# Investigation of Histone H3 Post-Translational Modifications in Pediatric Brainstem Glioma

> **NIH NIH K08** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $177,040

## Abstract

PROJECT SUMMARY / ABSTRACT
 Diffuse intrinsic pontine glioma (DIPG) is the most deadly solid tumor in children, with rapid disease
progression, poor response to therapy, and average survival less than one year from diagnosis. Epigenetic
regulation of gene expression has been implicated in a variety of human diseases, including cancer. Recently,
point mutations in histone H3 have been identified in up to 80% of DIPG, causing altered chromatin function
and extensive transcriptome reprogramming. Here, we describe a hypothesis-driven research plan to elucidate
the mechanism by which histone H3 post-translational modifications contribute to pediatric brainstem glioma
(DIPG) formation and progression. A career development plan is also described to facilitate successful
transition from a mentored investigator to an independent investigator. In support of the hypothesis that histone
modifications in H3K27M mutant pediatric brainstem glioma contribute to disease pathogenesis, we will
characterize alterations in gene expression in DIPG associated with specific histone H3 transcriptional
regulatory marks. Further, we will investigate the enzymatic mechanisms responsible for these histone
modifications, to determine if these represent rational therapeutic targets. In order to investigate the effect of
Histone H3 modifications on gene transcription in DIPG, we will perform chromatin immunoprecipitation in
association with DNA sequencing (ChIP-Seq) to characterize genomic locations of specific H3 marks, and
correlate these findings with gene expression (RNA-Seq). We will then characterize the effects of altered
expression of specific oncogenes (PDGFRA) and tumor suppressor genes (p21), and enzymes responsible for
identified H3 modifications, on DIPG tumor biology in vitro and in vivo. Human H3K27M mutant and wild type
DIPG tumor cells will be used for in vitro studies, while a mouse xenograft model of DIPG will be used for in
vivo investigations. The aims of this proposal are: 1) To determine DIPG transciptomes with respect to histone
H3 modifications; 2) To elucidate the enzymatic basis of histone H3 modifications in DIPG, and determine
whether specific enzymatic activities are actionable for treating DIPG; and 3) To validate specific oncogene
activations and tumor suppressor gene inactivations as causally associated with DIPG malignant phenotypes
The findings of this proposal will demonstrate the effect of epigenetic dysregulation on gene expression in
pediatric brainstem glioma, providing novel insight on the mechanism of DIPG tumorigenesis and a potential
for developing rational, effective treatment for children with this disease.

## Key facts

- **NIH application ID:** 10572799
- **Project number:** 7K08NS097624-05
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Amanda Muhs Saratsis
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $177,040
- **Award type:** 7
- **Project period:** 2022-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10572799

## Citation

> US National Institutes of Health, RePORTER application 10572799, Investigation of Histone H3 Post-Translational Modifications in Pediatric Brainstem Glioma (7K08NS097624-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10572799. Licensed CC0.

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