Born with a Broken Heart: Defining Mechanisms and Identifying New Targets for Congenital Heart Disease

Congenital heart defects (CHD) arise through genetic and environmental disruptions to normal heart development and are the most common form of birth defects. Although sequencing analyses of children with CHD have identified loss of function variants in numerous genes, the molecular mechanisms underlying most forms of CHD remain unknown. Importantly, determining the contribution of non-protein coding regions of the genome and pinpointing the specific subpopulations of cardiac progenitor cells affected in development are critical challenges in understanding the etiology of CHD and identifying novel therapeutic interventions. As a postdoctoral fellow under the mentorship of Deepak Srivastava, I directly addressed these problems by first generating a comprehensive and temporal single cell chromatin accessibility and transcriptomic atlas of early mouse heart development. In collaboration with Professor Katie Pollard (Gladstone Institute), we then developed novel machine learning algorithms to identify cell type enriched enhancers in cardiac and neural crest progenitors and showed how loss of a transcription factor, Tbx1, can disrupt essential cell signaling programs leading to CHD. Finally, we designed CRISPR-perturbation systems (CRISPR-a/i) in human pluripotent stem cell models to identify dosage sensitive genes on Chromosome 21 that lead to CHD in children with Down Syndrome. My future research program will integrate these established resources of single cell genomics, machine learning algorithms and CRISPR functional perturbation screens to provide novel insights into previously intractable problems in heart development and congenital disease. Contact Greg Crawford (greg.crawford at duke dot edu) and Debby Silver (debra.silver at duke dot edu) with any questions.