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Title: Brg1 modulates enhancer activation in mesoderm lineage commitment

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. In conclusion, 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:
 [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4]
  1. Gladstone Institute of Cardiovascular Disease, San Francisco, CA (United States); Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA (United States)
  2. Institute of Medical Biology (Singapore). A*STAR
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); DOE Joint Genome Institute, Walnut Creek, CA (United States)
  4. Gladstone Institute of Cardiovascular Disease, San Francisco, CA (United States); Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States)
Publication Date:
OSTI Identifier:
1256947
Grant/Contract Number:
AC02-05CH11231; R01HG003988; U54HG006997; U01DE020060NIH
Type:
Accepted Manuscript
Journal Name:
Development (Cambridge)
Additional Journal Information:
Journal Name: Development (Cambridge); Journal Volume: 142; Journal Issue: 8; Journal ID: ISSN 0950-1991
Research Org:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES Chromatin; Enhancers; Gene expression; Histone modification; Mesoderm; Stem cells