# Epigenetic Induction of Gliomagenesis in Neural Progenitor Cells

> **NIH NIH F32** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $65,310

## Abstract

Project Summary
Gliomas are incurable brain tumors that can be classified into distinct molecular subtypes. One glioma subtype
is characterized by isocitrate dehydrogenase 1 (IDH1) gain-of-function mutations and a CpG hypermethylator
profile (G-CIMP) directly caused by mutant IDH1 function. CpG methylation in a gene or promoter suppresses
gene expression, hence mutant IDH1 was thought to exert its oncogenic role by silencing tumor suppressor
genes. The Bernstein laboratory introduced new data that added CCCTC-binding factor (CTCF) binding sites
(insulators) to the list of methylated sites in IDH mutant glioma. CTCF partitions the genome into topologically
associated domains (TADs): insulated neighborhoods that allow gene-enhancer interactions inside the same
TAD while restricting outside interactions. Insulator methylation disrupts TADs and allows aberrant gene-
enhancer interactions to take place, driving gene expression. A recurrent insulator loss was identified in the
PDGFRA oncogene locus in IDH mutant glioma, allowing for a distal enhancer to upregulate PDGFRA, driving
proliferation in established glioma. It is not known whether this epigenetic mechanism can transform neural
progenitor cells (NPCs): the likely glioma cell of origin.
Hypothesis: Disruption of the PDGFRA insulator in NPCs is sufficient to drive hyper-proliferation and
gliomagenesis.
Aim 1: Determine the mechanistic effects of insulator dysfunction on PDGFRA expression in NPCs.
Aim 2: Assess the consequence of insulator dysfunction on NPCs in vivo.
The proposed studies will explore novel mechanisms by which glioma develops from NPCs and would be the
first demonstration of an epigenetic mechanism of tumor initiation. Further, the proposed studies can suggest
that treatment with hypomethylating agents (5-azacytidine) may be beneficial for mutant IDH1 glioma.
Additionally, the proposed studies will establish a faithful mouse model of glioma allowing for preclinical testing
of therapeutics in vivo. Mutations in IDH1, similar to those observed in glioma, can be observed in other tumors
suggesting that the findings from the study can be applicable to other tumor types.
Training plan and environment: The proposed research will take place in the Bernstein lab at Massachusetts
General Hospital (MGH) that has spearheaded major advances in epigenomics research. All the necessary
equipment is available either in the Bernstein lab or at research cores located in MGH. With affiliations at
Harvard Medical School, the Broad Institute, and MGH, I will have ample opportunities to attend seminars and
workshops that will help me shape my career as I progress towards an independent research position. As part
of my training plan, I will also mentor students in the lab, present my research both locally and nationally, and
apply to transition awards allowing me to pursue an independent career in cancer research.

## Key facts

- **NIH application ID:** 9852881
- **Project number:** 5F32CA236432-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Gilbert J Rahme
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852881

## Citation

> US National Institutes of Health, RePORTER application 9852881, Epigenetic Induction of Gliomagenesis in Neural Progenitor Cells (5F32CA236432-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852881. Licensed CC0.

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