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Epigenetic Control of Glioma Cell States Elucidated in New Studies

NEW YORK – A pair of research papers published Thursday in Nature Genetics detail how epigenetics associates with transcriptional cell state diversity in glioma models at the single-cell level.

The work details the epigenetic mechanisms underlying tumor cell resilience and identifies some of the epigenetic regulators of cellular plasticity and environmental stress response, which could be exploited therapeutically in the future.

A study led by Dan Landau and Mario Suvà of the New York Genome Center and Harvard University, respectively, profiled thousands of individual cells from patient brain tumors. The team mapped distinct cellular states to profiles that integrated genetic mutations, gene activity, and DNA methylation — epigenetic marks that control DNA accessibility — for each cell.

The team identified four distinct cancer states, ranging from more stem cell-like to more mature. Distinct DNA methylation patterns accompanied the shift between each state. These epigenetic patterns, the authors suggested, could become therapeutic targets, aimed at slowing tumor growth by suppressing cellular state changes.

The multiomic snapshots acquired by Landau, Suvà and their colleagues over time enabled them to calculate "lineage trees" for each cell, displaying the history of these cells' states, going back to the origin of the tumor.

"What [that] allows you to do," Landau said in an interview, "is to ask a novel question in somatic evolution of primary human samples, which is what is the heritability of these cell states?"

Researchers can then use biodynamic methods to estimate the probabilities for cells to be in a given state and for transitioning from one state to another.

"We're excited to apply these kinds of perspectives," Landau said, "more broadly in cancer but also in chromosomal mosaicism, or somatic mutations that are found within normal tissue."

The group is now investigating how perturbations like therapeutic interventions affect lineage trees, in an effort to understand how gliomas respond to different treatments.

Similar to Landau and Suvà's study, an international team of researchers led by Roel Verhaak and Kevin Johnson, of the Jackson Laboratory for Genomic Medicine, illustrated how errors in replicating DNA methylation patterns — called DNA methylation disorder — help glioma cells overcome cell stress, increase cellular plasticity, and become more resistant to treatment.

Integrating single-cell data from 914 methylomes, 55,284 transcriptomes, and bulk multiomic profiles of 11 adult gliomas of the IDH-mutant and IDH-wild type subtypes, the team found that diverse DNA methylation patterns led to multiple cellular states, each of which conferred its own relative fitness advantages in the nutrient-restricted tumor environment. The researchers suggested that together, these heterogeneous states contribute to disease progression.

"We used integrative single-cell genomic analyses to identify epigenetic regulators of glioma cell state diversity and adaptation to environmental stressors such as therapy," Johnson explained via email.

In their study, they observed epigenetic diversity arising from random errors in the cellular machinery responsible for replicating DNA methylation during cell division, which was exacerbated by environmental stimuli, such as hypoxia and irradiation.

Hypoxia is a common feature of IDH-wild type gliomas, while IDH-mutant cells produce an oncometabolite called 2-hydroxyglutarate that further interferes with DNA methylation.

Other methylation-altering stimuli included broad chromosomal alterations. The Jackson Lab group suggested that these may contribute to metabolic disruption and epigenetic diversity through increased reactive oxygen species.

"Our integrated analysis of different single-cell and bulk approaches of glioma patient specimens has helped to identify a role for epigenetics in the mechanisms used by glioma cells to deal with limited resources in the microenvironment," Verhaak explained via email.

Both studies' findings suggest that a better understanding of therapeutically vulnerable cell states could lead to more effective targeted treatments.

"Future work that longitudinally performs single-cell multiomic sequencing on patient tissue samples before and after treatment will provide critical insights into the epigenetic mechanisms of cancer resistance," said Johnson.

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