 and Bcl-6. Although gene expression is critically influenced by the status of chromatin structure, little is known about the role of chromatin remodeling factors for regulation of GC formation. Here, we show that the SWI/SNF chromatin remodeling complex is required for GC reactions. Mice lacking Srg3/mBaf155, a core component of the SWI/SNF complex, showed impaired differentiation of GC B and follicular helper T cells in response to T cell-dependent antigen challenge. The SWI/SNF complex regulates chromatin structure at the Blimp-1 locus and represses its expression by interacting cooperatively with Bcl-6 and corepressors. The defect in GC reactions in mice lacking Srg3 was due to the derepression of Blimp-1 as supported by genetic studies with Blimp-1–ablated mice. Hence, our study identifies the SWI/SNF complex as a key mediator in GC reactions by modulating Bcl-6–dependent Blimp-1 repression.

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SWI/SNF-Brg1 Regulates Self-Renewal and Occupies Core Pluripotency-Related Genes in Embryonic Stem Cells

Cited by 223 publications

References 59 publications

An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency

An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

The SWI/SNF chromatin remodeling complex regulates germinal center formation by repressing Blimp-1 expression

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