title: SNF5 is an essential executor of epigenetic regulation during differentiation.
abstract: Nucleosome occupancy controls the accessibility of the transcription machinery to DNA regulatory regions and serves an instructive role for gene expression. Chromatin remodelers, such as the BAF complexes, are responsible for establishing nucleosome occupancy patterns, which are key to epigenetic regulation along with DNA methylation and histone modifications. Some reports have assessed the roles of the BAF complex subunits and stemness in murine embryonic stem cells. However, the details of the relationships between remodelers and transcription factors in altering chromatin configuration, which ultimately affects gene expression during cell differentiation, remain unclear. Here for the first time we demonstrate that SNF5, a core subunit of the BAF complex, negatively regulates OCT4 levels in pluripotent cells and is essential for cell survival during differentiation. SNF5 is responsible for generating nucleosome-depleted regions (NDRs) at the regulatory sites of OCT4 repressed target genes such as PAX6 and NEUROG1, which are crucial for cell fate determination. Concurrently, SNF5 closes the NDRs at the regulatory regions of OCT4-activated target genes such as OCT4 itself and NANOG. Furthermore, using loss- and gain-of-function experiments followed by extensive genome-wide analyses including gene expression microarrays and ChIP-sequencing, we highlight that SNF5 plays dual roles during differentiation by antagonizing the expression of genes that were either activated or repressed by OCT4, respectively. Together, we demonstrate that SNF5 executes the switch between pluripotency and differentiation.
authors: Departments of Urology and Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angles, California, United States of America.
authors: Jueng Soo
authors: JS
authors: You
authors: Daniel D
authors: DD
authors: De Carvalho
authors: Chao
authors: C
authors: Dai
authors: Minmin
authors: M
authors: Liu
authors: Kurinji
authors: K
authors: Pandiyan
authors: Xianghong J
authors: XJ
authors: Zhou
authors: Gangning
authors: G
authors: Liang
authors: Peter A
authors: PA
authors: Jones
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D050814:Octamer Transcription Factor-3 / Q000235:genetics
chemical_list: D050814:Octamer Transcription Factor-3
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