Transcriptional Regulation of Cardiac Ventricular Development

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2004-05-04

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Congenital heart disease is the leading non-infectious cause of death in children. Disruption of cardiac gene expression during development can result in congenital heart defects. Numerous transcription factors regulate specific temporo-spatial events during cardiac differentiation and morphogenesis, however the mechanisms that regulate such events are largely unknown. Using a novel modified subtractive hybridization method to identify early cardiac-specific genes, we found Bop, a histone deacetylase-dependent transcriptional repressor. Bop was expressed specifically in the myocardium of the heart and somites during development. Targeted deletion of Bop in mouse resulted in hypoplasia of the right ventricle and expansion of the extracellular matrix between the myocardium and endocardium of the embryonic heart, suggesting a persistence of immature ventricular cardiomyocytes. Expression of dHAND, the evolutionarily conserved bHLH factor necessary for proper right ventricle development, was downregulated in the heart of the Bop-null embryo. In an effort to understand the mechanism by which Bop functions in cardiac differentiation and morphogenesis, the yeast two-hybrid assay was used to identify factors that interact with m-Bop in the embryonic heart. The DNA-binding factor, skNAC, and the inhibitor of mitosis, TRB3, were identified. TRB3 enhanced repression of SV40-driven luciferase activity by m-Bop. Disruption of this interaction resulted in the inability of TRB3 to enhance m-Bop's repressive activity, suggesting a novel function for TRB3 as a corepressor of m-Bop in the developing heart. skNAC was expressed in the myocardium of the heart and somites, strikingly similar to the expression pattern of Bop. While early in vitro attempts to study m-Bop and skNAC failed, in vivo efforts to study a genetic interaction are ongoing.

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