Transcriptional alterations in Glioma: DNA methylation is the tip of the “epigenetic” iceberg

Transcriptional alterations in Glioma:  DNA methylation is the tip of the “epigenetic” iceberg

In cancer cells, aberrant DNA methylation is commonly associated with transcriptional alterations, including silencing of tumor suppressor genes. However, multiple epigenetic mechanisms, including polycomb repressive marks, contribute to gene deregulation in cancer. In its last study  (Court et al.,  2019) the team " Genomic Imprinting and the epigenetic control of cell fate determination" used glioma, one the most widespread type of brain tumor, to evaluate for the first time the relative contribution of DNA methylation-independent mechanisms on transcriptional alteration at CpG-island (CGI)/promoter-associated genes in cancer cells. They found that most transcriptional alterations in tumor samples were DNA methylation-independent. Instead, altered histone H3 trimethylation at lysine 27 (H3K27me3) was the predominant molecular defect at deregulated genes.

Their results also suggest that the presence of a bivalent chromatin signature at CpG island promoters in stem cells predisposes not only to hypermethylation, as widely documented, but more generally to all types of transcriptional alterations in transformed cells. In addition, the gene expression strength in healthy brain cells influences the choice between DNA methylation- and H3K27me3-associated silencing in glioma. Highly expressed genes were more likely to be repressed by H3K27me3 than by DNA methylation. These  findings support a model in which altered H3K27me3 dynamics, more specifically defects in the interplay between polycomb protein complexes and the brain-specific transcriptional machinery, is the main cause of transcriptional alteration in glioma cells. This study provides the first comprehensive description of epigenetic changes in glioma and their relative contribution to transcriptional changes. It may be useful for the design of drugs targeting cancer-related epigenetic defects.

This study has been highlighted on the CBNRS INSB website

Last modified: 09/02/2020