Transcriptional alterations in glioma result primarily from DNA methylation-independent mechanisms

• Published in: Genome research Vol. 29; no. 10; pp. 1605 - 1621
• Main Authors: Court, Franck, Le Boiteux, Elisa, Fogli, Anne, Müller-Barthélémy, Mélanie, Vaurs-Barrière, Catherine, Chautard, Emmanuel, Pereira, Bruno, Biau, Julian, Kemeny, Jean-Louis, Khalil, Toufic, Karayan-Tapon, Lucie, Verrelle, Pierre, Arnaud, Philippe
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.10.2019
• Subjects: Adult; Biochemistry, Molecular Biology; Brain cancer; Brain tumors; Cancer; Cell Line, Tumor; Chromatin; Chromatin - genetics; CpG islands; CpG Islands - genetics; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; Drug delivery; Drug development; Epigenesis, Genetic - genetics; Epigenetics; Female; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Gene silencing; Genomics; Glioma - genetics; Glioma - pathology; Glioma cells; Histone H3; Histones - genetics; Humans; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Jumonji Domain-Containing Histone Demethylases - genetics; Life Sciences; Lysine; Male; Molecular biology; Molecular Networks; Polycomb group proteins; Promoter Regions, Genetic; Stem cells; Transcription, Genetic; Transformed cells; Tumor suppressor genes; transcriptional defects; Epigenetics; CpG-island; Glioma
• ISSN: 1088-9051; 1549-5469
• DOI: 10.1101/gr.249219.119

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. To dissect the relative contribution of DNA methylation-dependent and -independent mechanisms to transcriptional alterations at CpG island/promoter-associated genes in cancer, we studied 70 samples of adult glioma, a widespread type of brain tumor, classified according to their isocitrate dehydrogenase ( ) mutation status. We 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. Our 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. Our 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. Our 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.