Wednesday, December 31, 2025 12/31/2025

The role of genome folding in regulating gene expression and chromatin state

Award Number: R35GM152103
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: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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The role of genome folding in regulating gene expression and chromatin state - PROJECT SUMMARY Knowledge of how three-dimensional (3D) genome organization is linked to gene expression and chromatin state is paramount to understanding human health and disease. The cohesin complex is a major regulator of genome organization that dynamically extrudes DNA loops to bring together enhancers, promoters, and insulators. While the insulator protein CTCF is known to capture and stabilize an extruding cohesin complex, it is not clear how cohesin is stabilized at enhancers and promoters that lack CTCF. Furthermore, the causal role of cohesin-mediated loops in regulating gene expression is not understood. We recently discovered that cohesin variant complexes, composed of either STAG1 or STAG2 subunits and either PDS5A or PDS5B subunits, colocalize across the genome, yet have surprisingly distinct effects on gene expression. In this proposed study, we will answer the next set of questions about cohesin biology. We hypothesize that cohesin complexes at specific genomic sites have distinct biochemical properties and binding partners that mediate effects on transcription and chromatin state defined by histone modifications. To test these hypotheses, we are using an integrative approach that combines genetic, biochemical, genomic, and proteomic assays in embryonic stem cells and differentiated cells following genome editing, protein depletion, acute degradation, or inhibition with small molecules. These studies will 1) identify novel cohesin-interacting proteins using proteomic approaches, 2) investigate the properties of cohesin complexes at different genomic sites and with different binding partners, and 3) elucidate the role of cohesin-mediated DNA loops in regulation of transcription and chromatin state at genomic sites lacking CTCF. The proposed multi-disciplinary approach leverages our extensive experience in functional genomics and expands on our recent findings that demonstrated roles for cohesin subunits and cohesin regulators in DNA loop formation and transcription. This will contribute to our long-term goal of applying cutting-edge technologies to uncover the molecular mechanisms that define how 3D genome organization influences chromatin state and transcriptional control to govern cell identity. Completion of this project will fill critical gaps in knowledge about gene regulation that inform our understanding of human developmental disorders and cancers linked to epigenetic defects.


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: 2026 ( Subtotal = $373,010 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	3	12/16/2025	NON-COMPETING CONTINUATION	$373,010
														Subtotal = $373,010

Issue Date FY: 2025 ( Subtotal = $414,455 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	002	2	8/13/2025	NON-COMPETING CONTINUATION	$41,445
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	2	12/13/2024	NON-COMPETING CONTINUATION	$373,010
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	1	11/12/2024	NEW	$0
														Subtotal = $414,455

Issue Date FY: 2024 ( Subtotal = $520,255 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	001	1	5/13/2024	SUPPLEMENT FOR EXPANSION	$105,800
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Biomedical Research and Research Training	000	1	12/14/2023	NEW	$414,455
														Subtotal = $520,255

Grand Total All Awards = $1,307,720

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The role of genome folding in regulating gene expression and chromatin state

Award Number: R35GM152103

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: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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