Photo Credit: X. Wang (Boyer& Kellis Labs) We focus on understanding the transcriptional and chromatin regulatory mechanisms that control mammalian stem cells and lineage commitment. Specifically, we developed integrative computational and experimental approaches to investigate the molecular circuitry of heart development that can be summarized as the following fundamental contributions. (1) We devised methods to globally identify transcriptional enhancers that are crucial for tissue specific gene activation during cardiac lineage commitment. This work represents a major advance in the field because it provided the first epigenomic map that allowed us to better understand how TFs coordinate with developmental cues to promote cardiac lineage commitment. (2) We used these models to show that common genetic variants associated with increased risk of sudden cardiac death are enriched in transcriptional enhancers that disrupt expression of key genes, revealing how subtle alteration in DNA sequence contributes to human complex traits. This study is important because it highlights potential new genes that can be used as an early diagnostic for sudden cardiac death, which is a devastating silent killer affecting many people. (3) We discovered the first long non-coding RNA (lncRNA; Braveheart) critical for early cardiac commitment that functions through a unique RNA structure to regulate cardiac gene expression, revealing a previously unrecognized layer of regulation and opening the door for studying lncRNAs in heart development and disease. (4) We are leveraging these discoveries to devise novel strategies for stimulating cardiac regeneration in response to injury through modulation of gene programs. Collectively, our work has provided unprecedented molecular insights into how the regulation of complex gene circuits produce robust developmental outcomes. We envision that our discoveries and tools will continue to broadly impact the scientific community.