Genome-wide DNA methylation encodes cardiac transcriptional reprogramming in
human ischemic heart failure.
Authors Pepin ME, Ha CM, Crossman DK, Litovsky SH, Varambally S, Barchue JP, Pamboukian
SV, Diakos NA, Drakos SG, Pogwizd SM, Wende AR
Submitted By Adam Wende on 8/20/2018
Status Published
Journal Laboratory investigation; a journal of technical methods and pathology
Year 2018
Date Published
Volume : Pages Not Specified : Not Specified
PubMed Reference 30089854
Abstract 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.

Investigators with authorship
Adam WendeUniversity of Alabama at Birmingham