The Epigenetic Landscape of Heart Development

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 DESCRIPTION (provided by applicant): The NHLBI Cardiovascular Development Consortium (CvDC) aims to provide an integrated functional understanding of regulators of heart development, in order to apply this knowledge to congenital heart disease (CHD), which results from dysregulation of transcriptional pathways. A global approach is required to truly achieve the network-level insight that will bring together the components of gene regulation that are operative in heart development. With this knowledge, it will be possible to discover the molecular pathways through which gene regulation is disrupted in CHD. The finding that mutations in genes encoding transcriptional regulators and chromatin modulators underlie CHD provides significant motivation to understand the networks in which such factors function to control cardiac differentiation and morphogenesis. Our CvDC group has deployed a broad set of approaches to mechanistically understand the basis of cardiac gene regulation. We are particularly motivated to understand the dynamic chromatin interactions that enable distal regulatory elements to regulate cell-type specific gene expression and how these mechanisms fail to be appropriately deployed in the face of mutations that cause CHD. A concerted approach involving significant collaborative efforts is required to achieve these goals. Rapid and free data and resource sharing will enable other groups to benefit instantly from our efforts, allowing them to launch complementary investigations based on CvDC efforts. With this philosophy in place the CvDC, together with many other labs, will yield significant insights into cardiac gene regulation as it applies to CHD. We propose a center project, a collaborative project, and essential cores, to collaboratively propel CHD research forward. For the center project, we propose the following aims: Aim 1: To define the transcription factor (TF) networks that regulate cardiac differentiation. Aim 2: To determine the three-dimensional interactions that coordinate cardiac gene expression. Aim 3: To define the functional significance of regulatory elements in heart development. For the collaborative project, we propose the following aims: Aim 1: To characterize the transcriptional changes that result from CHD-associated mutations in genes encoding epigenetic factors and transcription factors. Aim 2: To define the epigenomic changes that result from mutations in genes encoding epigenetic and transcription factors. The two projects we propose, together with a focus on collaboration and data sharing, and a training plan philosophy that emphasizes cross-disciplinary interactions, will propel the CvDC towards its next phase of discovery. Our investigations will provide new and important insights into CHD, providing a solid and broad platform for translational development of diagnostic and therapeutic approaches.