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. These findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions. SUMMARY: The chromatin remodeling factor Brg1 is essential for mesoderm induction and, by modulating active and repressive chromatin states, is involved in promoting the activation of dynamic enhancers.

[1]  Bing Ren,et al.  Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis , 2014, Genome research.

[2]  M. Sung,et al.  Overlapping Chromatin Remodeling Systems Collaborate Genome-wide at Dynamic Chromatin Transitions , 2013, Nature Structural &Molecular Biology.

[3]  J. Carroll,et al.  Development of an Illumina-based ChIP-exonuclease method provides insight into FoxA1-DNA binding properties , 2013, Genome Biology.

[4]  Ming Yu,et al.  Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation , 2013, Genes & development.

[5]  R. Young,et al.  Super-Enhancers in the Control of Cell Identity and Disease , 2013, Cell.

[6]  Gene W. Yeo,et al.  Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment , 2013, Genes & development.

[7]  Stephen C. J. Parker,et al.  Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants , 2013, Proceedings of the National Academy of Sciences.

[8]  David A. Orlando,et al.  Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes , 2013, Cell.

[9]  J. Wysocka,et al.  Modification of enhancer chromatin: what, how, and why? , 2013, Molecular cell.

[10]  L. M. Wu,et al.  Olig2 Targets Chromatin Remodelers to Enhancers to Initiate Oligodendrocyte Differentiation , 2013, Cell.

[11]  Alexander R. Pico,et al.  Dynamic and Coordinated Epigenetic Regulation of Developmental Transitions in the Cardiac Lineage , 2012, Cell.

[12]  X. Zhou,et al.  Dense Chromatin Activates Polycomb Repressive Complex 2 to Regulate H3 Lysine 27 Methylation , 2012, Science.

[13]  P. Scacheri,et al.  Histone Demethylase UTX and Chromatin Remodeler BRM Bind Directly to CBP and Modulate Acetylation of Histone H3 Lysine 27 , 2012, Molecular and Cellular Biology.

[14]  S. Nishikawa,et al.  Molecular basis for Flk1 expression in hemato-cardiovascular progenitors in the mouse , 2011, Development.

[15]  Keji Zhao,et al.  Regulation of nucleosome landscape and transcription factor targeting at tissue-specific enhancers by BRG1. , 2011, Genome research.

[16]  E. Ashley,et al.  Chromatin regulation by Brg1 underlies heart muscle development and disease , 2011, Nature.

[17]  Raja Jothi,et al.  esBAF Facilitates Pluripotency by Conditioning the Genome for LIF/STAT3Signalingand by Regulating Polycomb Function , 2011, Nature Cell Biology.

[18]  Raffaele Giancarlo,et al.  Genome‐wide characterization of chromatin binding and nucleosome spacing activity of the nucleosome remodelling ATPase ISWI , 2011, The EMBO journal.

[19]  Raymond K. Auerbach,et al.  Diverse Roles and Interactions of the SWI/SNF Chromatin Remodeling Complex Revealed Using Global Approaches , 2011, PLoS genetics.

[20]  Timothy J. Durham,et al.  "Systematic" , 1966, Comput. J..

[21]  Ryan A. Flynn,et al.  A unique chromatin signature uncovers early developmental enhancers in humans , 2011, Nature.

[22]  R. Mark Henkelman,et al.  Chromatin remodelling complex dosage modulates transcription factor function in heart development , 2011, Nature communications.

[23]  Gordon Keller,et al.  Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. , 2011, Cell stem cell.

[24]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer , 2011, Nature Biotechnology.

[25]  Mark Groudine,et al.  Functional and Mechanistic Diversity of Distal Transcription Enhancers , 2011, Cell.

[26]  B. Bernstein,et al.  Charting histone modifications and the functional organization of mammalian genomes , 2011, Nature Reviews Genetics.

[27]  A. Terzic,et al.  SDF-1-Enhanced Cardiogenesis Requires CXCR4 Induction in Pluripotent Stem Cells , 2010, Journal of cardiovascular translational research.

[28]  L. Boyer,et al.  Polycomb group proteins set the stage for early lineage commitment. , 2010, Cell stem cell.

[29]  Olivier Pourquié,et al.  Signaling gradients during paraxial mesoderm development. , 2010, Cold Spring Harbor perspectives in biology.

[30]  G. Crabtree,et al.  Chromatin remodelling during development , 2010, Nature.

[31]  Benoit G. Bruneau,et al.  Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors , 2009, Nature.

[32]  Alexey I Nesvizhskii,et al.  An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency , 2009, Proceedings of the National Academy of Sciences.

[33]  G. Crabtree,et al.  Understanding the Words of Chromatin Regulation , 2009, Cell.

[34]  Cole Trapnell,et al.  Ultrafast and memory-efficient alignment of short DNA sequences to the human genome , 2009, Genome Biology.

[35]  David A. Nix,et al.  Empirical methods for controlling false positives and estimating confidence in ChIP-Seq peaks , 2008, BMC Bioinformatics.

[36]  Simon Kasif,et al.  Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains , 2008, PLoS genetics.

[37]  Megan F. Cole,et al.  Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells , 2008, Cell.

[38]  Timothy J. Nelson,et al.  CXCR4+/FLK‐1+ Biomarkers Select a Cardiopoietic Lineage from Embryonic Stem Cells , 2008, Stem cells.

[39]  K. Stankunas,et al.  Endocardial Brg1 represses ADAMTS1 to maintain the microenvironment for myocardial morphogenesis. , 2008, Developmental cell.

[40]  Megan F. Cole,et al.  Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells , 2006, Cell.

[41]  T. Magnuson,et al.  A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in beta-globin expression and erythroid development. , 2005, Genes & development.

[42]  J. Boeke,et al.  Genome-wide identification of Isw2 chromatin-remodeling targets by localization of a catalytically inactive mutant. , 2005, Genes & development.

[43]  S. Batalov,et al.  A gene atlas of the mouse and human protein-encoding transcriptomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[44]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Chun Li Zhang,et al.  Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy , 2002, Cell.

[46]  D. Srivastava,et al.  Bop encodes a muscle-restricted protein containing MYND and SET domains and is essential for cardiac differentiation and morphogenesis , 2002, Nature Genetics.

[47]  R. Kingston,et al.  Cooperation between Complexes that Regulate Chromatin Structure and Transcription , 2002, Cell.

[48]  K. Kinzler,et al.  Small changes in expression affect predisposition to tumorigenesis , 2002, Nature Genetics.

[49]  E. Carver,et al.  The Mouse Snail Gene Encodes a Key Regulator of the Epithelial-Mesenchymal Transition , 2001, Molecular and Cellular Biology.

[50]  Y. Saga,et al.  Transcriptional regulation of Mesp1 and Mesp2 genes: differential usage of enhancers during development , 2001, Mechanisms of Development.

[51]  F Randazzo,et al.  A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. , 2000, Molecular cell.

[52]  Dimitris Thanos,et al.  Ordered Recruitment of Chromatin Modifying and General Transcription Factors to the IFN-β Promoter , 2000, Cell.

[53]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[54]  M. Yaniv,et al.  Altered control of cellular proliferation in the absence of mammalian brahma (SNF2α) , 1998, The EMBO journal.

[55]  M. Yaniv,et al.  Purification and biochemical heterogeneity of the mammalian SWI‐SNF complex. , 1996, The EMBO journal.

[56]  Michael R. Green,et al.  Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex , 1994, Nature.

[57]  Thomas C. Kaufman,et al.  brahma: A regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2 SWI2 , 1992, Cell.

[58]  F. Klippel.  Where is the mouse , 1990 .