# Perturbation of Polycomb-mediated gene repression by histone H3 mutations.

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $50,520

## Abstract

Project Summary: Perturbation of Polycomb-mediated gene repression by histone H3 mutations
Recurrent missense mutations in genes encoding histone H3 that substitute lysine to methionine (H3 “K-to-M”
mutations) were recently identified in diffuse intrinsic pontine glioma (H3K27M) and a subset of head and
neck squamous cell carcinomas and undifferentiated pediatric sarcomas (H3K36M) that together are
characterized by poor prognosis and have few effective treatment options. Biochemical and structural
data indicate that H3K27M and H3K36M dominantly inhibit the specific histone methyltransferases (HMTs) for
each lysine in trans. However, how these histone mutants promote malignant transformation is largely
unknown, with initial work implicating aberrant Polycomb-mediated gene repression in cells expressing either
mutation. My preliminary evidence suggests that crosstalk between histone methylation and DNA
methylation is responsible for redistribution of H3K27me3-binding Polycomb Repressive Complex 1 (PRC1) in
H3K36M mesenchymal progenitor cells that promotes a neoplastic undifferentiated state through derepression
of polycomb target genes. In Aim 1, I plan to (a) test the hypothesis that loss of the DNA methyltransferases
DNMT3a and DNMT3b recapitulates the chromatin landscape changes elicited by H3K36M, and (b) determine
if recruitment of DNMT3a/b to chromatin is impacted downstream of HMT inhibition by H3K36M. Expression of
H3K27M similarly derepresses polycomb target genes, however my preliminary data suggests that it is not
phenotypically equivalent to chemical inhibition of the H3K27 methyltransferase PRC2, possibly due to the
persistence of H3K27me3 islands at select genomic loci that have been implicated in DIPG tumor
maintenance. To better understand the formation and function of these persistent islands, in Aim 2 I seek to
(a) identify genes that maintain Polycomb-mediated repression in H3K27M cells, and (b) determine if the
genomic position of H3K27M influences where H3K27me3 islands form genome-wide. Through these studies, I
expect to gain insight into the chromatin landscape changes induced by H3 “K-to-M” mutations that perturb
Polycomb-mediated gene repression to drive oncogenesis, which will provide a basis for developing new
therapeutic strategies.

## Key facts

- **NIH application ID:** 9830023
- **Project number:** 5F30CA224971-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Daniel N Weinberg
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-01-15 → 2021-01-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830023

## Citation

> US National Institutes of Health, RePORTER application 9830023, Perturbation of Polycomb-mediated gene repression by histone H3 mutations. (5F30CA224971-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830023. Licensed CC0.

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