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J Biol Chem. 2016 Jul 22;291(30):15428-46. doi: 10.1074/jbc.M116.719633. Epub 2016 May 16.

Reciprocal Regulation of the Cardiac Epigenome by Chromatin Structural Proteins Hmgb and Ctcf: IMPLICATIONS FOR TRANSCRIPTIONAL REGULATION.

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From the Departments of Anesthesiology.
Human Genetics.
Medicine, Human Genetics, Microbiology, Immunology and Molecular Genetics, and.
From the Departments of Anesthesiology, Medicine, Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 and.
Biological Chemistry.
the Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah 84112.
From the Departments of Anesthesiology, Medicine, Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095 and


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.


Ctcf; Hmgb2; cardiac hypertrophy; chromatin regulation; epigenetics; gene regulation; heart failure

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