macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma.
Nikolic A., Maule F., Bobyn A., Ellestad K., Paik S., Marhon SA., Mehdipour P., Lun X., Chen H-M., Mallard C., Hay AJ., Johnston MJ., Gafuik CJ., Zemp FJ., Shen Y., Ninkovic N., Osz K., Labit E., Berger ND., Brownsey DK., Kelly JJ., Biernaskie J., Dirks PB., Derksen DJ., Jones SJM., Senger DL., Chan JA., Mahoney DJ., De Carvalho DD., Gallo M.
Self-renewal is a crucial property of glioblastoma cells that is enabled by the choreographed functions of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover an epigenetic axis of self-renewal mediated by the histone variant macroH2A2. With omics and functional assays deploying patient-derived in vitro and in vivo models, we show that macroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. macroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. Consistent with these results, our analyses of clinical cohorts indicate that high transcriptional levels of this histone variant are associated with better prognosis of high-grade glioma patients. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest additional treatment approaches for glioblastoma patients.