Some 80% of diffuse midline gliomas (DMGs)—a family of swiftly lethal pediatric brain cancers—are driven by the H3K27M histone mutation. How precisely this drives cancer is not entirely clear. Components of chromosomes, histones package and organize DNA in the nucleus and chemical, or “epigenetic”, modifications made to them help regulate gene expression. One effect of the H3K27M mutation is the global loss of H3K27 trimethylation, which is an epigenetic modification associated with gene silencing. Researchers led by Ludwig Oxford’s Yang Shi and Alan Jiao used a genetic screen in C. elegans to identify ways to potentially reverse the abrogation of H3K27 trimethylation. They reported in a November PNAS paper 20 suppressor mutations that to varying degrees reverse that effect. While 19 of them mapped to the H3K27M mutant itself, one suppressive mutation, surprisingly, was to the E2 ubiquitin-conjugating enzyme ubc-20. Loss of ubc-20 activity restored H3K27Me3 to nearly half that observed in normal cells. The researchers show that ubc-20 is responsible for generating diubiquitinated histone H2B, a previously unstudied modification. This suggests the effects of H3K27M may be modulated by H2B diubiquitination and that aberrations in such modifications might regulate the oncogenic effects of histones, though ubc-20 may have other substrates whose modifications could also impact K27M function. The discovery opens a door to new strategies for treating H3K27M-driven DMGs.
An E2 ubiquitin-conjugating enzyme links diubiquitinated H2B to H3K27M oncohistone function
PNAS, 2024 November 19