Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure
Rationale: In chronic heart failure, increased adrenergic activation contributes to structural remodeling and altered gene expression. While 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-DNA-binding protein (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 (TAC) 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 TAC or upon 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 TAC. Ablation of MeCP2 in cardiomyocytes facilitated recovery of failing hearts after rTAC. 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 which is important for cardiac adaptation during the development and recovery from heart failure.
- Received May 5, 2015.
- Revision received July 15, 2015.
- Accepted July 17, 2015.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.