Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas

Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

“…The same H3F3A knockdown did not alter survival time of an H3WT paediatric midline HGG. A second study utilized the CRISPR/Cas‐9 methodology in H3.3K27M DIPG xenografts to generate clones completely lacking the H3K27M mutation and compared tumourigenicity of these clones to both an unedited clone and the parental PDX . Here, clones lacking the H3K27M mutation were not able to generate tumours, while both the parental and unedited clones were.…”

“…DNA methylation can easily separate H3K27M and H3G34R/V histone mutant HGGs from each other and from other HGG subtypes, and the DNA methylation classifier (http://www.molecularneuropathology.org) is widely used by the scientific and clinical communities to classify brain tumours . An H3K27M‐driven increase in H3K27ac has been reported by multiple groups ; however, antibody specificity and ChIP‐seq normalization issues often complicate assessment of changes in levels of histone modifications. Mass spectroscopy revealed that H3K27M leads to increased H4 tail acetylation, loss of H3K27me1 and me2 in addition to H3K27me3 and gain of H3K36me2; however, not all of these epigenetic changes have been reported in all mass spec studies, which could reflect differences in models .…”

“…The H3K27M‐dependent increase in H3K27ac has been shown to reflect a genome wide increase, including both regions that show H3K27ac deposition in H3WT cells as well as interstitial gain . While these gains are modest at most loci, they may still have biological relevance.…”

“…While these gains are modest at most loci, they may still have biological relevance. Increased H3K27ac over regions containing endogenous retroviral elements (ERVs) have been shown to correlate with an increase in their transcription . Since expression of ERVs can induce an innate immune response, it was hypothesized that this increase could represent an H3K27M‐dependent vulnerability.…”

“…The potential impact of the H3K27M‐dependent gain of H3K27ac on the enhancer landscape in DIPGs has also been a topic of inquiry. While deletion of H3K27M in DIPGs has indicated that the size or number of super enhancers (SEs) in DIPGs is not H3K27M dependent , conditional expression of H3.1K27M vs . H3.3K27M in eOPCs produced different patterns of H3K27ac deposition .…”