Using Single-Cell Approaches to Determine the Mode of Disease Progression in IDH-Mutant Non-Codeleted Glioma
Abstract
To study tumor evolution in glioma, we performed single-cell DNA methylation, single-cell transcriptomic, single-cell chromatin accessibility, bulk whole-genome sequencing and bulk DNA methylation profiling of glioma tumors, from single time-points as well as time-separated. Using these datasets, we studied the dynamics and diversity of epigenetic signatures among mixed cell populations, and how epigenetic and transcriptomic cell states compare. 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. 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. Future analyses are using chromatin accessibility and transcriptome profiles from the same cells and from tumors across multiple timepoints to determine how epigenomic and transcriptomic cell states evolve under the influence of treatment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2021
- Accession Number
- AD1200917
Entities
People
- Roeland Gw Verhaak
Organizations
- Jackson Laboratory