Abnormalities in heart development result in congenital heart disease, the most frequent form of birth defects in humans. It has been estimated that nearly 1% of newborns are affected by a congenital cardiac defect. At the opposite end of the temporal spectrum, adult cardiac disease is the most common cause of death in the industrialized world. Thus, there is a major need for the development of new approaches for prevention, genetic diagnosis and treatments of cardiovascular disorders, which requires a detailed understanding of the underlying mechanisms. Numerous transcription factors have been implicated in cardiac myogenesis and morphogenesis, but much remains to be learned about the mechanisms of cardiac gene regulation. The activities of transcription factors are dependent on their association with transcriptional coactivators and corepressors, many of which are signal-responsive and cell type-restricted. The modulation of transcription factor activity by association with coactivators and corepressors allows the integration of multiple regulators and provides for specialized control of different transcriptional programs. In an effort to fully understand the molecular basis of cardiac gene expression, we have devised eukaryotic expression screens for coactivators and corepressors of cardiac transcription factors. Such screens have led to the discovery of a novel and highly potent coactivator of the cardiac homeodomain protein Nkx2.5. This coactivator translocates to the nucleus in response to specific calcium-dependent signals and cooperates with Nkx2.5 to activate cardiac target genes. Similarly, a coactivator of the T-box protein Tbx5, which enhances the transcriptional activity of Tbx5 by several orders of magnitude, has been identified. The long-term goals of this project are to understand the mechanism of action of these and other coactivators and to define their functions in the control of cardiac gene expression during development and disease. We will use a combination of biochemical, cell biological and genetic approaches in cultured cells and in mice to achieve these goals. The results of this project will provide a detailed understanding of the mechanisms involved in normal and abnormal cardiac gene expression and will have implications for many aspects of cardiac function and dysfunction during development and adulthood.
