macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma

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Nikolic, Ana | Maule, Francesca | Bobyn, Anna | Ellestad, Katrina | Paik, Seungil | Marhon, Sajid, A | Mehdipour, Parinaz | Lun, Xueqing | Chen, Huey-Miin | Mallard, Claire | Hay, Alexander, J | Johnston, Michael, J | Gafuik, Christopher, J | Zemp, Franz, J | Shen, Yaoqing | Ninkovic, Nicoletta | Osz, Katalin | Labit, Elodie | Berger, N. Daniel | Brownsey, Duncan, K | Kelly, John, J | Biernaskie, Jeff | Dirks, Peter, B | Derksen, Darren, J | Jones, Steven, J M | Senger, Donna, L | Chan, Jennifer, A | Mahoney, Douglas, J | de Carvalho, Daniel, D | Gallo, Marco

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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