Metabolic Regulation of the Epigenetic Landscape in T cell Exhaustion

摘要/项目摘要 我的首要目标是了解新陈代谢--表观遗传轴在癌症和癌症中的调节。 相关的病理学。T细胞衰竭(TeX)是由于持久性抗原引起的一种功能障碍状态 在慢性感染和肿瘤微环境中所经历的暴露。除了那口井 表征了TeX和功能效应器(Tef)细胞之间的表型差异；TeX的区别在于 一种独特的表观遗传格局的发展，导致功能基因的抑制。伴随而来的 随着表观遗传的变化，Tex也表现出糖酵解和线粒体代谢的代谢变化 在精疲力竭的时候很早就妥协了。这项提议的主要目标是阐明导致 为了建立耗竭的表观基因组，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。染色质和新陈代谢在 不同的层次。首先，代谢产物作为底物和辅因子，由表观遗传酶进行后处理。 翻译修饰组蛋白(PTM)。其次，近年来越来越多的证据表明， 核内代谢酶亚群的兼职活动，在那里它们影响组蛋白PTM和 还从事各种染色质交易(基因表达、DNA修复、DNA复制)。因为细胞 分化涉及新陈代谢和表观遗传程序，这是肿瘤发育过程中的一个重要问题 精疲力竭是指这些过程是否以及如何连接起来，从而产生精疲力竭的命运。我假设早些时候 在T细胞耗竭过程中，新陈代谢通过两种方式有助于建立耗竭的表观遗传格局。 在第一次相互作用中，慢性感染细胞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。其次，在精疲力竭时，几种新陈代谢 影响甲基化的酶-MAT2A、Idh3g、Fh1和Mthfd1-被招募到细胞核，在那里它们 直接影响代谢产物的产生，从而改变基因表达。为了检验这一假设，我将 追求三个目标。目的1是确定代谢酶MAT2A、Idh3、Fh1和Mthfd1是否调节 Tex表型，目标2是确定MAT2A、Idh3g、Fh1和Mthfd1在力竭过程中如何影响染色质 在目标3中，我将调查精疲力竭时的代谢情况。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启动表观遗传格局的机械论见解 精疲力竭。我们对代谢酶调节表观基因组影响CD8+T细胞的理解 发展将有助于我们开发治疗策略，以改善癌症和癌症中耗尽的细胞功能 慢性感染。

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.