Defining Cardiac Conduction System Gene Regulatory Networks




Bhattacharyya, Samadrita

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The cardiac conduction system initiates and propagates each heartbeat. Specialized conducting cells are a well-conserved phenomenon across vertebrate evolution, although mammalian and avian species harbor specific components unique to organisms with four-chamber hearts. Early histological studies in mammals provided evidence for a dominant pacemaker within the right atrium and clarified the existence of the specialized muscular axis responsible for atrioventricular conduction. Building upon these seminal observations, contemporary genetic techniques in a multitude of model organisms has characterized the developmental ontogeny, gene regulatory networks, and functional importance of individual anatomical compartments within the cardiac conduction system. Cis-regulatory DNA elements mediate transcriptional control (called enhancers in cases of transcriptional activation and silencers in cases of repression) by recruiting TFs. These collectively determine spatio-temporal regulation of each gene during development. Thus, determining the evolutionary history of participating enhancers provides key information on the origins of morphological trait diversity. My dissertation describes the development of novel genetic models, sensitive biochemical assays, and consistent genomic methodologies complemented with bioinformatics to highlight the gene regulatory networks that act during cardiac conduction system development and homeostasis with a particular emphasis on networks implicated in human electrical variation by large genome-wide association studies. As part of future directions of my doctoral work, I have also outlined some ongoing studies on determining the ontogeny of the cardiac pacemaker cells. I finally conclude with the translational impact of my research whereby we have made an impressive headway towards interrogating the development of the cardiac conduction system and onset of cardiomyopathies in human heart specimens.

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