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: 10383145
• 负责人: Paula Andrea Agudelo Garcia
• 金额: --
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383145
• 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

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/项目总结 我的首要目标是了解癌症和癌症中代谢-表观遗传轴的调节 相关的病理。T细胞耗竭（Tex）是由于持续抗原 在慢性感染和肿瘤微环境中经历的暴露。除了井 Tex和功能效应细胞（Teff）之间的特征性表型差异; Tex的区别在于 一个独特的表观遗传景观的发展，导致功能基因的抑制。伴随 随着表观遗传变化，Tex也表现出代谢改变，如糖酵解和线粒体代谢。 在疲惫的早期就被破坏了本提案的主要目标是阐明导致 为了建立枯竭的表观基因组，我将专门研究核代谢的影响， 组蛋白甲基化和基因表达过程中的酶。染色质和新陈代谢相交于 不同的层次。首先，代谢产物被表观遗传酶用作底物和辅因子，以进行后处理。 修饰组蛋白（PTM）。近年来，越来越多的证据表明， 细胞核中代谢酶的一个子集的兼职活动，在那里它们影响组蛋白PTM， 还参与各种染色质交易（基因表达，DNA修复，DNA复制）。因为蜂窝小区 分化涉及代谢和表观遗传程序，这是发育过程中的一个重要问题。 衰竭是指这些过程是否以及如何连接，从而产生衰竭的命运。我假设， 在T细胞耗竭中，代谢以两种方式促成耗竭的表观遗传景观的建立。 在第一种相互作用中，慢性感染细胞中的代谢变化改变了可用于 组蛋白修饰，主要影响组蛋白H3甲基化。第二，在疲惫的时候， 影响甲基化的酶--Mat 2a、Idh 3g、Fh 1和Mthfd 1--被募集到细胞核中， 直接影响代谢产物的产生，从而改变基因表达。为了验证这个假设，我将 追求三个目标。目的1是确定代谢酶Mat 2a、Idh 3、Fh 1和Mthfd 1是否调节细胞的生长。 Tex表型，目的2是确定Mat 2a、Idh 3g、Fh 1和Mthfd 1在耗竭过程中如何影响染色质 在目标3中，我将研究疲劳时的代谢状况。总的来说，这项研究将有助于阐明 对慢性感染早期代谢改变如何引发表观遗传景观的机械见解 因为疲劳。我们对代谢酶如何调节表观基因组以影响CD 8 + T细胞的理解 开发将帮助我们开发治疗策略，以改善癌症中疲惫的细胞功能， 慢性感染