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Developmental biology - Heart|
Reprogramming Congestive Heart Failure
"Altogether, we believe that epigenetic changes encode a so-called 'metabolic plasticity' in failing hearts, the reversal of which may repair [or attempt to repair] the ischemic and failing heart."
Researchers found increased DNA methylation directly reduced genetic ability to metabolize oxygen. However, the transcription factor KLF15 does regulate metabolic gene function, but is suppressed by epigenetic regulator EZH2.
EZH2 offers a new target for future heart based therapy. Co-author Sooryanarayana Varambally has spent 15 years studying EZH2, making progress treating cancers with inhibitors that regulate EZH2.
This current study is published in Nature - Laboratory Investigation. In addition to a wide range of bioinformatic tools, first author Mark Pepin used the publicly available R program to analyze multi-Omic datasets and compare their findings to animal-based studies as well as other public databases. Wende: "Supplying the coding scripts is our way of demonstrating the rigor and reproducibility that should be expected of any bioinformatics study."
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.
Authors: Mark E. Pepin, Chae-Myeong Ha, David K. Crossman, Silvio H. Litovsky, Sooryanarayana Varambally, Joseph P. Barchue, Salpy V. Pamboukian, Nikolaos A. Diakos, Stavros G. Drakos, Steven M. Pogwizd and Adam R. Wende. Pepin is a sixth year MD PhD student at UAB and is currently completing the PhD portion of his training in the Medical Scientist Training Program.
Financial support was provided by National Institutes of Health grants DK076169, HL133011, TR001417, MD008620, HL135121, HL132067, HD071866 and HL137240; the American Heart Association Heart Failure Strategically Focused Research Network grant 16SFRN29020000; and the Nora Eccles Treadwell Foundation.
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A comparison of healthy heart with contracted muscle (left) and a weakened heart with over-stretched muscle (right). Image Credit: Wiki-Media.