Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response.
JGM, Brain Neoplasms, Cell Plasticity, Clonal Evolution, DNA Copy Number Variations, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Genetic Heterogeneity, Genome, Human, Glioma, Humans, Mutation, Phylogeny, Promoter Regions, Genetic, Single-Cell Analysis, Stress, Physiological, Tumor Microenvironment
Nat Genet 2021 Oct; 53(10):1456-1468
CA237208, NS114873, CA034196
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.
Johnson, Kevin C; Anderson, Kevin J; Courtois, Elise T; Gujar, Amit D; Barthel, Floris P; Varn, Frederick S; Luo, Diane; Seignon, Martine; Yi, Eunhee; Kim, Hoon; Estecio, Marcos R H; Zhao, Dacheng; Tang, Ming; Navin, Nicholas E; Maurya, Rahul; Ngan, Chew Yee; Verburg, Niels; de Witt Hamer, Philip C; Bulsara, Ketan; Samuels, Michael; Das, Sunit; Robson, Paul; and Verhaak, Roel G W, "Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response." (2021). Faculty Research 2021. 232.