Transcriptional regulation of cardiac morphogenesis

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ABSTRACT Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses. CHDs that present with defective ventricular morphogenesis allow for the mixing of oxygenated and deoxygenated blood via ventricular septal defects (VSDs) and/or impaired contractile function both of which put limits on vitality. Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the many forms of ventricular CHDs. Hand1 is expressed within the developing left ventricle (LV) myocardium and the myocardial cuff (MC) between embryonic day (E) E8.5 and E13.5. HAND1 is established as required for normal LV and cardiac conduction system morphogenesis. Cardiomyocyte deletion of Hand1 results in surviving mice that present with CHDs effecting LV morphology and cardiac function. HAND1 single nucleotide polymorphisms have been identified in patients diagnosed with QRS conduction defects. These HAND1 polymorphisms reside within an evolutionarily conserved transcriptional enhancer, and act by disrupting GATA factor DNA binding. Hand1 gene expression is downregulated by the loss-of function of chromatin organizing protein CTCF within cardiomyocytes. Our preliminary data show that HAND1 is organized into a single topologically active domain (TAD) that isolates Hand1 from other genes within the TAD loop concurrent with its expression. Further examination of the epigenic regulation of the HAND1 locus is needed to elucidate how chromatin organization modulates the expression of critical morphogenetic transcription networks within LV cardiomyocytes. In other studies, we will determine HAND1 DNA occupancy within the genome, evaluate the changes in cardiomyocyte expression within occupied genes, and identify key transcriptional partners that interact with HAND1 to facilitate its role in ventricular morphogenesis. RELEVANCE CHDs resulting in ventricle phenotypes have the poorest clinical outcomes. Thus, gaining a better understanding of the etiology and molecular mechanisms that cause CHDs resulting in altered ventricular morphogenesis has the potential to benefit thousands of pediatric patients annually. As HAND1 plays a key role in cardiomyocyte patterning, gaining insight into the cellular and molecular mechanism of this understudied developmental process is critical for informing the development of non-surgical treatments for CHD patients.