Description

Dr. Casey Gifford, Assistant Professor in the Department of Pediatrics and Genetics at Stanford University will present her talk entitled, 'The beat goes on: using cardiac organoids to study heart development and disease. ' Abstract: Defining the temporal gene regulatory programs that drive human organogenesis is essential for understanding the origins of congenital defects. In this talk, I will discuss how we combined a time-resolved, single-cell multi-omic atlas of human induced pluripotent stem cell -derived cardiac organoids with base-resolution deep learning sequence models of chromatin accessibility, which enabled systematic discovery of cis-regulatory syntax underlying early heart development. This framework identified cell-state-specific regulatory rules and motif syntax involving TEAD, HAND, and TBX transcription factor families, linked motif instances to candidate target genes, and resolved distinct programs governing lineage divergence, including ventricular versus pacemaker cardiomyocyte specification.  We validated these predictions by perturbing Myocardin (MYOCD), which abolished ventricular cardiomyocyte specification and redirected cell fate. Finally, integrating cell-state-resolved chromatin and expression profiles with computationally predicted effects of genetic variants identified in congenital heart disease (CHD) cohorts enabled the prioritization of noncoding variants predicted to disrupt discrete developmental transitions, supporting the paradigm that CHD etiology derives from perturbations to gene regulatory networks governing cardiogenesis. This study bridges developmental gene regulation with disease genetics and establishes a framework for discovering the genetic and molecular basis of congenital disorders.