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

基本信息

  • 批准号:
    10295030
  • 负责人:
  • 金额:
    $ 3.47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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/摘要 衰老是心血管疾病、癌症和其他慢性疾病的主要危险因素。 神经变性随着美国人口继续老龄化,这些疾病的流行将 增加因此,确定支持长寿干预的机制,如热量, 限制(CR)是一个重要的优先事项。尽管CR干预改善了导致细胞死亡的因素, 在衰老过程中,它对染色质重塑的影响仍然研究不足。我的论文是要了解 酵母菌中静止染色质结构的建立和维持 酿酒酵母的时间老化及其对CR等长寿干预措施的反应。了解这些变化 在染色质组织中的作用将促进新干预措施的发展, CR的寿命。 在初步实验中,我发现CR优化了转录条件, 核苷酸,乙酰辅酶A水平和乙酰辅酶A合成酶(Acs 2),因为细胞开始过渡到静止。我 提出阐明这些条件如何诱导转录调控级联反应的机制, 增强了安静。首先在目标1中,我将定义CR如何在时间和结构上增强染色质 当细胞进入静止期时,细胞会紧密结合。其次,我将检验CR诱导早期波的假设。 通过Acs 2积累乙酰辅酶A进行转录。然后,这种积累导致组蛋白高度乙酰化, 通过Gcn 5组蛋白乙酰转移酶复合物(佐贺)的相关靶启动子。第三,我会测试贡献 转录的核苷酸缓冲和后来的抑制染色质在静止状态下的建立。这些 研究将提供CR在建立时序老化过程中静止的作用的机制见解。 染色质致密化对维持静止状态至关重要,但老化过程中发生的结构变化 或对CR的反应未知。因此,在目标2中,我将描述维持镇压的特点。 染色质结构在时序老化。我假设转录抑制因子和染色质 结构蛋白随着年龄的增长而耗尽,因此不利于静止。首先,我会检测 衰老细胞中抑制性染色质结构的分解及其对转录的影响, ATAC-Seq和PRO-Seq.第二,我将使用串联的方法来表征CLS中染色质因子的耗尽。 质量标记(TMT)实验。第三,我将确定在静止期染色质开放是否驱动细胞 SNF 1 β和GCN 5 β突变体中的周期再进入或细胞死亡。这些实验将确定CR对 在衰老过程中抑制性染色体结构的时间和结构维持。

项目成果

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Elisa Enriquez Hesles其他文献

Elisa Enriquez Hesles的其他文献

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{{ truncateString('Elisa Enriquez Hesles', 18)}}的其他基金

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:
    10463876
  • 财政年份:
    2020
  • 资助金额:
    $ 3.47万
  • 项目类别:
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