Mechanism and Function of Cardiac Transcriptional Repression Networks

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Abstract Congenital heart disease (CHD) remains the most common congenital malformation. Therefore, attaining a mechanistic understanding of cardiomyocyte formation is crucial for improving outcomes to structural heart disease. Though much emphasis in the last few years has been placed on transcription factor networks that control cardiomyocyte differentiation, these studies have mainly focused on transcriptional activation. However, there is growing recognition that alterations in transcriptional repression also lead to CHDs. Transcriptional repression involves not only cardiac transcription factors but also broadly expressed multiprotein machines that modify and remodel chromatin. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex. In this proposal we address the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic core component of the NuRD complex. The critical nature of CHD4 is highlighted by mutations in Chd4 being causative to CHDs. The goal of the current application is to test the central hypothesis that CHD4 functions with the NuRD complex to regulate cardiac chromatin architecture. This will be achieved by: 1) Determine whether CHD4 both represses and activates cardiac gene expression. 2) Delineate how CHD4 and NuRD are recruited to cardiac loci. 3) Establish how the human Chd4 missense mutations lead to cardiac disease.