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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
Nature communications, 05/2023, Letnik: 14, Številka: 1Journal Article
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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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