Title

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

Document Type

Article

Publication Date

10-1-2021

Publication Title

Nature genetics

Keywords

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

JAX Source

Nat Genet 2021 Oct; 53(10):1456-1468

Volume

53

Issue

10

First Page

1456

Last Page

1468

ISSN

1546-1718

PMID

34594038

DOI

https://doi.org/10.1038/s41588-021-00926-8

Grant

CA237208, NS114873, CA034196

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.

Comments

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.

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