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DOI
10.1038/s41588-021-00926-8
PubMed
34594038
PubMed Central
PMC8570135
Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response
Kevin C Johnson, Kevin J Anderson, Elise T Courtois, Amit D Gujar, Floris P Barthel, Frederick S Varn, Diane Luo, Martine Seignon, Eunhee Yi, Hoon Kim, Marcos RH Estecio, Dacheng Zhao, Ming Tang, Nicholas E Navin, Rahul Maurya, Chew Yee Ngan, Niels Verburg, Philip C de Witt Hamer, Ketan Bulsara, Michael L Samuels, Sunit Das, Paul Robson, Roel GW Verhaak 2021. Nat Genet. 2021 Oct;53(10):1456-1468

Background

Methods

Results

Conclusion

Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response.

Johnson KC(#)(1), Anderson KJ(#)(2), Courtois ET(2), Gujar AD(2), Barthel FP(2)(3), Varn FS(2), Luo D(2), Seignon M(2), Yi E(2), Kim H(2), Estecio MRH(4), Zhao D(2), Tang M(5), Navin NE(6), Maurya R(2), Ngan CY(2), Verburg N(7), de Witt Hamer PC(7), Bulsara K(8), Samuels ML(2), Das S(9)(10)(11), Robson P(2)(12), Verhaak RGW(13).

Author information: (1)The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. kevin.c.johnson@jax.org. (2)The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. (3)Department of Pathology, Brain Tumor Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. (4)Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5)Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (6)Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7)Department of Neurosurgery, Brain Tumor Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. (8)Division of Neurosurgery, The University of Connecticut Health Center, Farmington, CT, USA. (9)Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for SickKids, University of Toronto, Toronto, Ontario, Canada. (10)Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. (11)Division of Neurosurgery, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada. (12)Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA. (13)The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. roel.verhaak@jax.org. (#)Contributed equally

Comment in Nat Genet. 2021 Oct;53(10):1403-1404. doi: 10.1038/s41588-021-00932-w.

Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell transcriptomes and bulk multi-omic profiles across 11 adult IDH mutant or IDH wild-type gliomas to delineate sources of intratumoral heterogeneity. We showed that local DNA methylation disorder is associated with cell-cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption and is altered during the environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identified an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.