Dynamics and molecular mechanisms linking metabolism and the epigenome

连接代谢和表观基因组的动力学和分子机制

• 批准号: 10624003
• 负责人: JOHN M DENU
• 金额: $ 66.93万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624003
• 关键词: Acceleration; Acetyl Coenzyme A; Acetylation; Acetyltransferase; Animals; Biochemical; Biochemistry; Biophysics; Catalysis; Cell physiology; Cells; Chromatin; Communication; DNA Methylation; DNA Sequence; Deacetylase; Deacetylation; Diet; Disease; Environment; Enzymes; Epigenetic Process; Etiology; Foundations; Gene Expression; Genetic; Genome; Goals; Histones; Human body; In Vitro; Instruction; Investigation; Knowledge; Link; Lysine; Macronutrients Nutrition; Metabolism; Methylation; Methyltransferase; Modeling; Molecular; Molecular Machines; Nicotinamide adenine dinucleotide; Nuclear; Nucleosomes; Pathway interactions; Pharmacology; Post-Translational Protein Processing; Production; Protein Acetylation; Proteins; Research; S-Adenosylhomocysteine; S-Adenosylmethionine; Signal Pathway; Signal Transduction; Sirtuins; Untranslated RNA; Work; alpha ketoglutarate; cell type; drug development; epigenome; extracellular; insight; microbiota; non-histone protein; response

Project Summary/Abstract Cellular responses to available macronutrients and extra-cellular signals rely on the unique epigenetic state of the cell, defined by a layer of biochemical information above the genome that dictates specific gene expression. The epigenome consists of DNA sequence-dependent proteins, non-coding RNAs, DNA methylation and histone post-translation modifications (PTMs) such as lysine acetylation and methylation. The latter two mechanisms are catalyzed by enzymes that must ‘interpret’ incoming signals, ‘read’ the existing epigenetic landscape and ‘respond’ appropriately. Enzymes that modify histones and non-histone proteins such as methyltransferases, demethylases, acetyltransferases and deacetylases use central metabolites (S- adenosyl methionine, SAM; α-ketoglutarate, αKG; acetyl-CoA and nicotinamide adenine dinucleotide, NAD+, respectively) as co-substrates. New evidence suggests that fluctuation in such epi-metabolites caused by diet, environment, microbiota and genetics can drive PTM dynamics, however the relevant mechanisms remain unclear in most cases. Are changes in epi-metabolites sensed by signaling pathways or by substrate-level driven catalysis or both? Also, does local production of epi-metabolites enable/accelerate gene expression mechanisms on chromatin? Non-histone protein acetylation is a major PTM that can regulate many aspects of cellular function and occurs in all cellular compartments. But despite broad knowledge of what gets modified, the most pressing challenge is to understand the how, the why and the when, which constitutes an overarching theme of this proposal. A major portion of the research to understand reversible protein acetylation as a regulatory PTM will involve knowledge of how pathway-specific acetyl-CoA (and other acyl-CoAs) production leads to dynamic acetylation after extra-cellular stimulation. Also, this work will focus on the detailed molecular mechanisms by which nuclear NAD+-dependent deacetylases SIRT6/7 (Sirtuins 6 & 7) are regulated and how these enzymes perform such exquisite deacetylation of nucleosomes. A sub-theme of this proposal that connects these two projects is to understand the fundamental principles that govern PTM enzymes acting on chromatin/nucleosomes. This proposal is uniquely poised to make major advances to these salient questions. To accomplish these goals, the projects synergistically employ in vitro biochemistry/biophysics, complementary genetics and pharmacology, and cell- and animal-based models. Results from these investigations will provide i.) insight into the etiology of diseases resulting from the link between metabolism and the epigenome, ii.) foundations for drug development against the enzymes described here, and iii.) a fundamental understanding of how the cell ‘interprets’ incoming signals in the context of existing epigenetic information and ‘responds’ appropriately.

项目摘要/摘要 细胞对可用大量营养素和细胞外信号的反应依赖于独特的表观遗传状态 该细胞由基因组上方的生化信息层定义，该信息决定了特定的基因 表达。表观基因组由DNA序列依赖性蛋白，非编码RNA，DNA组成 甲基化和Hisstone翻译后修饰（PTM），例如赖氨酸乙酰化和甲基化。这 后两种机制是由必须“解释”传入信号的酶催化的 表观遗传景观和适当的“反应”。修饰组蛋白和非内酮蛋白的酶 例如甲基转移酶，去甲基酶，乙酰转移酶和脱乙酰基酶使用中央代谢物（S- 腺苷蛋氨酸，SAM； α-酮戊二酸，αkg;乙酰辅酶A和烟酰胺腺苷二核苷酸，NAD+， 分别为共覆盖物。新的证据表明，在饮食引起的这种Epi-Inetabolites中的波动， 环境，微生物群和遗传学可以驱动PTM动力学，但是相关机制仍然存在 在大多数情况下不清楚。是通过信号通路或底物级感所感受到的Epi-Metabolites的变化 驱动的催化还是两者兼而有之？此外，局部产生的Epi-亚代谢产物是否可以启用/加速基因表达 染色质的机制？ 非Histone蛋白乙酰化是一个主要的PTM，可以调节细胞功能的许多方面并发生 在所有细胞室中。但是目的地广泛了解被修改的内容，最紧迫的挑战 是要了解构成该提案的总体主题的方式，为什么和何时。一个 研究的主要部分了解可逆蛋白乙酰化作为调节PTM 了解途径特异性乙酰辅酶A（和其他乙酰辅酶AS）的生产如何导致动态乙酰基 细胞外刺激后。此外，这项工作将集中在详细的分子机制上 核NAD+依赖性脱乙酰基酶SIRT6/7（SIRTUINS 6和7）受到调节，这些酶的性能如何 这种核组的独家脱乙酰化。该提案连接这两个项目的子主题是 了解控制作用于染色质/核小体的PTM酶的基本原理。这 提案被毒死了，可以在这些突出的问题上取得重大进展。为了实现这些目标， 这些项目协同采用体外生物化学/生物物理学，完整的遗传学和 药理学以及基于细胞和动物的模型。这些投资的结果将提供i。）深入了解 由代谢与表观基因组之间的联系产生的疾病的病因，ii。） 针对此处描述的酶的药物开发，以及III。）对细胞的基本了解 在现有表观遗传信息的背景下，“解释”传入信号，并适当地响应。