TRANSCRIPTIONAL REGULATION OF CARDIOMYOCYTE DEVELOPMENT

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DESCRIPTION (adapted from the applicant's abstract): Much has been learned about the molecular mechanisms that regulate the differentiation of the skeletal muscle lineages during mammalian development. In contrast, relatively little is currently understood about molecular bases of cardiac myocyte differentiation. Recent studies have demonstrated that distinct transcriptional pathways regulate skeletal and cardiac- specific gene expression and differentiation. However, until recently, the identity of the important transcription factors that regulate cardiac-specific gene expression have remained unclear. Members of the GATA family of zinc finger transcription factors have been shown to play important roles in the differentiation of multiple hematopoietic lineages. Recent evidence from the applicant and others suggests an important role for a new member of this family, GATA-4, in the coordinate regulation of cardiac-specific gene expression during heart development. GATA-4 expression is restricted to the pre-cardiac mesoderm and folding heart tube in the early mouse embryo. Moreover, GATA-4 expression precedes that of the cardiac contractile proteins by 0.5-1 day during mouse embryogenesis. Most importantly, GATA-4 binds to the promoter-enhancer elements of multiple cardiac genes, including the cardiac troponin C and troponin T genes, the ANF gene, the myosin light chain 1 gene, and the alpha-MHC gene. In addition, the forced expression of GATA-4 can directly transactivate the expression of at least some of these cardiac- specific promoter-enhancers in non-muscle cells. Taken together, these studies are consistent with the hypothesis that GATA-4 is one of the important cardiac myocyte determining genes. The studies described in this application are intended to (i) map the important functional domains of the GATA-4 transcription factor, (ii) directly test the role of GATA-4 in the regulation of cardiac gene expression and cardiac myocyte differentiation by studying the effects of targeted disruptions of the GATA-4 gene on cardiac myocyte development in vitro and in vivo, and (iii) map the regions of GATA-4 that are necessary for cardiac myocyte differentiation and gene expression during the in vitro differentiation of ES cells into embryoid bodies.