Advisory Committee Chair
Adam R Wende
Advisory Committee Members
Jennifer Pollock
Stephen Lloyd
Jianyi Zhang
Anath Shalev
Jeremy Day
Document Type
Dissertation
Date of Award
2019
Degree Name by School
Doctor of Philosophy (PhD) School of Engineering
Abstract
Heart failure (HF) is the clinical endpoint of numerous diseases that negatively impact the heart’s capacity to pump and/or fill with blood. A variety of genetic and environmental factors have been identified as critical determinants of HF susceptibility; however, these factors cannot independently explain the phenotypic diversity of human HF. Instead, a complex interplay has been theorized to exist between genetics and the environment, although the molecular underpinnings of this synergy remain poorly understood. Of the possible mechanisms, epigenetic influences are uniquely capable of explaining how acute stressors of the cardiac microenvironment trigger the stable – yet reversible – reprogramming of gene expression. DNA methylation is one such epigenetic modification that has been previously associated with metabolic adaptation to various cellular stresses in other contexts; however, its contribution to cardiac remodeling in HF remains unknown. The current dissertation therefore tests the hypothesis that epigenetics, specifically DNA methylation, encodes a cardiac transcriptional reprogramming in response to etiology-specific environmental stresses. To test this hypothesis, we first used left ventricle (LV) samples obtained from either human subjects with end-stage (NYHA Class IV-D) HF or donor controls. These cardiac biopsies were analyzed using whole-genome DNA methylation and paired next-generation RNA-sequencing. Integrative analysis revealed a robust reprogramming of cardiac DNA methylation in HF. Differential DNA methylation disproportionately affected metabolic genes in a manner consistent with the failing heart’s reactivation of a glycolytic, or “fetal-like,” program. Specifically, we identified promoter hyper-methylation and gene silencing of numerous oxidative intermediates, along with hypo-methylation and increased expression of glycolytic genes relative to non-failing donor hearts. Subsequent analysis from within a single cohort of HF patients also displayed marked etiologic distinctions between ischemic HF and non-ischemic HF. In ischemic HF, we found hyper-methylation and gene suppression of 22 pathway intermediates involved in TCA cycle, beta-oxidation, and electron transport chain. Additionally, we identified polycomb methyltransferase EZH2 as an epigenetic regulator of this metabolic remodeling via methyltransferase (SET)-dependent inhibition of KLF15. In summary, the studies described herein provide the first evidence to support a central role of epigenetics, specifically DNA methylation, in the metabolic reprogramming of human heart failure. Identifying the epigenetic of HF susceptibility may both explain its clinical heterogeneity and accelerate the development of precision-based medical therapies.
Recommended Citation
Pepin, Mark Emile, "Genetic and Epigenetic Underpinnings of End-Stage Human Heart Failure" (2019). All ETDs from UAB. 2705.
https://digitalcommons.library.uab.edu/etd-collection/2705