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Multimodal single-cell and bulk glioma analyses

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 show that local DNA methylation disorder associates with cell-to-cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption, and is altered in 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 identifies an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001007769 Illumina HiSeq 4000 914
EGAD00001007770 Illumina NovaSeq 6000 60
EGAD00001007771 Illumina NovaSeq 6000 22
EGAD00001007772 Illumina HiSeq 4000 Illumina NovaSeq 6000 11
EGAD00010002157 Illumina Infinium MethylationEPIC BeadChip 11
Publications Citations
Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response.
Nat Genet 53: 2021 1456-1468
87
Glioblastoma heterogeneity at single cell resolution.
Oncogene 42: 2023 2155-2165
14
Dissecting the tumor microenvironment of epigenetically driven gliomas: Opportunities for single-cell and spatial multiomics.
Neurooncol Adv 5: 2023 vdad101
0