1. Transcriptional alterations in glioma result primarily from DNA methylation–independent mechanisms
- Author
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Mélanie Müller-Barthélémy, Elisa Le Boiteux, Franck Court, Julian Biau, Lucie Karayan-Tapon, Toufic Khalil, Pierre Verrelle, Philippe Arnaud, Jean-Louis Kemeny, Anne Fogli, Catherine Vaurs-Barrière, Bruno Pereira, Emmanuel Chautard, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie et Génétique Moléculaire [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Thérapie ciblée combinatoire en Onco-Hématologie (EA3846), Université d'Auvergne - Clermont-Ferrand I (UdA), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire de pathologie, Service de Neurochirurgie [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], Institut National de la Transfusion Sanguine [Paris] (INTS), Arnaud, Philippe, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Service de Biochimie Médicale et Biologie Moléculaire [CHU Clermont-Ferrand], Centre Jean Perrin, CRLCC Jean Perrin, Unité de biostatistiques, CHU Clermont-Ferrand-Hôpital Montpied, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), CHU Clermont-Ferrand-Hôpital Gabriel Montpied, Service de Neurochirurgie [CHU Clermont-Ferrand], ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Adult ,Male ,Jumonji Domain-Containing Histone Demethylases ,Transcription, Genetic ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease_cause ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genetics ,medicine ,Humans ,transcriptional defects ,Epigenetics ,Promoter Regions, Genetic ,Gene ,ComputingMilieux_MISCELLANEOUS ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Mutation ,Research ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN] ,Promoter ,Glioma ,DNA Methylation ,Chromatin ,Isocitrate Dehydrogenase ,3. Good health ,Cell biology ,Gene Expression Regulation, Neoplastic ,[SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN] ,CpG site ,CpG-island ,Cancer cell ,DNA methylation ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,CpG Islands ,Female ,030217 neurology & neurosurgery ,Bivalent chromatin - Abstract
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 (IDH1) 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.
- Published
- 2019