Histone tails as an energy reservoir for mitochondrial function

 描述(申请人提供)：新陈代谢代表细胞内维持生命所必需的有机和化学过程。它也是细胞与能源相互作用的方式，协调能量的吸收、储存和利用，最终允许细胞正常生长和功能。新陈代谢中的一个关键分子是乙酰辅酶A，这是一种位于多条代谢途径的十字路口的分子，同时也是组蛋白乙酰化的底物，组蛋白乙酰化是基因组中的主要表观遗传标记之一。最近的研究表明，乙酰辅酶A可获得性的波动可以直接影响组蛋白乙酰化水平，但是否有可能逆转仍是未知的。换句话说，组蛋白标志物中的醋酸盐是否可以作为一个储存库来调节乙酰辅酶A水平，以维持代谢平衡？如果是这样的话，表观基因组的变化是否会因为直接影响醋酸盐的利用率而影响新陈代谢？在这种情况下，环境压力，如电离辐射(IR)或低氧，可能直接影响表观基因组，进而影响其缓冲乙酰-辅酶A水平的潜力。这一假设代表了R21/R33提案的主要焦点。具体地说，在第一个探索阶段(R21)，目的是：1-建立一种使用稳定同位素示踪的脉冲追逐分析来跟踪细胞核和线粒体之间的串扰；以及2-确定环境胁迫条件下依赖NAD的组蛋白脱乙酰酶SIRT6在从染色质中动员醋酸盐中的作用。这些实验应该为发展第二个R33阶段奠定基础，重点是：3-分析环境和营养应激在调节表观遗传学-新陈代谢串扰中的作用，4-确定细胞核作为能量储存库的体内意义。总之，这些实验应该为细胞核作为代谢库的作用提供直接证据，这可能指出调控表观遗传标记可能作为对抗代谢性疾病和环境压力的策略。

 DESCRIPTION (provided by applicant): Metabolism represents the organic and chemical processes within a cell that are necessary to maintain life. It is also the way that a cell interacs with energy sources, coordinating energy intake, storage, and utilization, ultimately allowing proper cellular growth and function. A key molecule in metabolism is Acetyl-CoA, a molecule sitting at the crossroads of multiple metabolic pathways, while also serving as a substrate for histone acetylation, one of the main epigenetic marks in the genome. Recent studies have demonstrated that fluctuations in availability of Acetyl-CoA can directly impinge on levels of histone acetylation, yet whether the reverse is possible remains unknown. In other words, may acetate from histone marks serve as a reservoir to modulate Acetyl- CoA levels in order to sustain metabolic homeostasis? And if so, can changes in the epigenome affect metabolism due to a direct effect on acetate availability? In this context, environmental stresses such as ionizing radiation (IR) or hypoxia may directly affect the epigenome, in turn affecting its potentil to buffer Acetyl-CoA levels. This hypothesis represents the main focus of this R21/R33 proposal. Specifically, in the first exploratory (R21) phase the intent is to: 1- Develop a pulse-chase assay using stable-isotope tracing to follow crosstalk between the nucleus and the mitochondria; and 2- Determine the role of the NAD-dependent histone deacetylase SIRT6 in mobilizing acetate from chromatin under conditions of environmental stress. These experiments should set the basis to develop the second R33 phase, where the focus is to: 3- Analyze the role of environmental and nutrient stress in modulating this epigenetics-metabolism crosstalk and 4- Determine the in vivo significance for the nucleus as an energy reservoir. All together, these experiments should provide direct evidence for a role of the nucleus as a metabolic reservoir, which may point to strategies where modulation of epigenetic marks may serve as a strategy against metabolic diseases and environmental stresses.