macroH2A2 shapes chromatin accessibility at enhancer elements in glioblastoma to modulate a targetable self-renewal epigenetic network
Self-renewal is a crucial property of glioblastoma cells and is enabled by the choreographed function of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could represent an important step toward developing new and effective treatments for this universally lethal cancer. Here we uncover a targetable epigenetic axis of self-renewal mediated by the histone variant macroH2A2. Using patient-derived in vitro and in vivo models, we show that macroH2A2 has a direct role in shaping chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. Pharmaceutical inhibition of the chromatin remodeler Menin increased macroH2A2 levels and repressed self-renewal. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest new treatment approaches for glioblastoma patients.