title: BAF250a Protein Regulates Nucleosome Occupancy and Histone Modifications in Priming Embryonic Stem Cell Differentiation.
abstract: The unique chromatin signature of ES cells is fundamental to the pluripotency and differentiation of ES cells. One key feature is the poised chromatin state of master developmental genes that are transcriptionally repressed in ES cells but ready to be activated in response to differentiation signals. Poised chromatin in ES cells contains both H3 Lys-4 trimethylation (H3K4me3) and H3 Lys-27 trimethylation (H3K27me3) methylation, indicating activating and repressing potential. However, the contribution of non-covalent chromatin structure to the poised state is not well understood. To address whether remodeling of nucleosomes is important to the poised state, we characterized the function of BAF250a, a key regulatory subunit of the ES cell ATP-dependent Brahma-associated factor (BAF) chromatin remodeling complex (esBAF). Acute deletion of BAF250a disrupted the differentiation potential of ES cells by altering the expression timing of key developmental genes and pluripotent genes. Our genome-wide nucleosome and histone modification analyses indicated that the disruption of gene expression timing was largely due to changes of chromatin structures at poised genes, particularly those key developmental genes mediated by BAF250a. Specifically, BAF250a deletion caused a nucleosome occupancy increase at H3K4me3- and/or H3K27me3-associated promoters. Moreover, H3K27me3 levels and the number of bivalent promoter genes were reduced in BAF250a KO ES cells. We revealed that BAF250a ablation led to elevated Brg1 but reduced Suz12 recruitment at nucleosome occupancy-increased regions, indicating an unexpected and complicated role of BAF250a in regulating esBAF and Polycomb repressive complex (PRC) activities. Together, our studies identified that BAF250a mediates esBAF and PRC functions to establish the poised chromatin configuration in ES cells, which is essential for the proper differentiation of ES cells.
authors.affiliation: From the Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Ienglam
authors.initials: I
authors.lastname: Lei
authors.affiliation: the Department of Molecular Biology and.
authors.forename: Jason
authors.initials: J
authors.lastname: West
authors.affiliation: the Genome Instability and Chromatin Remodeling Section, NIA, National Institutes of Health, Baltimore, Maryland 21224, and.
authors.forename: Zhijiang
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Peng
authors.initials: P
authors.lastname: Fang
authors.affiliation: the Department of Biological Science, Florida State University, Tallahassee, Florida 32306.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Dennis
authors.affiliation: From the Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Leonid
authors.initials: L
authors.lastname: Gnatovskiy
authors.affiliation: the Genome Instability and Chromatin Remodeling Section, NIA, National Institutes of Health, Baltimore, Maryland 21224, and.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.affiliation: the Department of Molecular Biology and.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Kingston
authors.affiliation: From the Department of Cardiac Surgery, Cardiovascular Research Center, University of Michigan, Ann Arbor, Michigan 48109, zhongw@med.umich.edu.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D058732:Embryoid Bodies / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006657:Histones / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D009707:Nucleosomes / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors; D024363:Transcription Initiation Site
chemical_list: C511511:Arid1a protein, mouse; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; D014157:Transcription Factors
keywords: BAF250a; chromatin remodeling; differentiation; embryonic stem cell; epigenetics; histone modification; nucleosome occupancy