title: Brg1 modulates enhancer activation in mesoderm lineage commitment.
abstract: The interplay between different levels of gene regulation in modulating developmental transcriptional programs, such as histone modifications and chromatin remodeling, is not well understood. Here, we show that the chromatin remodeling factor Brg1 is required for enhancer activation in mesoderm induction. In an embryonic stem cell-based directed differentiation assay, the absence of Brg1 results in a failure of cardiomyocyte differentiation and broad deregulation of lineage-specific gene expression during mesoderm induction. We find that Brg1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at distal enhancers that are activated during mesoderm induction. Brg1 is also required to maintain Polycomb-mediated repression of non-mesodermal developmental regulators, suggesting cooperativity between Brg1 and Polycomb complexes. Thus, Brg1 is essential for modulating active and repressive chromatin states during mesoderm lineage commitment, in particular the activation of developmentally important enhancers. These findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions.
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
authors: Jeffrey M
authors: JM
authors: Alexander
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
authors: Swetansu K
authors: SK
authors: Hota
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
authors: Daniel
authors: D
authors: He
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
authors: Sean
authors: S
authors: Thomas
authors: Institute of Medical Biology, A*STAR, Singapore 138648.
authors: Lena
authors: L
authors: Ho
authors: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA United States Department of Energy, Joint Genome Institute, Walnut Creek, CA 94598, USA.
authors: Len A
authors: LA
authors: Pennacchio
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA Department of Pediatrics, University of California, San Francisco, CA 94143, USA Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA bbruneau@gladstone.ucsf.edu.
authors: Benoit G
authors: BG
authors: Bruneau
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage; D002843:Chromatin / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D014157:Transcription Factors; D013629:Tamoxifen; C016601:afimoxifene; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: Chromatin; Enhancers; Gene expression; Histone modification; Mesoderm; Stem cells