Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas
Menée sur des échantillons tumoraux prélevés sur plusieurs cohortes de patients pédiatriques atteints d'un gliome de haut grade présentant la mutation K27M du gène de l'histone H3.3, cette étude met en évidence des mécanismes de nature épigénétique activant l'expression de gènes impliqués dans ce sous-type de gliome
Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in <50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs. "Dominant-negative effect of K27M mutant H3.3 results in global loss of H3K27me3 "Loss of H3K27me3 is caused by aberrant recruitment of PRC2 to K27M mutant H3.3 "Genome-wide analysis of H3K27me3 and DNA methylation in primary pHGGs "H3K27me3 loss and DNA hypomethylation lead to gene activation in K27M mutant pHGGs
Cancer Cell 2013