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An Embryonic Stem Cell Chromatin Remodeling Complex, Esbaf, Is Essential for Embryonic Stem Cell Self-Renewal and Pluripotency

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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 Lena Hoa, Jehnna L. Ronanb, Jiang Wuc, Brett T. Staahld, Lei Chenc, Ann Kuoc, Julie Lessardc,1, Alexey I. Nesvizhskiie, Jeff Ranishf, and Gerald R. Crabtreec,2 aProgram in Immunology, bProgram in Cancer Biology, cHoward Hughes Medical Institute and the Departments of Pathology and of Developmental Biology, and dProgram in Developmental Biology, Stanford University, Stanford, CA; eUniversity of Michigan, Department of Pathology and Center for Computational Medicine and Biology, Ann Arbor, MI; and fInstitute of Systems Biology, Seattle, WA Contributed by Gerald R. Crabtree, December 18, 2008 (sent for review December 15, 2008) Mammalian SWI/SNF [also called BAF (Brg/Brahma-associated fac- In vitro, BAF complexes use energy generated from ATP tors)] ATP-dependent chromatin remodeling complexes are essen- hydrolysis to alter DNA-nucleosome contacts (21) and can also tial for formation of the totipotent and pluripotent cells of the exchange histones or generate torsional stress on nucleosomal early embryo. In addition, subunits of this complex have been templates. Although in Saccharomyces cerevisiae, SWI/SNF com- recovered in screens for genes required for nuclear reprogramming plexes primarily activate transcription (22, 23), mammalian BAF in Xenopus and mouse embryonic stem cell (ES) morphology. complexes can both activate and repress genes directly (24). BAF However, the mechanism underlying the roles of these complexes complexes have been found to work with known repressors such is unclear. Here, we show that BAF complexes are required for the as REST (25) and histone deacetylases (26) to mediate gene self-renewal and pluripotency of mouse ES cells but not for the repression. proliferation of fibroblasts or other cells. Proteomic studies reveal BAF complexes consist of 11 core subunits that are essentially that ES cells express distinctive complexes (esBAF) defined by the non-exchangeable in vitro, several of which are encoded by gene presence of Brg (Brahma-related gene), BAF155, and BAF60A, and families (10, 27). The diversity of complexes is derived from the absence of Brm (Brahma), BAF170, and BAF60C. We show that combinatorial assembly of alternative family members and is this specialized subunit composition is required for ES cell main- postulated to confer functional specificity to BAF complexes. tenance and pluripotency. Our proteomic analysis also reveals that For example, the subunit composition of BAF complexes esBAF complexes interact directly with key regulators of pluripo- switches at mitotic exit in the vertebrate nervous system. Pre- tency, suggesting that esBAF complexes are specialized to interact mitotic neuronal progenitor BAF complexes are necessary and with ES cell-specific regulators, providing a potential explanation sufficient for neuronal progenitor proliferation and self-renewal (11). In contrast, postmitotic neuronal BAF complexes are for the requirement of BAF complexes in pluripotency. BIOLOGY essential for dendritic outgrowth (28). Functionally distinct complexes have also been identified in cardiac progenitors (29). DEVELOPMENTAL BAF complexes ͉ BAF155 ͉ Brg In addition, Polybromo-BAF (PBAF) complexes are defined by incorporation of BAF180 (Polybromo) and BAF200 and are S cells are pluripotent cells capable of both limitless self- required for heart development (30, 31). Erenewal and differentiation into all embryonic lineages. To understand the mechanism underlying the role of BAF These abilities are conferred by various mechanisms, including complexes in pluripotency, we performed functional and bio- transcription factors (1–3), possibly Polycomb complexes (4, 5), chemical characterization of BAF complexes in ES cells. Our microRNAs (6), and histone modification enzymes (7) that work studies indicate that a specialized esBAF complex is essential for in coordination to maintain the expression of pluripotency genes self-renewal and pluripotency. while repressing lineage-determinant genes. The involvement of such mechanisms in pluripotency has been investigated exten- Results sively in recent years (reviewed in ref. 8), but the role of Reduction of Brg Leads to Loss of Self-Renewal in ES Cells. Brg chromatin remodeling enzymes remains unclear. deletion leads to peri-implantation lethality because of the The mammalian genome encodes about 30 SWI2/SNF2-like failure of the inner cell mass (ICM) to proliferate and develop ATPases, which are assembled into SWI/SNF-like complexes (14). Consistent with this finding, we were unable to derive ES with ATP-dependent chromatin remodeling activity. Of these, cells after Cre-mediated deletion of Brg in ICM cells homozy- Brg and Brm are alternative ATPases of a family of 2-MDa gous for a conditional allele (data not shown), suggesting that multisubunit SWI/SNF or BAF complexes and make up the Brg is essential for ES cell formation. To circumvent this prototypic mammalian SWI/SNF-like chromatin remodeling problem, we depleted Brg in murine E14 ES cells using shRNA- complexes (9, 10). BAF complexes have been shown to be mediated knockdown. Under standard ES culture conditions, essential for many aspects of mammalian development (11–13). BrgshRNA ES cells show a marked reduction in self-renewal. Cell A role of BAF complexes in pluripotency is suggested by observations that deletion of Brg, BAF155 (or Srg3), and BAF47 Author contributions: L.H. and G.R.C. designed research; L.H. and J.L.R. performed research; (or hSNF5) all lead to peri-implantation lethality and failure of L.H., J.L.R., J.W., B.T.S., L.C., A.K., J.L., A.I.N., and J.R. contributed new reagents/analytic the totipotent cells that give rise to both the inner cell mass and tools; L.H. and A.I.N. analyzed data; and L.H. wrote the paper. trophoblast to survive and grow (14–16). The catalytic ATPase The authors declare no conflict of interest. subunit, Brg, also was recovered in screens for factors essential Freely available online through the PNAS open access option. for nuclear reprogramming (17) and to ES cell morphology (18). 1Present address: Institute for Research in Immunology and Cancer, University of Montreal, In addition, ES cells lacking BAF250 have defects in ES cell Montreal QC, Canada maintenance and differentiation (19, 20). However, the mech- 2To whom correspondence should be addressed. E-mail: [email protected]. anism by which BAF complexes help to establish and maintain This article contains supporting information online at www.pnas.org/cgi/content/full/ pluripotency is not understood. 0812889106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0812889106 PNAS ͉ March 31, 2009 ͉ vol. 106 ͉ no. 13 ͉ 5181–5186 Downloaded by guest on September 25, 2021 #1 #2 A shRNA shRNA C +GFP channel -GFP channel Control Control Brg Brg Brg Brg Hsp90 DAPI GFP pLKO Brg shRNA #1 Brg shRNA#2 Phase Passage 3 Passage 4 Passage 5 120 600 Contrast 400 90 300 28.1 28.5 400 24.7 60 Alkaline 200 # Cells # Cells # Cells 200 Phosphatase 100 30 10 4 0 0 0 10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 10 4 10 0 10 1 10 2 10 3 Oct4 GFP GFP GFP GFP- GFP+ 10 5 34.4 10 5 34.7 Nanog 10 4 10 4 3 46 9.43 3 23.8 15.4 BrdU10 BrdU10 Sox2 10 2 10 2 0 0 0 50000 100000 150000 200000 250000 0 50000 100000 150000 200000 250000 7AAD 7AAD B 80 pLKO C ontrol Brg shRNA#1 Brg shRNA#2 BrgshRNA #1 pLKO Control 60 BrgshRNA#2 100 100 100 80 80 80 40 **p=0.0016 60 60 60 40 52.3 40 27.6 40 31.8 % of Max % of Max % of Max 20 20 20 20 ***p<0.0001 0 0 3 4 5 0 0 0103 104 105 010 10 10 0103 104 105 Percentage GFP Positive Percentage 01234 BrdU BrdU BrdU Passage Number D 88hrs 96hrs 144hrs 88hrs 96hrs 144hrs Tamoxifen + - BRG DAPI Brgf/f;Actinp-CreER Fig. 1. Brg is essential for ES cell self-renewal and proliferation. (A) Immunoblotting of Brg and housekeeping gene Hsp90 protein levels 96 h after transduction of E14 ES cells with shRNA constructs (BrgshRNA#1 and Brg shRNA#2) compared with pLKO control. Colony morphology and alkaline phosphatase, Oct4, Nanog, and Sox staining of BrgshRNA ES cells 10 days following transduction of shRNA contructs. (B Left) Day 3- transduced ES cells (GFPϩ) were mixed with non-transduced ES cells at a 3:2 ratio. The co-cultures were passaged every 2 d, and the percentage of GFPϩ cells (mean value Ϯ SD; p-values by student’s t test) was determined by flow cytometry. (Right) BrdU incorporation 96 h following transduction in (A). (C) Brglox/lox primary MEFs were transfected with Cre to mediate deletion of Brg. GFPϩ marks transfected and deleted MEF cells (Top). Immunofluorescence for Brg protein. (Middle) Mixed cultures (GFPϮ) then were passaged serially over 5 d, and BrdU incorporation was performed on passage 4 MEFs (Bottom). (D) Colony morphology of Brglox/lox;Actinp-CreERϩ ES cells over a timecourse after addition of either tamoxifen or ethanol vehicle control. (Left) Brightfield and (Right) immunofluorescence for Brg. cycle analysis following knockdown by 2 different constructs (Fig. 1D). Similar to BrgshRNA ES cells, Brg knockout ES cells (Fig. 1A Upper) revealed reduced transition into S phase and lose proliferative capacity immediately upon reduction of Brg decreased cell numbers compared with control (Fig. 1B), in protein levels, forming small colonies with flattened morphology addition to losing colony morphology and alkaline phosphatase indicative of spontaneous differentiation (Fig. 1D). staining (Fig. 1A). When co-cultured with wild-type ES cells Although decreased proliferation was evident immediately fol- (Fig. 1B, Left), BrgshRNA ES cells were lost rapidly from the lowing the reduction of Brg protein, BrgshRNA ES cells lost expres- cultures compared with control.
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