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Mechanisms of chromatin remodeling at RNA polymerase II promoters

Award Number: R01GM104111
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: 09/01/2013
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Mechanisms of chromatin remodeling at RNA polymerase II promoters - 7. PROJECT SUMMARY/ABSTRACT A fundamental aspect of all biological processes is gene expression, which is controlled at a variety of levels, the first step being transcription. Transcription is regulated not only by sequence-specific factors such as activators and repressors, but also by the underlying chromatin structure of the chromosomal DNA. This structure is determined by various chromatin remodeling pathways. Genes encoding regulators of chromatin remodeling pathways are frequently mutated in human cancers. Perturbation of chromatin regulators promotes cancer progression in part by reverting the `on' or `off' chromatin states committed during tissue development to a poised, stem-like state, thereby increasing gene expression plasticity that enables cancer cells to evolve and adapt. Histone H2A.Z is an important chromatin regulator that poises genes for transcription. It is inserted into nucleosomes immediately downstream of the promoters of most genes. Hyper-accumulation of H2A.Z makes cancer cells more invasive and is linked with poor prognosis in cancer patients. Using the budding yeast model system, I previously demonstrated that the highly conserved, ATP- dependent remodeler SWR replaces nucleosomal H2A with H2A.Z in a unidirectional manner in vitro. During the current funding period, my lab found that H2A.Z is subjected to rapid turnover at both actively and infrequently transcribed genes and that the transcription machinery targets H2A.Z nucleosomes for disassembly in vivo. In addition, we developed a novel method for globally determining the levels of H2A.Z and H2A-containing nucleosomes in yeast and human cells called VivosX. This proposal will extend this work to (1) dissect the molecular mechanisms by which the SWR chromatin remodeling enzyme inserts H2A.Z into specific sites on chromatin and (2) elucidate the molecular events at promoters after H2A.Z insertion. This knowledge may ultimately reveal molecular targets for drugs that can counteract the aberrant levels of H2A.Z in cancer cells.


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: 2024 ( Subtotal = -$1,296 )
2024	2022	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	9	7/17/2024	NON-COMPETING CONTINUATION	-$1,296
														Subtotal = -$1,296

Issue Date FY: 2022 ( Subtotal = $332,233 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	9	8/1/2022	NON-COMPETING CONTINUATION	$33,223
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	9	2/18/2022	NON-COMPETING CONTINUATION	$299,010
														Subtotal = $332,233

Issue Date FY: 2021 ( Subtotal = $332,233 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	8	2/27/2021	NON-COMPETING CONTINUATION	$332,233
														Subtotal = $332,233

Issue Date FY: 2020 ( Subtotal = $332,233 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	7	2/11/2020	NON-COMPETING CONTINUATION	$332,233
														Subtotal = $332,233

Issue Date FY: 2019 ( Subtotal = $332,233 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	004	6	9/24/2019	COMPETING CONTINUATION	$23,621
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	002	6	4/1/2019	COMPETING CONTINUATION	$332,233
2019	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	003	5	9/24/2019	NON-COMPETING CONTINUATION	-$23,621
2019	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	5	3/27/2019	NON-COMPETING CONTINUATION	$0
2019	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	5	11/28/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $332,233

Issue Date FY: 2017 ( Subtotal = $296,292 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	002	5	8/21/2017	NON-COMPETING CONTINUATION	$296,292
2017	2016	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	001	4	3/30/2017	EXTENSION WITH OR WITHOUT FUNDS	$246
2017	2015	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	3	3/30/2017	NON-COMPETING CONTINUATION	-$246
														Subtotal = $296,292

Issue Date FY: 2016 ( Subtotal = $296,292 )
2016	2016	SUNY, STONY BROOK	OFFICE OF RESEARCH SERVICES	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	4	8/6/2016	EXTENSION WITH OR WITHOUT FUNDS	$296,292
														Subtotal = $296,292

Issue Date FY: 2015 ( Subtotal = $296,292 )
2015	2015	SUNY, STONY BROOK	OFFICE OF RESEARCH SERVICES	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	3	7/22/2015	NON-COMPETING CONTINUATION	$296,292
														Subtotal = $296,292

Issue Date FY: 2014 ( Subtotal = $296,292 )
2014	2014	SUNY, STONY BROOK	OFFICE OF RESEARCH SERVICES	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	2	8/19/2014	NON-COMPETING CONTINUATION	$296,292
														Subtotal = $296,292

Issue Date FY: 2013 ( Subtotal = $295,530 )
2013	2013	SUNY, STONY BROOK	OFFICE OF RESEARCH SERVICES	STONY BROOK	NY	11794	SUFFOLK	USA	Biomedical Research and Research Training	000	1	8/8/2013	NEW	$295,530
														Subtotal = $295,530

Grand Total All Awards = $2,808,334

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Mechanisms of chromatin remodeling at RNA polymerase II promoters

Award Number: R01GM104111

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: 09/01/2013

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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