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

Kevin C Johnson, The Jackson Laboratory
Kevin J Anderson, The Jackson Laboratory
Elise T Courtois, The Jackson Laboratory
Amit D Gujar, The Jackson Laboratory
Floris P Barthel, The Jackson Laboratory
Frederick S Varn, The Jackson Laboratory
Diane Luo, The Jackson Laboratory
Martine Seignon, The Jackson Laboratory
Eunhee Yi, The Jackson Laboratory
Hoon Kim, The Jackson Laboratory
Marcos R H Estecio
Dacheng Zhao, The Jackson Laboratory
Ming Tang
Nicholas E Navin
Rahul Maurya, The Jackson Laboratory
Chew Yee Ngan, The Jackson Laboratory
Niels Verburg
Philip C de Witt Hamer
Ketan Bulsara
Michael Samuels, The Jackson Laboratory
Sunit Das
Paul Robson, The Jackson Laboratory
Roel G W Verhaak, The Jackson Laboratory


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.