UCLA

Heart failure is a syndrome resulting from multiple genetic and environmental factors. In response to neural/hormonal changes or hemodynamic stress, the heart can generate extra force through hypertrophic growth. Chronic hypertrophy, however, is deleterious because it leads to irreversible decrease of cardiac contractility. This process requires many molecular and cellular abnormalities in the cells of the failing heart. Cardiac hypertrophy and heart failure arise as the result of multiple biological processes acting within the context of multicomponent, interrelated cellular networks. The past decade has seen an explosion of research using high-throughput techniques, identifying hundreds of genes involved in disease pathogenesis. These studies raise the question of how global, coordinated changes in transcription are precisely regulated within the cardiac nucleus. We reason that altered chromatin structure and DNA methylation endow distinct gene expression patterns during the development of disease.

This dissertation details several systems biology approaches aimed at defining cardiac epigenomic variations in the hypertrophied and failing heart. Chapter 1 reports the genome-wide nucleosome positioning in normal and pressure overload-induced hypertrophic cardiac myocytes. Because nucleosomes are the basic units of chromatin, their localization fundamentally affects the actions many types of regulatory machinery. In Chapter 2, we examined the non-histone chromatin structural protein High Mobility Group Protein B2, which we had previously determined to be a regulator of hypertrophic growth. We measured its genome-wide binding pattern in both normal and alpha-adrenergic receptor agonist-induced hypertrophic cardiac myocytes. Our findings demonstrate that HMGB2 is reorganized away from coding regions in the genome of the hypertrophic myocyte, an action we interpret as globally coordinated relaxation of specific loci. In Chapter 3, we detail a comprehensive analysis of the DNA methylome in both normal and beta-adrenergic agonist-induced failing heart. We used two different mouse strains with different susceptibility to heart failure and identified several strain-specific DNA methylation modules. The results presented here advance our understanding of the cardiac epigenome and provided essential insights into global mechanisms of chromatin structural remodeling.