The Role of Cysteine Rich Protein2 Binding Protein in Cardiovascular Development

Texas A&M University Health Science Ctr, College Station TX

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Abstract

DESCRIPTION (provided by applicant): De novo activation of smooth muscle genes during the early specification of the cardiovascular system very likely requires SRF, the master regulatory platform, to form combinatorial interactions with other enriched co-factors to drive cardiovascular specified gene activity. Although SRF is indispensable for myogenic contractile protein gene expression, SRF alone is not sufficient for regulating cardiovascular cell differentiation. Previous studies implicated the involvement of chromatin acetylation-deacetylation in the control of smooth muscle gene expression. Combining bioinformatic predictions and experimental evidence, we identified a novel and important HAT that activates the nascent smooth muscle gene program. We provided multiple lines of evidence that support the concept that CSRP2BP is a novel and powerful SRF dependent Smooth Muscle Histone Acetyl-Transferase, renamed SM-HAT may be central for controlling embryonic smooth muscle gene expression and possibly vascular smooth muscle gene programs and the formation of the cardiovascular system. These studies will provide new insights in cardiovascular development and disease, and will advance strategies for regeneration and repair of the cardiovascular system. The specific aims of this project are: Specific Aim 1: To determine the function(s) of SM-HAT by gene inactivation in mice, embryonic stem (ES) cells and pro-epicardial cells. Specific Aim 2: To define the mechanisms shared between SRF and the smooth muscle enriched chromatin remodeling factor, SM-HAT Specific Aim 3: To Identify the overlapping gene networks shared between SRF and the smooth muscle enriched chromatin remodeling factor, SM-HAT PUBLIC HEALTH RELEVANCE: We identified a novel and important HAT that activates the nascent smooth muscle gene program. We provided multiple lines of evidence that support the concept that CSRP2BP is a novel and powerful SRF dependent Smooth Muscle Histone Acetyl-Transferase, renamed SM-HAT may be central for controlling embryonic smooth muscle gene expression and possibly vascular smooth muscle gene programs and the formation of the cardiovascular system. We will determine the function(s) of SM-HAT by gene inactivation in mice, embryonic stem (ES) cells and pro-epicardial cells. We will define the mechanisms shared between SRF and SM-HAT and Identify their overlapping gene networks.