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

Emma Monte; Manuel Rosa-Garrido; Elaheh Karbassi; Haodong Chen; Rachel Lopez; Christoph D. Rau; Jessica Wang; Stanley F. Nelson; Yong Wu; Enrico Stefani; Aldons J. Lusis; Yibin Wang; Siavash K. Kurdistani; Sarah Franklin; Thomas M. Vondriska

doi:10.1074/jbc.M116.719633

Reciprocal Regulation of the Cardiac Epigenome by Chromatin Structural Proteins Hmgb and Ctcf

IMPLICATIONS FOR TRANSCRIPTIONAL REGULATION*

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

↵7 To whom correspondence should be addressed: Depts. of Anesthesiology and Medicine and Physiology, David Geffen School of Medicine at UCLA, BH 557 CHS Bldg., 650 Charles Young Dr., Los Angeles, CA 90095. E-mail: tvondriska{at}mednet.ucla.edu.

↵1 Both authors contributed equally to this work.

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.

Footnotes

↵2 Recipient of American Heart Association Fellowship PRE14430015.
↵3 Recipient of American Heart Association Fellowship 16POST27780019.
↵4 Recipient of American Heart Association Fellowship PRE22700005.
↵5 Recipient of American Heart Association Fellowship PRE7290056.
↵6 Recipient of American Heart Association Fellowship 14UFEL20130049.
↵* This work was supported in part by National Institutes of Health Grants HL105699 (to T. M. V.), HL115238 (to T. M. V.), HL114437 (to A. J. L. and Y. Wang), and HL129639 (to T. M. V. and Y. Wang), American Heart Association Grant IRG18870056 (to T. M. V.), Thermo Fisher Scientific, and the Department of Anesthesiology at UCLA. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.