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

ABSTRACT:

Background

Heterozygous 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.

Results

We 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 independe

SUBMITTER: Bhattarai S 

PROVIDER: S-EPMC12032731 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature