Genome-Wide Analysis of Cardiac Development in Zebrafish

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 DESCRIPTION (provided by applicant): The Utah Cardiovascular Development (CvDC) Research Center is a collaborative team of zebrafish developmental biologists, zebrafish cardiac physiologists, and experts in chromatin structure, genome-wide gene network profiling, proteomics and bioinformatics. Our goal is to discover the etiologies of Congenital Heart Disease (CHD). Our strategic plan to reach this goal is to (1) utilize zebrafish to generate large multifaceted genome-wide databases (RNA-seq, bisulfite DNA-seq, ChIP-seq) to discover the Gene Regulatory Networks (GRNs) that operate at precise time points in normal development and, importantly, in a multitude of genetic pathway perturbations that result in aberrant cardiac development, giving rise to CHD; (2) understand the cell lineages in which these GRNs operate, and the interdependence of these GRNs in CHDs; (3) collaboratively apply these approaches to test candidate genes that arise from human genetics studies in the Pediatric Cardiac Genomics Consortium (PCGC) and from studies in cell culture and mouse models in other centers of the CvDC. We enthusiastically expect that the inputs into this zebrafish model system will continue to evolve through interactions in the consortia; (4) continue to develop novel bioinformatics tools and technological innovations for the discovery of mutations and mechanisms that alter GRNs in CHD, and most importantly (5) continue to share these resources across the B2B consortia and with the research community at large, by developing and enhancing web-based tools, including the CvDC Data Sharing Hub. As new candidate genes or other perturbations (including pharmacological or environmental) arise within the Cardiac Development Consortium and Pediatric Cardiac Genomics Consortium, they will be incorporated into this multi-layered genome-wide molecular profiling program in zebrafish. Our GRN analysis can then enhance the search for genetic pathways that cause CHD in humans. Our infrastructure will make these datasets readily accessible to the consortia for trans-species comparisons to uncover conserved molecular signatures relevant to human Congenital Heart Disease.