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Caloric Restriction directs topological chromatin reorganization to enter and maintain enhanced quiescence

Award Number: F30AG067760
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Caloric Restriction directs topological chromatin reorganization to enter and maintain enhanced quiescence - PROJECT SUMMARY/ABSTRACT Aging is the leading risk factor for chronic diseases such as cardiovascular disease, cancer and neurodegeneration. As the U.S. population continues to grow older, the prevalence of these diseases will increase. Therefore, determining the mechanisms underpinning pro-longevity interventions, such as caloric restriction (CR) is an important priority. Although CR intervention improves factors contributing to cellular demise in the aging process, its impact on chromatin remodeling remains understudied. My dissertation is to understand the establishment and maintenance of quiescent chromatin architecture in the context of Saccharomyces cerevisiae chronological aging and its response to longevity interventions like CR. Understanding these changes in chromatin organization will facilitate the development of novel interventions, mimicking the beneficial effects of CR on longevity. In preliminary experiments, I have found that CR optimizes transcription conditions with abundant intracellular nucleotide, acetyl-CoA levels, and acetyl-CoA synthetase (Acs2), as cells start the transition into quiescence. I propose to elucidate the mechanism of how these conditions induce a transcriptional regulatory cascade that enhances quiescence. First in Aim 1, I will define how CR temporally and structurally enhances chromatin compaction as cells enter quiescence. Second, I will test the hypothesis that CR induces the early wave of transcription via acetyl-CoA accumulation by Acs2. This accumulation then results in histone hyperacetylation at relevant target promoters by Gcn5 histone acetyltransferase complex (SAGA). Third, I will test the contribution of nucleotide buffering to transcription and the later establishment of repressive chromatin in quiescence. These studies will provide mechanistic insights of CR's role in establishing quiescence during chronological aging. Chromatin compaction is vital to maintaining quiescence, yet the architectural changes that occur during aging or in response to CR are unknown. Therefore, in Aim 2, I will characterize the maintenance of repressive chromatin structure during chronological aging. I hypothesize that transcriptional repressors and chromatin architectural proteins become depleted with age, and thus detrimental to quiescence. First, I will detect breakdown of repressive chromatin structure in aged cells and its effect on transcription using a combination of ATAC-Seq and PRO-Seq. Second, I will characterize the depletion of chromatin factors in CLS using tandem mass tagging (TMT) experiments. Third, I will determine if chromatin openness during quiescence drives cell cycle re-entry or cell death in snf1∆ and gcn5∆ mutants. These experiments will define CR's impact on the temporal and structural maintenance of repressive chromosomal architecture during aging.


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 = -$3,241 )
2024	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	3	4/24/2024	NON-COMPETING CONTINUATION	-$3,241
														Subtotal = -$3,241

Issue Date FY: 2022 ( Subtotal = $47,360 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	001	3	7/29/2022	NON-COMPETING CONTINUATION	$47,360
2022	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	2	7/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $47,360

Issue Date FY: 2021 ( Subtotal = $34,698 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	001	2	8/6/2021	NON-COMPETING CONTINUATION	$34,698
2021	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	1	5/12/2021	NEW	$0
														Subtotal = $34,698

Issue Date FY: 2020 ( Subtotal = $34,182 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Aging Research	000	1	8/10/2020	NEW	$34,182
														Subtotal = $34,182

Grand Total All Awards = $112,999

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Caloric Restriction directs topological chromatin reorganization to enter and maintain enhanced quiescence

Award Number: F30AG067760

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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