Characterizing epigenetic intratumoral heterogeneity in IDH-mutant glioma using single-cell reduced representation bisulfite sequencing

Identification: Johnson, Kevin C.


Description

Characterizing epigenetic intratumoral heterogeneity in IDH-mutant glioma using single-cell reduced representation bisulfite sequencing

Kevin C Johnson1*, Mohan Bolisetty1, Ming Tang2, Marcos RH Est├ęcio3, Paul Robson1, Roel GW Verhaak1

1The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; 2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Epigenetics and Molecular Carcinogenesis, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

*Corresponding author

Determining the cellular mechanisms that govern glioma heterogeneity can impact the development of novel therapies, protect patients from side effects of unnecessary treatment, and prevent glioma recurrence. Emerging evidence suggests that molecular subtypes in glioma, based on genotype (e.g., IDH1 mutations) and DNA methylation profiles (glioma CpG Island Methylator Phenotype, G-CIMP), can provide clinically relevant tumor classifications. However, traditional bulk sampling of gliomas to profile molecular features fails to adequately capture the full complement of epigenomic heterogeneity in tumor cells, and may mask deadly features present in less abundant glioma cells. Therefore, single-cell epigenomic resolution is needed to characterize the epigenetic intratumoral heterogeneity in glioma, detect rare cell populations, and to identify therapeutic vulnerabilities to prevent recurrence. To optimize our investigation of the glioma epigenome we initially performed single-cell Reduced Representation Bisulfite Sequening (scRRBS) on 134 patient-derived glioma sphere-forming cells. Our results highlight that the scRRBS assay is able to cover an average of 150,000 DNA methylation sites and is highly reproducible across biological replicates. Analyses of single-cell DNA methylation profiles from primary IDH-mutant tumors are now underway. Together, our study aims to generate a cellular hierarchy of primary IDH-mutant gliomas shaped by epigenetic programs that drive tumor growth.

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Credits: None available.

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