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

Single-cell DNA methylation and transcriptomic glioma analyses link local DNA methylation disorder and cellular plasticity. Increases in disorder are associated with stress and disease progression, suggesting a role in shaping the therapeutic response. 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.

Automated summary

Single-cell DNA methylation and transcriptomic glioma analyses reveal the association between local DNA methylation disorder and cellular plasticity, with implications for disease progression and therapeutic response shaping. Glioma cells exhibit increased DNA methylation disorder under environmental stress, highlighting an epigenetically facilitated adaptive stress response process.