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  • One of these factors SWI SNF

    2018-10-24

    One of these factors, SWI/SNF, is a large chromatin-remodeling complex that contains either BRG1 or BRM exclusively as the catalytic ATPase subunit that drives the alteration of DNA-nucleosome structure and thus regulates gene transcription (Fryer and Archer, 1998; Trotter and Archer, 2008; Wang et al., 1996). Previous studies revealed that deletions of BRG1 or core subunits of the SWI/SNF complex, such as BAF155 and BAF47, led to peri-implantation lethality due to compromised survival of totipotent tachykinin receptor that give rise to both the inner cell mass and trophoblast, suggesting a requirement of the SWI/SNF complex for totipotency in vivo (Bultman et al., 2005; Kim et al., 2001; Klochendler-Yeivin et al., 2000). In addition, deficiency of SWI/SNF components also affects the developmental potential of various types of cells (e.g., neurons, hematopoietic cells, and germ cells) (Chi et al., 2003; Gebuhr et al., 2003; Griffin et al., 2008; Hang et al., 2010; Kim et al., 2012; Wang et al., 2012; Yoo and Crabtree, 2009), supporting the notion that the SWI/SNF complex plays a role in tissue development. Recently, a series of reports demonstrated that the SWI/SNF complex also plays a role in the pluripotency of mESCs. Deficiency of BRG1, BAF155, or BAF250a/b impaired the ability of mESCs to proliferate and to differentiate into three germ layers (Gao et al., 2008; Ho et al., 2009a, 2009b, 2011; Kaeser et al., 2008; Kidder et al., 2009; Schaniel et al., 2009; Yan et al., 2008). Chromatin immunoprecipitation-coupled DNA sequencing (ChIP-seq) revealed that BRG1 colocalizes with core pluripotent factors (OCT4 and SOX2) at a large number of loci in target genes to fine-tune their regulation. In addition, BRG1 also potentiates LIF/STAT3 signaling in mESCs by opposing polycomb (PcG) function via alteration of H3K27me3 levels (Ho et al., 2009a, 2009b, 2011; Kidder et al., 2009). The mammalian SWI/SNF complex contains 15 core subunits called BRG1- or BRM-associated factors (BAFs), including several ones not found in yeast (Kadoch et al., 2013). Different assemblies of BAF components have been implicated in their tissue-specific functions (Wu et al., 2009). For instance, BAF60c, but not BAF60b, protein is selectively expressed in embryonic heart, and its deficiency results in defective cardiac development and embryonic lethality at 10–11 days postcoitum (dpc) (Lickert et al., 2004). In mESCs, BRG1 (but not BRM) and BAF155 (but not BAF170) are enriched with BAF60a to form the so-called “esBAF” complex (Ho et al., 2009b). Deficiency of either BRG1 or BAF155 leads to a loss of pluripotency in mESCs that cannot be rescued by overexpression of BAF170 (Ho et al., 2009b). Thus, the specific composition of the BAF is critical for its function in mESCs.
    Results
    Discussion Although both mESCs and hESCs are derived from the inner cell mass of blastocysts, they differ remarkably in terms of colony morphology, cell-doubling time, and the signaling pathways that maintain their self-renewal capacity. The extent to which these differences are observed at a molecular level remains only partially described. The recent generation of primed EpiSCs has added another layer of complexity (Brons et al., 2007; Tesar et al., 2007). Although hESCs share some defining features with mEpiSCs in terms of growth properties and signaling responses, they differ from mEpiSCs in several aspects (De Los Angeles et al., 2012). For instance, hESCs express REX1, a marker associated with naive mESCs, but do not express FGF5, a key mEpiSC marker (Greber et al., 2010). These differences further complicate efforts to simply extrapolate the rodent paradigm to humans. In the case of the SWI/SNF complex, the nature and importance of its role in hESCs is an important area of investigation. In this study, we found that depletion of the major catalytic subunit of the SWI/SNF complex, BRG1, compromised the self-renewal capacity of hESCs and their murine counterparts, mESCs and mEpiSCs. In addition, BRG1 deficiency impaired mesodermal development from hESCs, as revealed by both in vitro EB differentiation and in vivo teratoma formation. We further demonstrated that BRG1 participated in a broad range of biological processes in hESCs through genes and pathways distinct from those of mESCs and mEpiSCs, thus indicating that BRG1 differently regulates the pluripotency of stem cells across species. Our data define an essential and conserved role of BRG1 in ESC biology, and also provide mechanistic insights into how the BRG1-mediated SWI/SNF complex affects the maintenance of human stem cells.