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Combinatorial Regulation of Gene Networks During Cardiac Development and Disease

Award Number: P01HL146366
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Combinatorial Regulation of Gene Networks During Cardiac Development and Disease - PROJECT SUMMARY/ABSTRACT OVERALL COMPONENT Cardiovascular disease is the most common cause of mortality in adults, and congenital heart defects (CHDs) are the most common form of birth defects. An important concept that has emerged in recent years is that dysregulation of cardiac transcription factor (TF) networks and related chromatin remodeling machinery contributes to CHDs and heart failure. Forced expression of the core members of the TF network is sufficient to reprogram non-myocytes into cardiomyocyte-like cells for regenerative medicine purposes, suggesting a combinatorial code for determining cell fate. As genome-wide roles for critical TFs are being discovered, a conceptual understanding of their function in higher order DNA organization is emerging. Evidence that the three-dimensional organization of DNA promotes activation or repression of genomic loci has raised the question of how cooperative protein-protein interactions involving TF and chromatin remodeling complexes participate in this process. We have integrated a multidisciplinary team of developmental cardiologists, computational biologists, and systems biologists, with expertise in CRISPR/Cas9 genome engineering in human iPS cells, to investigate how the genome is regulated by TFs and chromatin remodelers to control cardiac gene expression and fate. The specific hypotheses that we test in this proposal, which involve a combination of core cardiac TFs that interact with one another to coordinately regulate cardiac gene expression, are as follows: 1) that the cardiac TFs GATA4 and TBX5 interact in a lineage-specific fashion with the nuclear pore complex to regulate the 3D genomic architecture and subsequent transcriptional output; 2) that specific BAF chromatin remodeling complexes form dynamically to coordinate regulation of distinct aspects of cardiac morphogenesis and lineage decisions through interaction with cardiac TFs; and 3) that the MEF2C-myocardin complex, which interacts with GATA4, TBX5 and BAF60c, recruits a transcriptional complex influenced by upstream signaling and myocardin dimerization to regulate cardiac gene expression. To address these questions, we have integrated unique expertise in the study of protein-protein interactions and post-translational modifications through the Advanced Proteomics Core; the ability to analyze complex datasets of PPIs, DNA-binding, and transcriptional output related to transcriptional regulators through the Advanced Bioinformatics Core; and the ability to leverage state-of-the-art genome engineering approaches through the Genome Engineering Core. The questions in this proposal will be studied in the context of human disease-causing mutations to reveal underlying mechanisms and paradigms that control normal and abnormal cardiogenesis. The integrated knowledge developed here will enable a clear reading of the transcriptional “code” for cardiac cell fate determination and differentiation that may be leveraged for interventions in CHD and for regenerative medicine.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	5	10/30/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $2,723,920 )
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	5	8/25/2023	NON-COMPETING CONTINUATION	$2,723,920
														Subtotal = $2,723,920

Issue Date FY: 2022 ( Subtotal = $2,723,920 )
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	4	8/29/2022	NON-COMPETING CONTINUATION	$2,723,920
														Subtotal = $2,723,920

Issue Date FY: 2021 ( Subtotal = $2,731,995 )
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	3	8/19/2021	NON-COMPETING CONTINUATION	$2,731,995
														Subtotal = $2,731,995

Issue Date FY: 2020 ( Subtotal = $2,731,195 )
2020	2020	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	2	8/21/2020	NON-COMPETING CONTINUATION	$2,731,195
														Subtotal = $2,731,195

Issue Date FY: 2019 ( Subtotal = $2,750,645 )
2019	2019	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	1	8/31/2019	NEW	$2,750,645
														Subtotal = $2,750,645

Grand Total All Awards = $13,661,675

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Combinatorial Regulation of Gene Networks During Cardiac Development and Disease

Award Number: P01HL146366

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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