Epigenetic regulation of heart development

Regulation of cardiogenic gene expression at the chromatin level has recently emerged as a key controlling mechanism for proper heart development. However, our current knowledge of epigenetic regulation of cardiogenesis and its contribution to congenital heart diseases is largely limited. The long term goal of this project is to reveal how various genetic and epigenetic factors act in concert to promote normal heart development in mammals and ultimately to translate our discoveries into clinical applications. CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities and Ear anomalies) is a severe developmental disorder affecting multiple organs and is mainly caused by mutations in CHD7, which encodes an ATP-dependent chromatin remodeling factor. More than 75% of CHARGE patients display inborn heart defects, and yet only a few studies have attempted to address the role of CHD7 in developing hearts. We recently identified CHD7 as an embryonic heart interaction partner of SMADs1, 5, and 8 (SMADs1/5/8), which are BMP receptor-activated SMADs (R-SMADs). We further showed that CHD7 directly regulates expression of Nkx2.5, which is a core cardiogenic transcription factor downstream of BMP signaling. How pathogenic mutations affect CHD7 in regulating cardiogenesis has never been examined in the literature, and thus a direct connection between the cardiogenic role of CHD7 and the heart defects observed in CHARGE patients has not been established. Our central hypothesis is that pathogenic mutations of CHD7 impair BMP activity and other cardiogenic signaling in developing cardiomyocytes. In this study we will primarily focus on two disease causing mutations, including S834F and R2418X. Three aims are proposed. In aim 1, we will determine how the two mutations affect the biochemical properties of CHD7. In aim 2, we will test the effect of the two mutations on BMP activity and other cardiogenic signaling using in vitro model systems. In aim 3, we will test how the two mutations affect cardiogenesis in mouse embryos. Successfully accomplishing the goals of this project will not only provide essential information for understanding the developmental basis of the heart defects in CHARGE, but also significantly improve our fundamental knowledge of the epigenetic regulation of mammalian cardiogenesis. (AHA Program: Grant-in-Aid)