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Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure
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Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure
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Journal Article
Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in human ischemic heart failure
2019
Overview
Ischemic cardiomyopathy (ICM) is the clinical endpoint of coronary heart disease and a leading cause of heart failure. Despite growing demands to develop personalized approaches to treat ICM, progress is limited by inadequate knowledge of its pathogenesis. Since epigenetics has been implicated in the development of other chronic diseases, the current study was designed to determine whether transcriptional and/or epigenetic changes are sufficient to distinguish ICM from other etiologies of heart failure. Specifically, we hypothesize that genome-wide DNA methylation encodes transcriptional reprogramming in ICM. RNA-sequencing analysis was performed on human ischemic left ventricular tissue obtained from patients with end-stage heart failure, which enriched known targets of the polycomb methyltransferase EZH2 compared to non-ischemic hearts. Combined RNA sequencing and genome-wide DNA methylation analysis revealed a robust gene expression pattern consistent with suppression of oxidative metabolism, induced anaerobic glycolysis, and altered cellular remodeling. Lastly, KLF15 was identified as a putative upstream regulator of metabolic gene expression that was itself regulated by EZH2 in a SET domain-dependent manner. Our observations therefore define a novel role of DNA methylation in the metabolic reprogramming of ICM. Furthermore, we identify EZH2 as an epigenetic regulator of KLF15 along with DNA hypermethylation, and we propose a novel mechanism through which coronary heart disease reprograms the expression of both intermediate enzymes and upstream regulators of cardiac metabolism such as KLF15.
Human ischemic cardiomyopathy is defined by DNA hypermethylation, methyltransferase EZH2 induction, and transcription factor KLF15 suppression. Together these changes may mediate a gene expression pattern reflecting decreased oxidative phosphorylation and increased cellular remodeling. This study therefore identifies a novel mechanism through which coronary heart disease may be regulated.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Aged
/ Animals
/ DNA
/ Enhancer of Zeste Homolog 2 Protein - genetics
/ Enhancer of Zeste Homolog 2 Protein - metabolism
/ Etiology
/ Genomes
/ Heart Ventricles - metabolism
/ Humans
/ Ischemia
/ Kruppel-Like Transcription Factors - genetics
/ Kruppel-Like Transcription Factors - metabolism
/ Male
/ Medicine
/ Myocardial Ischemia - genetics
/ Myocardial Ischemia - metabolism
/ Nuclear Proteins - metabolism
/ Rats
/ Recombinant Proteins - genetics
/ Recombinant Proteins - metabolism
/ RNA
