# Defining mechanisms of metabolic-epigenetic crosstalk that drive glioma initiation

> **NIH NIH K99** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $124,200

## Abstract

PROJECT SUMMARY
Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system
tumors in the United States each year and are among the most lethal and treatment-resistant human cancers.
Hot-spot, mono-allelic, gain-of-function mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are
present in more than 70% of certain subtypes of gliomas, thus representing the genetic hallmark of these
malignant brain tumors. The ‘oncometabolite’ (R)-2-hydroxyglutarate [(R)-2HG], produced by IDH mutant
enzymes, modulates the activities of certain 2-oxoglutarate (2OG) dependent DNA and histone demethylases,
which subsequently promotes neural cell transformation. Accordingly, broad changes in histone and DNA
methylation are strongly associated with IDH mutations in glioma. Despite these discoveries, the precise
molecular mechanisms linking oncometabolite-dependent chromatin remodeling with gliomagenesis remain
obscure. I propose to directly address this knowledge gap and test a new conceptual model to explain
oncometabolite-driven tumorigenesis. In Aim 1, I will perform time-resolved single cell and bulk RNA-seq and
ATAC-seq analyses of the molecular and cellular changes that occur during brain tumor initiation in a novel
genetically engineered mouse (GEM) model of glioma to reveal key mechanisms of (R)-2HG dependent
malignant transformation. In Aim 2, I will conduct integrative analyses of sequencing datasets from human glioma
samples and murine glioma samples from our GEM models to discover functional targets of (R)-2HG in IDH
mutant gliomas. In Aim 3, I will leverage novel mouse brain organoid models to investigate the impact of
oncometabolite activity on neural cell specification during brain development. If successful, my work will provide
a new conceptual framework for understanding the deterministic and stochastic functions of oncometabolite
signaling to chromatin and their influence on cell fate. This advance would deepen our understanding of how
metabolic alterations signal to chromatin in cancer and other diseases. Furthermore, identifying the molecular
processes that functionally link oncometabolites with brain tumor initiation may reveal new therapeutic targets to
combat this disease.

## Key facts

- **NIH application ID:** 10817068
- **Project number:** 5K99CA277576-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Yi Xiao
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $124,200
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817068

## Citation

> US National Institutes of Health, RePORTER application 10817068, Defining mechanisms of metabolic-epigenetic crosstalk that drive glioma initiation (5K99CA277576-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10817068. Licensed CC0.

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