"Defining genomic regulators of coronary artery disease using chromatin accessibility"

Understanding biological systems demands an intimate understanding of cellular processes. Cellular processes involve controlled variation in DNA access that impacts transcriptional activity. Over the past decade, the field of epigenetics has generated immense data to capture both transcriptional activity and transcriptomic changes and their effects on protein expression (1–3). However, in several biological systems, the field lacks a comprehensive understanding of the mechanisms by which these changes occur. This lack of understanding is especially apparent in studies of the highest contributor to mortality among cardiovascular diseases (CVD): coronary artery disease (CAD). To address this challenge, researchers conducted several genome-wide association studies (GWAS), identifying hundreds of loci associated with CAD; yet, the regulatory mechanisms for candidate variants remain mostly unknown and are only recently starting to be defined (4,5). Furthermore, as most disease-associated variants reside in non-coding, cis-regulatory elements, understanding their function demands assays capable of illustrating the activity of noncoding genomic regions. To uncover, illustrate, and prioritize the mechanisms of CAD epigenetic risk loci, we evaluated the epigenomic landscape in bulk human coronary artery (HCA) segments using ATAC-seq and RNA-seq. This thesis communicates 1) novel epigenetic mechanisms in HCA segments at various stages of atherosclerosis, 2) CAD-associated variants related to these stages that may modulate transcription factor binding sites (e.g. IRF1, STAT3, NRF1, and SPI1), 3) CAD-related HCA sample groupings based on chromatin accessibility-based axes of variation, and 4) possible mechanisms and enrichments for expressed genes in gene regulatory networks upregulated in CAD (e.g. TIMP3 and IL32). We believe the mechanisms of CAD risk loci and gene regulatory networks in CAD will be better understood through continued illustration of chromatin accessibility in coronary artery specimens.