DNA methylation alterations facilitate cellular stress response and intratumoral heterogeneity.
Major Finding: DNA methylation alterations facilitate cellular stress response and intratumoral heterogeneity.
Concept: Single-cell profiles determined epigenetic heterogeneity and its contribution to tumor evolution.
Impact: This study highlights the role of epigenetic heterogeneity in the adaptive stress response and therapeutic outcomes.
Diffuse gliomas are the most common brain tumor in adults and continue to be incurable. This is largely due to these tumors exhibiting inter- and intratumoral heterogeneity, which contributes to therapeutic resistance, and is further complicated by cellular plasticity which allows cells to transiently move between states in response to different stimuli. This process has been shown to controlled, in part, through epigenetic modifications, including DNA methylation (DNAme). However, the specific epigenetic mechanisms that regulate this cellular plasticity and tumor heterogeneity in glioma remain poorly understood. Johnson, Anderson, and colleagues analyzed single-cell DNA methylomics, single-cell transcriptomics, and single-cell copy number profiles along with bulk genetic profiles from 11 glioma patient samples to dissect the heterogeneous nature of tumor cell populations. Increased disorder of DNA methylation was associated with epigenetic heterogeneity, with higher levels of disorder supporting epigenetic remodeling. This phenotype was observed at regions that are critical for gene regulation, and the perturbation of epigenetic control by DNAme disorder promoted the adoption of epigenetic states that allowed tumor cells to respond to stress stimuli including hypoxia and therapeutics. Conversely, environmental stress, through either hypoxia or radiation-induced DNAme disorder, as well as genetic stimuli such as somatic copy number alterations and aneuploidy-related replication stress also shifted the cellular state of glioma cells. Furthermore, DNA methylation changes that supported these shifts and response to stress were recurrently selected, and enhancement of DNA methylation disorder was associated with accelerated disease progression, with more aggressive tumors exhibiting increased local DNA methylation disorder. This study was able to define epigenetic states that contribute to glioma evolution as well as provide insight into the source of intratumoral heterogeneity that fuels this disease.
Johnson KC, Anderson KJ, Courtois ET, Gujar AD, Barthel FP, Varn FS, et al. Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response. Nat Genet 2021;53:1456–68.
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