H3F3A K27M Mutations Drives a Repressive Transcriptome by Modulating Chromatin Accessibility, Independent of H3K27me3 in Diffuse Midline Glioma.
Suraj BhattaraiFaruck L HakkimCharles A DayFlorina GrigoreAlyssa LangfaldIgor EntinEdward H HinchcliffeJames P RobinsonPublished in: bioRxiv : the preprint server for biology (2024)
This study is the first to demonstrate that H3F3A K27M mutations drive a repressive transcriptome by modulating chromatin accessibility independently of H3K27 trimethylation in Diffuse Midline Glioma (DMG). By isolating the effects of H3.3 K27me3 loss from those of the K27M mutation, we identified common and unique genes and pathways affected by each. We found that genes uniquely deregulated by K27M showed increased chromatin accessibility and upregulated gene expression, unlike other gene subsets affected by PRC2 knockout. Importantly, we determined the PRC2-independent function of K27M is also essential for tumorigenesis, as xenografts of H3.3 K27M/PRC2 WT cell lines formed tumors, while H3.3WT/PRC2 WT and K27M/PRC2 knockout cells did not. This research builds upon and advances prior studies, such as those identifying EZH2 as a therapeutic target in H3.3K27M DMGs, by revealing critical new pathways for gliomagenesis. The translational significance lies in identifying novel therapeutic targets against this aggressive pediatric cancer.
Keyphrases
- genome wide
- gene expression
- dna methylation
- copy number
- dna damage
- transcription factor
- genome wide identification
- induced apoptosis
- signaling pathway
- low grade
- papillary thyroid
- squamous cell carcinoma
- single cell
- rna seq
- long non coding rna
- high grade
- oxidative stress
- squamous cell
- cell death
- long noncoding rna
- lymph node metastasis