Metabolic Regulation of the Epigenetic Landscape in T cell Exhaustion

T 细胞耗竭过程中表观遗传景观的代谢调节

• 批准号: 10598676
• 负责人: Paula Andrea Agudelo Garcia
• 金额: $ 7.17万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-30 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598676
• 关键词: Acute; Affect; Antigens; Binding; Binding Sites; CD8-Positive T-Lymphocytes; CRISPR screen; CRISPR/Cas technology; Cell Differentiation process; Cell Fractionation; Cell Nucleus; Cell physiology; Cells; Cellular biology; Chromatin; Chronic; DNA Repair; DNA biosynthesis; Data; Development; Effector Cell; Enzymes; Epigenetic Process; Exhibits; Exposure to; Fumarates; Gene Expression; Genes; Genetic Transcription; Genome; Glycolysis; Goals; Histone H3; Histones; IL7R gene; Immune response; Infection; Inflammatory; Isocitrates; Knock-out; Lead; Lymphocytic choriomeningitis virus; Lysine; Malates; Malignant Neoplasms; Maps; Memory; Metabolic; Metabolic Pathway; Metabolism; Methylation; Modeling; Nuclear; Pathology; Performance; Phenotype; Play; Process; Production; Protein Methylation; Regulation; Repression; Role; Running; Signal Transduction; System; T cell regulation; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Transact; Virus Diseases; alpha ketoglutarate; base; cancer cell; chronic infection; cofactor; cytokine; cytotoxicity; enzyme activity; enzyme substrate; epigenetic regulation; epigenome; exhaust; exhaustion; experience; experimental study; fitness; histone methylation; histone modification; immune checkpoint blockade; improved; in vivo; insight; knockout gene; methylation pattern; mitochondrial metabolism; mouse model; novel; overexpression; pathogen; prevent; programmed cell death protein 1; programs; receptor; recruit; therapeutic target; tumor; tumor microenvironment; Acute; Affect; Antigens; Binding; Binding Sites; CD8-Positive T-Lymphocytes; CRISPR screen; CRISPR/Cas technology; Cell Differentiation process; Cell Fractionation; Cell Nucleus; Cell physiology; Cells; Cellular biology; Chromatin; Chronic; DNA Repair; DNA biosynthesis; Data; Development; Effector Cell; Enzymes; Epigenetic Process; Exhibits; Exposure to; Fumarates; Gene Expression; Genes; Genetic Transcription; Genome; Glycolysis; Goals; Histone H3; Histones; IL7R gene; Immune response; Infection; Inflammatory; Isocitrates; Knock-out; Lead; Lymphocytic choriomeningitis virus; Lysine; Malates; Malignant Neoplasms; Maps; Memory; Metabolic; Metabolic Pathway; Metabolism; Methylation; Modeling; Nuclear; Pathology; Performance; Phenotype; Play; Process; Production; Protein Methylation; Regulation; Repression; Role; Running; Signal Transduction; System; T cell regulation; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Transact; Virus Diseases; alpha ketoglutarate; base; cancer cell; chronic infection; cofactor; cytokine; cytotoxicity; enzyme activity; enzyme substrate; epigenetic regulation; epigenome; exhaust; exhaustion; experience; experimental study; fitness; histone methylation; histone modification; immune checkpoint blockade; improved; in vivo; insight; knockout gene; methylation pattern; mitochondrial metabolism; mouse model; novel; overexpression; pathogen; prevent; programmed cell death protein 1; programs; receptor; recruit; therapeutic target; tumor; tumor microenvironment

ABSTRACT/PROJECT SUMMARY My overarching goal is to understand the regulation of the metabolism-epigenetic axis in cancer and cancer associated pathologies. T cell exhaustion (Tex) is a dysfunctional state developed due to persistent antigen exposure experienced during chronic infections and in the tumor microenvironment. Besides the well characterized phenotypic differences between Tex and functional effector (Teff) cells; Tex are distinguished by the development of a unique epigenetic landscape that leads to the repression of functional genes. Concomitant with epigenetic changes Tex also exhibit metabolic alterations as glycolysis and mitochondrial metabolism are compromised early during exhaustion. The major goal of this proposal is to elucidate the mechanisms that lead to the establishment of the exhausted epigenome, I will specifically study the influence of nuclear metabolic enzymes in the process of histone methylation and gene expression. Chromatin and metabolism intersect at various levels. Firstly, metabolic products are used as substrates and cofactors by epigenetic enzymes to post- translationally modify histones (PTMs). Secondly, in recent years increasing evidence has shown the moonlighting activity of a subset of metabolic enzymes in the nucleus, where they influence histone PTMs and also engage in a variety of chromatin transactions (gene expression, DNA repair, DNA replication). Because cell differentiation engages metabolic and epigenetic programs, one important question in the development of exhaustion is whether and how these processes connect to generate the exhausted fate. I hypothesize that early in T cell exhaustion, metabolism contributes to establishment of the exhausted epigenetic landscape in two ways. In the first interaction, metabolic changes in chronically infected cells alter the pool of metabolites available for histone modification, mainly affecting histone H3 methylation. Secondly, during exhaustion, several metabolic enzymes affecting methylation — Mat2a, Idh3g, Fh1 and Mthfd1 — are recruited into the nucleus where they directly influence production of metabolites and thereby alter gene expression. To test this hypothesis, I will pursue three aims. Aim 1 is to determine whether metabolic enzymes Mat2a, Idh3, Fh1 and Mthfd1 regulate the Tex phenotype, Aim 2 is to determine how Mat2a, Idh3g, Fh1 and Mthfd1 affect chromatin during exhaustion and in Aim 3 I will investigate the metabolic landscape during exhaustion. Overall, this study will help to elucidate mechanistic insights into how during early chronic infection metabolic alterations prime the epigenetic landscape for exhaustion. Our understanding of how metabolic enzymes regulate the epigenome to influence CD8+ T cell development will help us to develop therapeutic strategies to improve exhausted cell function in cancer and chronic infection.

摘要/项目摘要 我的总体目的是了解对癌症和癌症中新陈代谢 - 测试轴的调节 相关的病理。 T细胞耗尽（TEX）是由于持续的抗原而形成的功能失调状态 在慢性感染和肿瘤微环境中经历的暴露。除了井 Tex和功能效应子（TEFF）细胞之间的表型差异表征； Tex有区别 独特的表观遗传景观的发展，导致功能基因的表达。伴随 随着糖酵解和线粒体代谢是，随着表观遗传变化的形式，Tex也会表现出代谢改变 疲惫期间早期妥协。该提案的主要目标是阐明领导的机制 为了建立疲惫的表观基因组，我将专门研究核代谢的影响 在组蛋白甲基化和基因表达的过程中酶。染色质和代谢相交 各个级别。首先，代谢产物被表观遗传酶用作底物和辅因子，以便在 - 翻译修改组蛋白（PTMS）。其次，近年来越来越多的证据表明 核中代谢酶子集的月光活性，它们会影响组蛋白PTM和 还参与多种染色质交易（基因表达，DNA修复，DNA复制）。因为细胞 分化与代谢和表观遗传计划有关，这是发展的一个重要问题 精疲力尽是这些过程是否以及如何连接以产生疲惫的命运。我假设这很早就 在T细胞耗尽中，新陈代谢有助于通过两种方式建立疲惫的表观遗传景观。 在第一次相互作用中，长期感染细胞的代谢变化改变了可用于 Hisstone修改，主要影响Hisstone H3甲基化。其次，在疲惫期间，几种代谢 影响甲基化的酶 - MAT2A，IDH3G，FH1和MTHFD1 - 被募集到核中 直接影响代谢产物的产生，从而改变基因表达。为了检验这个假设，我将 追求三个目标。 AIM 1是确定代谢酶Mat2a，IDH3，FH1和MTHFD1是否调节 Tex表型，AIM 2是确定MAT2A，IDH3G，FH1和MTHFD1在耗尽过程中如何影响染色质 在AIM 3中，我将在耗尽期间调查代谢景观。总体而言，这项研究将有助于阐明 关于早期慢性感染代谢改变如何素养表观遗传景观的机械洞察力 精疲力尽。我们对代谢酶如何调节表观基因组如何影响CD8+ T细胞的理解 发展将帮助我们制定理论策略，以改善癌症中耗尽的细胞功能和 慢性感染。