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.

Public Health Relevance

Congenital heart disease is the most serious of all childhood illnesses, affecting over 1 in 100 babies, and resulting in significant mortality and long-term illness. Unfortunately, we still do not know the underlying causes of congenital heart disease. Our project will bring together multidisciplinary approaches to understand how certain genetic mutations that are associated with congenital heart disease affect the gene networks that are so critical for the normal formation of the heart. (End of Abstract)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
5UM1HL098179-08
Application #
9115228
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Schramm, Charlene A
Project Start
2009-09-30
Project End
2020-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Nora, Elphège P; Goloborodko, Anton; Valton, Anne-Laure et al. (2017) Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization. Cell 169:930-944.e22
Ang, Siang-Yun; Uebersohn, Alec; Spencer, C Ian et al. (2016) KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation. Development 143:810-21
Hota, Swetansu K; Bruneau, Benoit G (2016) ATP-dependent chromatin remodeling during mammalian development. Development 143:2882-97
Ang, Yen-Sin; Rivas, Renee N; Ribeiro, Alexandre J S et al. (2016) Disease Model of GATA4 Mutation Reveals Transcription Factor Cooperativity in Human Cardiogenesis. Cell 167:1734-1749.e22
Haliburton, Genevieve D E; McKinsey, Gabriel L; Pollard, Katherine S (2016) Disruptions in a cluster of computationally identified enhancers near FOXC1 and GMDS may influence brain development. Neurogenetics 17:1-9
Whalen, Sean; Truty, Rebecca M; Pollard, Katherine S (2016) Enhancer-promoter interactions are encoded by complex genomic signatures on looping chromatin. Nat Genet 48:488-96
Luna-Zurita, Luis; Stirnimann, Christian U; Glatt, Sebastian et al. (2016) Complex Interdependence Regulates Heterotypic Transcription Factor Distribution and Coordinates Cardiogenesis. Cell 164:999-1014
Zhang, Yu; Cao, Nan; Huang, Yu et al. (2016) Expandable Cardiovascular Progenitor Cells Reprogrammed from Fibroblasts. Cell Stem Cell 18:368-81
Nobuta, Hiroko; Cilio, Maria Roberta; Danhaive, Olivier et al. (2015) Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome. Acta Neuropathol 130:171-83
Kostka, Dennis; Friedrich, Tara; Holloway, Alisha K et al. (2015) motifDiverge: a model for assessing the statistical significance of gene regulatory motif divergence between two DNA sequences. Stat Interface 8:463-476

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