Title: Transcriptional regulation of cardiac cell fate
Abstract: Heart development depends critically on precise spatial and temporal control of gene expression patterns, and disruption of transcriptional networks underlies congenital heart disease (CHD).  We currently lack a detailed understanding of how chromatin regulation and gene expression are coordinated during mammalian developmental transitions. To this end, we interrogated the transcriptome and several histone modifications across the genome during several defined stages of in vitro cardiomyocyte (CM) differentiation. We find that distinct chromatin patterns are coordinated with stage-specific expression of functionally related genes, including many cardiac disease-associated genes. Using chromatin modification patterns, we also identify thousands of stage-specific distal enhancer elements and find enriched DNA binding motifs within these regions that predict sets of transcription factors that orchestrate cardiac differentiation.  Long non-coding RNAs (lncRNAs) have recently emerged as an additional regulatory layer of gene expression in part through interaction with chromatin modifiers. We show that long non-coding RNAs (lncRNAs) display stage specific expression during CM differentiation and identify Braveheart, a novel lncRNA that is necessary for activation of a core network of cardiovascular transcription factors through interaction with Polycomb group proteins. Together, our work demonstrates the diverse transcriptional mechanisms that cells employ to regulate cell fate and forms a basis for understanding CHD as well as for designing relevant therapeutic approaches for degenerative cardiac diseases.