Evidence map›Paper›PMID 40287708›Full record

ArticleEpigenetics & chromatin2025

H3F3A K27M mutations drive a repressive transcriptome by modulating chromatin accessibility independent of H3K27me3 in Diffuse Midline Glioma.

Suraj Bhattarai, Faruck L Hakkim, Charles A Day, Florina Grigore, Alyssa Langfald, Igor Entin, Edward H Hinchcliffe, James P Robinson

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Epigenetics & chromatin, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Total Synthesis and Anticancer Study of (+)-Verticillin A.Journal of the American Chemical Society · 2025
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

8 authors.

Suraj Bhattarai *The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA.
Faruck L Hakkim *The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA.
Charles A Day *The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA.
Florina GrigoreDepartment of Neurosurgery, University of Minnesota, Minneapolis, MN, USA.
Alyssa LangfaldThe Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA.
Igor EntinThe Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA.
Edward H HinchcliffeThe Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA.
James P RobinsonThe Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN, 55912, USA. Robinsoj@umn.edu.

Funding

National Institute of Health T32CA217836U.S. Department of Defense W81XWH-21-1-0546US Department of Defense W81XWH2211045-P00001
6 · The paper itself

Abstract

backgroundHeterozygous histone H3.3K27M mutation is a primary oncogenic driver of Diffuse Midline Glioma (DMG). H3.3K27M inhibits the Polycomb Repressive Complex 2 (PRC2) methyltransferase activity, leading to global reduction and redistribution of the repressive H3 lysine 27 tri-methylation (H3K27me3). This epigenomic rewiring is thought to promote gliomagenesis, but the precise role of K27M in gene regulation and tumorigenesis remains incompletely understood.

resultsWe established isogenic DMG patient-derived cell lines using CRISPR-Cas9 editing to create H3.3 wild-type (WT), H3.3K27M, and combinations with EZH2 and EZH1 co-deletion, thereby eliminating PRC2 function and H3K27me3. RNA-seq and ATAC-seq analysis revealed that K27M exerts a novel epigenetic effect independent of PRC2 inhibition. While PRC2 loss led to widespread gene induction including HOX gene clusters, and activation of biological pathways, K27M induced a balanced gene deregulation with an overall repressive effect on pathway activity. Genes uniquely affected by K27M, independent of PRC2 loss, showed concordant changes in chromatin accessibility, with upregulated genes becoming more accessible. Importantly, xenografts of H3.3K27M/EZH1/2 WT cells formed tumors, whereas /EZH1/2 knockout cells did not, demonstrating a PRC2-independent role of K27M in tumorigenesis.

conclusionOur findings reveal that the H3.3K27M mutation alters chromatin accessibility and uniquely deregulates gene expression independent of H3K27 methylation loss. These PRC2-independent functions of K27M contribute to changes in biological pathway activity and are necessary for tumor development, highlighting novel mechanisms of K27M-driven gliomagenesis.

Indexed as

Brain NeoplasmsChromatinGliomaHistonesTranscriptomeAnimalsCell Line, TumorEnhancer of Zeste Homolog 2 ProteinGene Expression Regulation, NeoplasticHumansMethylationMiceMutationPolycomb Repressive Complex 2ChromatinEnhancer of Zeste Homolog 2 ProteinEZH2 protein, humanHistonesPolycomb Repressive Complex 2DMGHistonePRC2

Identifiers

PMID40287708
PMCPMC12032731

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.