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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. 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:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1256947
Grant/Contract Number:  
AC02-05CH11231; R01HG003988; U54HG006997; U01DE020060NIH
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Development (Cambridge)
Additional Journal Information:
Journal Volume: 142; Journal Issue: 8; Journal ID: ISSN 0950-1991
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Chromatin; Enhancers; Gene expression; Histone modification; Mesoderm; Stem cells

Citation Formats

Alexander, Jeffrey M., Hota, Swetansu K., He, Daniel, Thomas, Sean, Ho, Lena, Pennacchio, Len A., and Bruneau, B. G. Brg1 modulates enhancer activation in mesoderm lineage commitment. United States: N. p., 2015. Web. doi:10.1242/dev.109496.
Alexander, Jeffrey M., Hota, Swetansu K., He, Daniel, Thomas, Sean, Ho, Lena, Pennacchio, Len A., & Bruneau, B. G. Brg1 modulates enhancer activation in mesoderm lineage commitment. United States. https://doi.org/10.1242/dev.109496
Alexander, Jeffrey M., Hota, Swetansu K., He, Daniel, Thomas, Sean, Ho, Lena, Pennacchio, Len A., and Bruneau, B. G. 2015. "Brg1 modulates enhancer activation in mesoderm lineage commitment". United States. https://doi.org/10.1242/dev.109496. https://www.osti.gov/servlets/purl/1256947.
@article{osti_1256947,
title = {Brg1 modulates enhancer activation in mesoderm lineage commitment},
author = {Alexander, Jeffrey M. and Hota, Swetansu K. and He, Daniel and Thomas, Sean and Ho, Lena and Pennacchio, Len A. and Bruneau, B. G.},
abstractNote = {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.},
doi = {10.1242/dev.109496},
url = {https://www.osti.gov/biblio/1256947}, journal = {Development (Cambridge)},
issn = {0950-1991},
number = 8,
volume = 142,
place = {United States},
year = {Thu Mar 26 00:00:00 EDT 2015},
month = {Thu Mar 26 00:00:00 EDT 2015}
}

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Cited by: 70 works
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Works referenced in this record:

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Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
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Super-Enhancers in the Control of Cell Identity and Disease
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Endocardial Brg1 Represses ADAMTS1 to Maintain the Microenvironment for Myocardial Morphogenesis
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Modification of Enhancer Chromatin: What, How, and Why?
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Polycomb Group Proteins Set the Stage for Early Lineage Commitment
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Chromatin regulation by Brg1 underlies heart muscle development and disease
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A unique chromatin signature uncovers early developmental enhancers in humans
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Mapping and analysis of chromatin state dynamics in nine human cell types
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Uncertainty in soil data can outweigh climate impact signals in global crop yield simulations
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Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis
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Overlapping chromatin-remodeling systems collaborate genome wide at dynamic chromatin transitions
journal, December 2013


An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency
journal, March 2009


Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants
journal, October 2013


Altered control of cellular proliferation in the absence of mammalian brahma (SNF2α)
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Signaling Gradients during Paraxial Mesoderm Development
journal, July 2009


Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment
journal, November 2013


Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis
journal, April 2014


Histone Demethylase UTX and Chromatin Remodeler BRM Bind Directly to CBP and Modulate Acetylation of Histone H3 Lysine 27
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The Mouse Snail Gene Encodes a Key Regulator of the Epithelial-Mesenchymal Transition
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Empirical methods for controlling false positives and estimating confidence in ChIP-Seq peaks
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Diverse Roles and Interactions of the SWI/SNF Chromatin Remodeling Complex Revealed Using Global Approaches
journal, March 2011


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journal, June 2008


Development of an Illumina-based ChIP-exonuclease method provides insight into FoxA1-DNA binding properties.
journalarticle, January 2013


Works referencing / citing this record:

Oncogene-dependent function of BRG1 in hepatocarcinogenesis
journal, February 2020


Baf53a is involved in survival of mouse ES cells, which can be compensated by Baf53b
journal, October 2017


The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers
journal, March 2017


Chromatin remodeling and bivalent histone modifications in embryonic stem cells
journal, October 2015


EOMES interacts with RUNX3 and BRG1 to promote innate memory cell formation through epigenetic reprogramming
journal, July 2019


Epigenomes in Cardiovascular Disease
journal, May 2018


Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate
journal, April 2019


Cdx2 Regulates Gene Expression through Recruitment of Brg1-associated Switch-Sucrose Non-fermentable (SWI-SNF) Chromatin Remodeling Activity
journal, January 2017


Tumor suppressor SMARCB1 suppresses super-enhancers to govern hESC lineage determination
journal, April 2019


Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders
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Dynamic BAF chromatin remodeling complex subunit inclusion promotes temporally distinct gene expression programs in cardiogenesis
journal, February 2019


mSWI/SNF promotes polycomb repression both directly and through genome-wide redistribution
posted_content, December 2020


SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation
journal, December 2016


β‐Actin‐dependent global chromatin organization and gene expression programs control cellular identity
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SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer
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ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice
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Role of Epigenetics in Cardiac Development and Congenital Diseases
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The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers
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ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice
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Oncogene-dependent function of BRG1 in hepatocarcinogenesis
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Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate
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EOMES interacts with RUNX3 and BRG1 to promote innate memory cell formation through epigenetic reprogramming
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Baf53a is involved in survival of mouse ES cells, which can be compensated by Baf53b
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