@article{5af11fc6e39d421a9c07fe8668c20af2,
title = "Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response",
abstract = "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.",
author = "Johnson, {Kevin C.} and Anderson, {Kevin J.} and Courtois, {Elise T.} and Gujar, {Amit D.} and Barthel, {Floris P.} and Varn, {Frederick S.} and Diane Luo and Martine Seignon and Eunhee Yi and Hoon Kim and Estecio, {Marcos R. H.} and Dacheng Zhao and Ming Tang and Navin, {Nicholas E.} and Rahul Maurya and Ngan, {Chew Yee} and Niels Verburg and {de Witt Hamer}, {Philip C.} and Ketan Bulsara and Samuels, {Michael L.} and Sunit Das and Paul Robson and Verhaak, {Roel G. W.}",
note = "Funding Information: We thank the patients and their families for their generous donation to biomedical research. We also thank the staff in the following groups at The Jackson Laboratory for Genomic Medicine: single-cell biology laboratory; flow cytometry core; and genomic technology core for assistance in data generation. We thank M. Wimsatt and Z. Reifsnyder for assistance in graphic design. We thank the University of Texas MD Anderson Epigenomics Profiling Core for their assistance in helping troubleshoot the scRRBS protocol. We thank the Henry Ford Hospital for sharing the patient-derived glioma spheroids. This work was supported by National Institutes of Health grants R01 CA237208 and R21 NS114873, Cancer Center Support Grant P30 CA034196, Department of Defense grant no. W81XWH1910246 (to R.G.W.V) and Jackson Laboratory Cancer Center Fast Forward funds. F.S.V. is supported by a postdoctoral fellowship from The Jane Coffin Childs Memorial Fund for Medical Research. F.P.B. is supported by the National Cancer Institute (grant no. K99 CA226387). E.Y. is a fellow of the American Brain Tumor Association. K.C.J. is the recipient of an American Cancer Society Fellowship (no. 130984-PF-17-141-01-DMC). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = oct,
day = "1",
doi = "https://doi.org/10.1038/s41588-021-00926-8",
language = "English",
volume = "53",
pages = "1456--1468",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "10",
}