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Uncovering the DNA recognition rules of cardiac transcription factors

Award Number: SC1GM127231
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Uncovering the DNA recognition rules of cardiac transcription factors - Project Summary/Abstract Transcription factors (TFs) are sequence-specific DNA-binding proteins that dictate cell fate by controlling selective usage of genomic information. Not surprisingly, malfunctioning TFs result in a broad range of diseases including cancer, autoimmune diseases, diabetes, and congenital heart defects. Mutations in cardiac transcription factors (TBX5, NKX2-5, and GATA4) have been linked to congenital heart diseases (CHD). CHDs represent the most common form of birth defects and are diagnosed in nearly 40,000 births every year in the US. Cardiac TFs (TBX5, NKX2-5, and GATA4) are part of an intricate gene regulatory networks that controls heart development. The long-term goal of the proposed work is to uncover the molecular mechanisms by which transcription factors (TFs) decode genomic information, and how genetic variation modulates TF- genome interactions that leads up to diseases. In Specific Aim 1, we will uncover the DNA-sequence specificity of multi-TF complexes involved in heart development and function. Using in vitro selection experiments coupled to next-generation sequencing (SELEX-Seq), we will determine the DNA-binding specificity of TBX5, NKX2-5, and GATA4 complexes. Our experiments will reveal the complex grammar of TF binding sites (TFBS) arrangements use by cooperative TF-complexes to regulate gene expression. Given their essential role in heart development and cardiac function, non-synonymous mutations of TBX5, NKX2-5, and GATA4 have been discovered in patients with a range of congenital heart defects (e.g., Tetralogy of Fallot, Holt-Oram syndrome, atrial and ventral septal defects). Several of these missense mutations have been mapped to the DNA-binding domain of the cardiac TFs. We hypothesized that missense mutations in the DNA- binding domains of cardiac TFs results in altered DNA-binding specificity landscapes, and subsequently reshape the gene regulatory networks controlling normal heart development and function. In Specific Aim 2, we will measure the comprehensive protein-DNA interactomes of missense mutants of TBX5, NKX2-5, and GATA4 using SELEX-Seq, and use bioinformatics tools to predict changes in gene targets between wild-type and mutant TFs. Moreover, over 93% of genetic variants associated with cardiovascular diseases occur in non- coding regions of the genome. These variants can potentially alter how TFs interact with the genome, either by disrupting existing or creating novel TF binding sites, and rewire gene regulatory pathways controlling cardiac homeostasis. In Specific Aim 3, we will integrate intrinsic DNA specificity of cardiac TFs with non-coding genetic variants associated with cardiovascular disease to identify putative TF binding sites that get disrupted or created. Disruption or creation of TFBS of cardiac TFs will be validated by in vitro binding experiments. Completion of the proposed project will enhance our understanding of how genetic variation (coding and non- coding) contributes to normal heart development and to congenital heart diseases at the molecular level.


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 = -$1,363 )
2025	2021	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	4	9/15/2025	NON-COMPETING CONTINUATION	-$1,363
														Subtotal = -$1,363

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	4	5/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	4	4/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $356,820 )
2021	2021	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	4	5/20/2021	NON-COMPETING CONTINUATION	$356,820
														Subtotal = $356,820

Issue Date FY: 2020 ( Subtotal = $335,750 )
2020	2020	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	3	5/19/2020	NON-COMPETING CONTINUATION	$335,750
														Subtotal = $335,750

Issue Date FY: 2019 ( Subtotal = $335,750 )
2019	2019	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	2	5/17/2019	NON-COMPETING CONTINUATION	$335,750
														Subtotal = $335,750

Issue Date FY: 2018 ( Subtotal = $344,080 )
2018	2018	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Biomedical Research and Research Training	000	1	5/14/2018	NEW	$344,080
														Subtotal = $344,080

Grand Total All Awards = $1,371,037

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Uncovering the DNA recognition rules of cardiac transcription factors

Award Number: SC1GM127231

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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