Metabolic Regulation of the Epigenetic Landscape in T cell Exhaustion

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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.