Histone tails as an energy reservoir for mitochondrial function

 描述（由申请人提供）：代谢代表细胞内维持生命所必需的有机和化学过程。它也是细胞与能量源相互作用的方式，协调能量摄入，储存和利用，最终允许适当的细胞生长和功能。代谢中的一个关键分子是乙酰辅酶A，这是一种位于多种代谢途径交叉路口的分子，同时也是组蛋白乙酰化的底物，组蛋白乙酰化是基因组中主要的表观遗传标记之一。最近的研究表明，乙酰辅酶A可用性的波动可以直接影响组蛋白乙酰化的水平，但是否有可能逆转仍然未知。换句话说，来自组蛋白标记的乙酸盐是否可以作为调节乙酰辅酶A水平的储存库，以维持代谢的稳态？如果是这样的话，表观基因组的变化是否会直接影响醋酸盐的可用性，从而影响新陈代谢？在这种情况下，环境应激如电离辐射（IR）或缺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。这一假设是R21/R33提案的主要重点。具体而言，在第一探索（R21）阶段，目的是：1-使用稳定同位素示踪开发脉冲追踪测定以追踪细胞核和线粒体之间的串扰;和2-确定NAD依赖性组蛋白脱乙酰酶SIRT 6在环境应激条件下从染色质动员乙酸盐中的作用。这些实验应该为开发第二个R33阶段奠定基础，其中重点是：3-分析环境和营养胁迫在调节这种表观遗传-代谢串扰中的作用; 4-确定细胞核作为能量储存器的体内意义。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，这可能指向表观遗传标记的调节可能作为对抗代谢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.