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Roles for chromatin remodeler RSC and histone acetyltransferases in regulating chromatin structure and transcription

Award Number: R15GM148919
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: 09/09/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Roles for chromatin remodeler RSC and histone acetyltransferases in regulating chromatin structure and transcription - PROJECT SUMMARY Dynamic changes to chromatin structure are essential for regulating gene expression in cells. These changes are mediated by chromatin-associated factors such as histone modifiers, chaperones, and chromatin remodelers. Mutations in these factors are strongly linked to many human diseases. For example, mutations in the conserved SWI/SNF family of ATP-dependent chromatin remodelers are linked to ~20% of human cancers. Some of these mutations are also linked to developmental and intellectual disability syndrome, such as Coffin-Siris syndrome (CSS). However, we do not fully understand what aspects of SWI/SNF remodeling activities are affected by the disease-causing mutations under physiological conditions. The Remodels the Structure of Chromatin (RSC) complex is a member of the SWI/SNF family, and is the only essential remodeler in budding yeast. RSC regulates many biological processes, including transcription by all three RNA polymerases. It is critically involved in maintaining canonical chromatin structure near gene-promoters. Many domains have been identified within the RSC ATPase subunit Sth1 that modulate its remodeling activity. Additional domains are implicated in interacting with DNA and nucleosomes. However, the contributions of these domains in dictating RSC function in living cells are poorly understood. Furthermore, the mechanisms that regulate the association of RSC with chromatin are also not clear. RSC could bind to specific regions of chromatin using its bromodomains that have been shown to bind acetylated histones in vitro. How RSC exploits histone acetylation for its recruitment or to execute its function under physiological conditions remains to be understood. Using Saccharomyces cerevisiae as a model organism, in the specific AIM 1), we will investigate the impact of mutations in various regulatory and nucleosome-binding domains, and some of the mutations that are linked to developmental abnormalities on chromatin structure, including accessibility and gene expression. We will examine how mutations in these important domains affect the ability of cells to respond to stress. In the specific AIM 2), we will identify the histone tail residues that promote RSC association with chromatin and those that help RSC disengage from chromatin. The extent to which acetylated residues affect RSC ability to make DNA accessible will also be determined, genome-wide. Furthermore, we will examine the role of RSC in regulating transcription during elongation steps. These studies will be valuable in understanding how histone modifiers and chromatin remodelers cooperate to regulate gene expression.


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 = $0 )
2026	2023	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Biomedical Research and Research Training	001	1	1/23/2026	SUPPLEMENT FOR EXPANSION	$0
2026	2022	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Biomedical Research and Research Training	002	1	2/18/2026	NEW	$0
2026	2022	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Biomedical Research and Research Training	000	1	1/21/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Biomedical Research and Research Training	001	1	9/10/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2022	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Biomedical Research and Research Training	000	1	9/10/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $62,364 )
2023	2023	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Biomedical Research and Research Training	000	1	5/19/2023	SUPPLEMENT FOR EXPANSION	$62,364
														Subtotal = $62,364

Issue Date FY: 2022 ( Subtotal = $429,835 )
2022	2022	OAKLAND UNIVERSITY	2200 N SQUIRREL RD	ROCHESTER	MI	48309	OAKLAND	USA	Biomedical Research and Research Training	000	1	9/9/2022	NEW	$429,835
														Subtotal = $429,835

Grand Total All Awards = $492,199

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Roles for chromatin remodeler RSC and histone acetyltransferases in regulating chromatin structure and transcription

Award Number: R15GM148919

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: 09/09/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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