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

热量限制指导拓扑染色质重组进入并维持增强的静止状态

• 批准号: 10295030
• 负责人: Elisa Enriquez Hesles
• 金额: $ 3.47万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295030
• 关键词: ATAC-seq; Acetate-CoA Ligase; Acetyl Coenzyme A; Address; Age; Aging; Animal Model; Architecture; Automobile Driving; Bioinformatics; Biological Models; Buffers; Caloric Restriction; Cardiovascular Diseases; Cell Cycle; Cell Death; Cell physiology; Cells; Chromatin; Chromatin Structure; Chronic Disease; Chronology; Complex; Development; Disease; Gene Activation; Gene Expression; Genes; Genetic Transcription; Glucose; Goals; Hi-C; Histone Deacetylase; Histones; Impairment; Intervention; Longevity; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Nerve Degeneration; Nuclear; Nucleotides; Organizational Change; Phase; Phenotype; Population; Prevalence; Process; Production; Proteins; Psychological reinforcement; Regimen; Research; Research Personnel; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; SAGA; Saccharomyces cerevisiae; Saccharomycetales; Serine; Structure; Testing; Threonine; Training Programs; Transcription Coactivator; Transcription Repressor; XBP1 gene; Yeasts; cell age; cellular longevity; chromatin remodeling; dietary; epigenome; experimental study; healthspan; healthy aging; histone acetyltransferase; improved; insight; interest; mimetics; mutant; novel; prevent; promoter; response

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.

项目总结/文摘