Format

Send to

Choose Destination
Circ Res. 2015 Sep 11;117(7):622-33. doi: 10.1161/CIRCRESAHA.115.306721. Epub 2015 Jul 20.

Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure.

Author information

1
From the Institute of Experimental and Clinical Pharmacology and Toxicology (S.C.M., R.G., S.P., E.B.M.O., T.S., N.B., A.L., C.R., H.I., J.O., K.A., L.H.), Hermann-Staudinger-Graduiertenschule (S.P.), University Heart Center Freiburg-Bad Krozingen (T.S., A.L., H.B., C.H., F.B., C.B., B.S.), Department of Medicine IV, Nephrology and Primary Care, Medical Center (J.W.), Institute of Anatomy and Cell Biology (O.K.), Renal Division, University Clinic Freiburg (O.K.), Medical Physics (D.E.), and BIOSS Centre for Biological Signalling Studies (L.H.), University of Freiburg, Freiburg, Germany; Department of Molecular Biology, UT Southwestern Medical Center at Dallas, TX (N.B.); Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany (F.R., M.S.); Department of Cardiothoracic Surgery, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany (A.S., M.S., T.D.); Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany (U.B.); Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IFB-Tx (S.K.G., T.T.) and REBIRTH Excellence Cluster (T.T.), Hannover Medical School, Hannover, Germany; Max-Planck-Institut für Herz- und Lungenforschung, Bad Nauheim, Germany (M.K.); and National Heart and Lung Institute, Imperial College, London, United Kingdom (T.T.).
2
From the Institute of Experimental and Clinical Pharmacology and Toxicology (S.C.M., R.G., S.P., E.B.M.O., T.S., N.B., A.L., C.R., H.I., J.O., K.A., L.H.), Hermann-Staudinger-Graduiertenschule (S.P.), University Heart Center Freiburg-Bad Krozingen (T.S., A.L., H.B., C.H., F.B., C.B., B.S.), Department of Medicine IV, Nephrology and Primary Care, Medical Center (J.W.), Institute of Anatomy and Cell Biology (O.K.), Renal Division, University Clinic Freiburg (O.K.), Medical Physics (D.E.), and BIOSS Centre for Biological Signalling Studies (L.H.), University of Freiburg, Freiburg, Germany; Department of Molecular Biology, UT Southwestern Medical Center at Dallas, TX (N.B.); Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany (F.R., M.S.); Department of Cardiothoracic Surgery, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany (A.S., M.S., T.D.); Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany (U.B.); Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IFB-Tx (S.K.G., T.T.) and REBIRTH Excellence Cluster (T.T.), Hannover Medical School, Hannover, Germany; Max-Planck-Institut für Herz- und Lungenforschung, Bad Nauheim, Germany (M.K.); and National Heart and Lung Institute, Imperial College, London, United Kingdom (T.T.). lutz.hein@pharmakol.uni-freiburg.de.

Abstract

RATIONALE:

In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. Although adrenergic signaling alters histone modifications, it is unknown, whether it also affects other epigenetic processes, including DNA methylation and its recognition.

OBJECTIVE:

The aim of this study was to identify the mechanism of regulation of the methyl-CpG-binding protein 2 (MeCP2) and its functional significance during cardiac pressure overload and unloading.

METHODS AND RESULTS:

MeCP2 was identified as a reversibly repressed gene in mouse hearts after transverse aortic constriction and was normalized after removal of the constriction. Similarly, MeCP2 repression in human failing hearts resolved after unloading by a left ventricular assist device. The cluster miR-212/132 was upregulated after transverse aortic constriction or on activation of α1- and β1-adrenoceptors and miR-212/132 led to repression of MeCP2. Prevention of MeCP2 repression by a cardiomyocyte-specific, doxycycline-regulatable transgenic mouse model aggravated cardiac hypertrophy, fibrosis, and contractile dysfunction after transverse aortic constriction. Ablation of MeCP2 in cardiomyocytes facilitated recovery of failing hearts after reversible transverse aortic constriction. Genome-wide expression analysis, chromatin immunoprecipitation experiments, and DNA methylation analysis identified mitochondrial genes and their transcriptional regulators as MeCP2 target genes. Coincident with its repression, MeCP2 was removed from its target genes, whereas DNA methylation of MeCP2 target genes remained stable during pressure overload.

CONCLUSIONS:

These data connect adrenergic activation with a microRNA-MeCP2 epigenetic pathway that is important for cardiac adaptation during the development and recovery from heart failure.

KEYWORDS:

DNA methylation; MeCP2 protein; epigenomics; heart failure; microRNAs; receptors, adrenergic

PMID:
26195221
PMCID:
PMC4568894
DOI:
10.1161/CIRCRESAHA.115.306721
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center