Multi-omics dissection of acquired and inherited heart failure

Abstract

The primary aim of this thesis is to investigate the epigenetic and transcriptional changes in diseased hearts using multi-omics approaches, enabling us to better understand the pathological mechanisms underlying the diseases. The first part of the thesis focuses on acquired heart failure due to several common causes, including kidney disease, aging, gender, and aortic stenosis-induced hypertension. The second part of the thesis focuses on inherited heart failure due to multiple mutations. Both hypertrophic and dilated cardiomyopathies are addressed, followed by a set of promising candidates and their regulated biological functions per disease. Since kidney dysfunction, female gender, and aging are three key risk factors of acquired heart failure, in Chapter 2 we studied the influence of estrogen on cardiorenal syndrome. Particularly, we presented an overview of the biological signaling of estrogen on the microvasculature, which plays a central role in cardiac and kidney interactions. In Chapter 3 we investigated the deleterious effect of accumulated uremic toxin (indoxyl sulfate) due to kidney dysfunction on the endothelium using RNA-seq. We obtained the transcriptome changes in endothelial cells exposed to the toxin and studied their affected pathways. In Chapter 4 we revealed the histone modification in remodeled non-failing human hearts due to aortic stenosis-induced hypertension using ChIP-seq. Connecting these chromatin changes to the gene expression changes obtained by RNA-seq, we presented a list of transcription factors that could pose a dominant influence on myocardial remodeling. In Chapter 5 we employed ChIP-seq, RNA-seq, and proteomics to investigate HCM hearts carrying MYBPC3 mutations. Using two independent analytical methods to process the multi-omics data, we obtained a set of candidates that were driving the biological processes in HCM hearts. Chapter 6 presents the database of the altered protein profiles in HCM versus control hearts. Moreover, by comparing HCM hearts with and without known mutations, we identified mutation-specific changes and investigated the affected signaling in disease-mimicking mouse models. In Chapter 7 we examined the association between 52 QRS-related loci and altered DNA regulatory regions in HCM versus control hearts. We performed a comprehensive in silico functional annotations and identified a novel set of potentially disease-causing genes. In Chapter 8 we first studied the epigenomic and transcriptional changes in end-stage DCM hearts carrying PLN R14del mutation. From the promising candidates obtained at the tissue level, we further investigated their mRNA and protein expression patterns in human induced pluripotent stem cell-derived cardiomyocytes with and without PLN R14del mutation. Chapter 9 provides a general summary of the key findings in the previous chapters and discusses their potentials with future therapeutic and diagnostic directions.