Nature Communications (May 2023)
macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma
- Ana Nikolic,
- Francesca Maule,
- Anna Bobyn,
- Katrina Ellestad,
- Seungil Paik,
- Sajid A. Marhon,
- Parinaz Mehdipour,
- Xueqing Lun,
- Huey-Miin Chen,
- Claire Mallard,
- Alexander J. Hay,
- Michael J. Johnston,
- Christopher J. Gafuik,
- Franz J. Zemp,
- Yaoqing Shen,
- Nicoletta Ninkovic,
- Katalin Osz,
- Elodie Labit,
- N. Daniel Berger,
- Duncan K. Brownsey,
- John J. Kelly,
- Jeff Biernaskie,
- Peter B. Dirks,
- Darren J. Derksen,
- Steven J. M. Jones,
- Donna L. Senger,
- Jennifer A. Chan,
- Douglas J. Mahoney,
- Daniel D. De Carvalho,
- Marco Gallo
Affiliations
- Ana Nikolic
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Francesca Maule
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Anna Bobyn
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Katrina Ellestad
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Seungil Paik
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Sajid A. Marhon
- Princess Margaret Cancer Centre
- Parinaz Mehdipour
- Princess Margaret Cancer Centre
- Xueqing Lun
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Huey-Miin Chen
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Claire Mallard
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Alexander J. Hay
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Michael J. Johnston
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Christopher J. Gafuik
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Franz J. Zemp
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Yaoqing Shen
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer
- Nicoletta Ninkovic
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Katalin Osz
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Elodie Labit
- Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary
- N. Daniel Berger
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Duncan K. Brownsey
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- John J. Kelly
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Jeff Biernaskie
- Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary
- Peter B. Dirks
- Program in Developmental and Stem Cell Biology, Hospital for Sick Children
- Darren J. Derksen
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Steven J. M. Jones
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer
- Donna L. Senger
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Jennifer A. Chan
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Douglas J. Mahoney
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- Daniel D. De Carvalho
- Princess Margaret Cancer Centre
- Marco Gallo
- Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary
- DOI
- https://doi.org/10.1038/s41467-023-38919-2
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 22
Abstract
Abstract 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.