title: Reciprocal Regulation of the Cardiac Epigenome by Chromatin Structural Proteins Hmgb and Ctcf: IMPLICATIONS FOR TRANSCRIPTIONAL REGULATION.
abstract: Transcriptome remodeling in heart disease occurs through the coordinated actions of transcription factors, histone modifications, and other chromatin features at pathology-associated genes. The extent to which genome-wide chromatin reorganization also contributes to the resultant changes in gene expression remains unknown. We examined the roles of two chromatin structural proteins, Ctcf (CCCTC-binding factor) and Hmgb2 (high mobility group protein B2), in regulating pathologic transcription and chromatin remodeling. Our data demonstrate a reciprocal relationship between Hmgb2 and Ctcf in controlling aspects of chromatin structure and gene expression. Both proteins regulate each others' expression as well as transcription in cardiac myocytes; however, only Hmgb2 does so in a manner that involves global reprogramming of chromatin accessibility. We demonstrate that the actions of Hmgb2 on local chromatin accessibility are conserved across genomic loci, whereas the effects on transcription are loci-dependent and emerge in concert with histone modification and other chromatin features. Finally, although both proteins share gene targets, Hmgb2 and Ctcf, neither binds these genes simultaneously nor do they physically colocalize in myocyte nuclei. Our study uncovers a previously unknown relationship between these two ubiquitous chromatin proteins and provides a mechanistic explanation for how Hmgb2 regulates gene expression and cellular phenotype. Furthermore, we provide direct evidence for structural remodeling of chromatin on a genome-wide scale in the setting of cardiac disease.
authors.affiliation: From the Departments of Anesthesiology.
authors.forename: Emma
authors.initials: E
authors.lastname: Monte
authors.affiliation: From the Departments of Anesthesiology.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rosa-Garrido
authors.affiliation: From the Departments of Anesthesiology.
authors.forename: Elaheh
authors.initials: E
authors.lastname: Karbassi
authors.affiliation: From the Departments of Anesthesiology.
authors.forename: Haodong
authors.initials: H
authors.lastname: Chen
authors.affiliation: From the Departments of Anesthesiology.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lopez
authors.affiliation: From the Departments of Anesthesiology.
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Rau
authors.affiliation: Medicine.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wang
authors.affiliation: Human Genetics.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: From the Departments of Anesthesiology.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Departments of Anesthesiology.
authors.forename: Enrico
authors.initials: E
authors.lastname: Stefani
authors.affiliation: Medicine, Human Genetics, Microbiology, Immunology and Molecular Genetics, and.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: From the Departments of Anesthesiology, Medicine, Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 and.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Biological Chemistry.
authors.forename: Siavash K
authors.initials: SK
authors.lastname: Kurdistani
authors.affiliation: the Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Sarah
authors.initials: S
authors.lastname: Franklin
authors.affiliation: From the Departments of Anesthesiology, Medicine, Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 and tvondriska@mednet.ucla.edu.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Vondriska
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D057890:Epigenomics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D024261:HMGB2 Protein / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; C000619698:Ctcf protein, mouse; D024261:HMGB2 Protein; D012097:Repressor Proteins
keywords: Ctcf; Hmgb2; cardiac hypertrophy; chromatin regulation; epigenetics; gene regulation; heart failure