# Metabolic Regulation of the Epigenetic Landscape in T cell Exhaustion

> **NIH NIH F32** · OHIO STATE UNIVERSITY · 2022 · $71,733

## Abstract

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.

## Key facts

- **NIH application ID:** 10598676
- **Project number:** 7F32CA261023-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Paula Andrea Agudelo Garcia
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $71,733
- **Award type:** 7
- **Project period:** 2021-04-30 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598676

## Citation

> US National Institutes of Health, RePORTER application 10598676, Metabolic Regulation of the Epigenetic Landscape in T cell Exhaustion (7F32CA261023-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10598676. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*