Global hypo-methylation in a proportion of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape.

in eLife by James Boot, Gabriel Rosser, Dailya Kancheva, Claire Vinel, Yau Mun Lim, Nicola Pomella, Xinyu Zhang, Loredana Guglielmi, Denise Sheer, Michael Barnes, Sebastian Brandner, Sven Nelander, Kiavash Movahedi, Silvia Marino

TLDR

  • The study found that some glioblastomas have a bias towards being less methylated in certain parts of their DNA. These glioblastomas also have a shared history with a type of brain cell called astroglial progenitors. The study also found that these glioblastomas have a higher chance of being invasive and having macrophages in them. The study suggests that these findings could help researchers find new ways to treat glioblastoma.

Abstract

We describe a subset of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between these glioblastomas and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this subset of glioblastoma.

Overview

  • The study focuses on a subset of glioblastoma, the most prevalent malignant adult brain tumor, with a bias towards hypomethylation at defined differentially methylated regions. The hypothesis being tested is whether this epigenetic signature correlates with an enrichment for an astrocytic gene signature and whether it points to a shared ontogeny between these glioblastomas and astroglial progenitors. The methodology used for the experiment includes the analysis of DNA methylation data from The Cancer Genome Atlas (TCGA) database and the use of gene set enrichment analysis (GSEA) to identify differentially methylated regions and gene signatures. The primary objective of the study is to understand the molecular mechanisms underlying the development of glioblastoma and to identify potential therapeutic targets for this disease.

Comparative Analysis & Findings

  • The study compares the outcomes observed in glioblastomas with a bias towards hypomethylation at defined differentially methylated regions with those without such bias. The results show that glioblastomas with a bias towards hypomethylation at defined differentially methylated regions have a higher enrichment for an astrocytic gene signature and a shared ontogeny with astroglial progenitors. The study also identifies enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, which points to a shared ontogeny between these glioblastomas and astroglial progenitors. The key findings of the study suggest that glioblastomas with a bias towards hypomethylation at defined differentially methylated regions have increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration.

Implications and Future Directions

  • The study's findings suggest that glioblastomas with a bias towards hypomethylation at defined differentially methylated regions have a shared ontogeny with astroglial progenitors, which could have implications for the development of targeted therapies for this disease. The study also identifies potential therapeutic targets, such as transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification. Future research could explore the role of these transcription factors in the development of glioblastoma and the potential of targeting them for therapeutic purposes. Additionally, future research could investigate the role of macrophage infiltration in the development and progression of glioblastoma and the potential of targeting these cells for therapeutic purposes.
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