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.

Type: Other
Archiver: EGA European Genome-Phenome Archive

5 Datasets 1 Publication

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	This dataset includes 914 BAM files from 6 IDH-mutant, 5 IDH-wild-type glioma patient samples of unmatched initial and recurrent timepoints profiled using single-cell reduced-representation bisulfite sequencing.	Illumina HiSeq 4000	914
EGAD00001007770	This dataset includes 60 BAM files from HF2354, HF3016 glioblastoma cell lines subjected to continuous stress (hypoxia, 3-day and 9-day), stress followed by recovery (irradiation, 4-day stress exposure and 5-day recovery), and no stress/normoxia controls and profiled using reduced-representation bisulfite sequencing.	Illumina NovaSeq 6000	60
EGAD00001007771	This dataset includes 22 BAM files for tumor tissue and matched normal blood from 6 IDH-mutant, 5 IDH-wild-type glioma patient samples of unmatched initial and recurrent timepoints profiled using whole genome sequencing.	Illumina NovaSeq 6000	22
EGAD00001007772	This dataset includes paired-end fastq files from 6 IDH-mutant, 5 IDH-wild-type glioma patient samples of unmatched initial and recurrent timepoints profiled using single-cell RNA sequencing.	Illumina HiSeq 4000 Illumina NovaSeq 6000	11
EGAD00010002157	This dataset includes IDAT files from 6 IDH-mutant, 5 IDH-wild-type glioma patient samples of unmatched initial and recurrent timepoints profiled using the Illumina Infinium MethylationEPIC Array.	Illumina Infinium MethylationEPIC BeadChip	11

Publications	Citations
Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response. Johnson KC, Anderson KJ, Courtois ET, Gujar AD, Barthel FP, Varn FS, Luo D, Seignon M, Yi E, Kim H, Estecio MRH, Zhao D, Tang M, Navin NE, Maurya R, Ngan CY, Verburg N, de Witt Hamer PC, Bulsara K, Samuels ML, Das S, Robson P, Verhaak RGW. Nat Genet 53: 2021 1456-1468	43