Chromatin Remodeling in Cardiovascular Development

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Hearts defects are the most common congenital defect and a major contributor to heart disease. Frequently, congenital heart diseases are diagnosed late in their progression, when treatments become temporary and have significant side effects. The applicant's long term goal is to establish an independent laboratory leveraging discoveries about the molecular basis of heart development into improved diagnostics and therapies for heart disease. During the remainder of his postdoctoral training at Stanford University, coursework in lab management, study of cardiovascular biology, laboratory research, and publication of manuscripts will support the applicant's transition to independency. Mentored and independent research will focus on the applicant's discovery that endocardial BAF chromatin remodeling complexes have remarkably specific roles in two heart regions. In the ventricles, the BAF complex determines the extracellular matrix required for morphogenesis of muscle cells into trabeculae by repressing transcription of a matrix protease, ADAMTS1. This regulation appears to be dynamic, as later in development ADAMTS1 expression increases to prevent excessive trabeculation. At the endocardial cushions that develop into valves, the BAF complex regulates an endocardial-to-mesenchymal transformation (EMT) that gives rise to cushion-populating cells. I hypothesize that endocardial BAF complexes establish regulatory "switches" at key loci to control developmental events in different regions of the heart. In the ventricles, I propose the BAF complex is recruited to ADAMTS1 by specific cooperating factors to induce dynamic changes in nucleosome organization to repress transcription. In the cushions, I hypothesize the BAF complex regulates transcription of secreted regulators of Wnt signaling. Misexpression of these factors in the absence of the BAF complex induces a premature and ectopic activation of Wnt that blocks EMT. These hypotheses will be pursued using two Specific Aims: 1) Determine if microenvironment changes regulate cell signaling in the ventricles. Describe cis-and Trans acting factors that recruit the BAF complex to ADAMTS1. Delineate nucleosome modifications that cooperate with the BAF complex to repress ADAMTS1. 2) Determine if inhibiting Wnt signaling restores EMT in embryos lacking endocardial BAF complexes. Describe the expression of Wnt regulating transcripts as potential targets of the BAF complex in endocardial cushions.