Widespread overexpression from the four DNA hypermethylated HOX clusters in aggressive (IDHwt) glioma is associated with H3K27me3 depletion and alternative promoter usage
| العنوان: | Widespread overexpression from the four DNA hypermethylated HOX clusters in aggressive (IDHwt) glioma is associated with H3K27me3 depletion and alternative promoter usage |
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| المؤلفون: | Catherine Vaurs-Barrière, Elisa Le Boiteux, Isabelle Vaillant, Anne Fogli, Bruno M. Costa, Pierre Verrelle, Emmanuel Chautard, Lucie Karayan-Tapon, Pierre-Olivier Guichet, Franck Court, Philippe Arnaud |
| المساهمون: | Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Génétique, Reproduction et Développement (GReD), 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), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), 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) |
| المصدر: | Molecular Oncology Molecular Oncology, Elsevier, 2021, ⟨10.1002/1878-0261.12944⟩ Molecular Oncology, 2021, ⟨10.1002/1878-0261.12944⟩ Molecular Oncology, Vol 15, Iss 8, Pp 1995-2010 (2021) |
| بيانات النشر: | HAL CCSD, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, animal structures, Transcription, Genetic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gene mutation, Biology, Histones, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, glioma, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Humans, cancer, Epigenetics, alternative promoters, Promoter Regions, Genetic, Hox gene, Gene, Transcription factor, RC254-282, Research Articles, ComputingMilieux_MISCELLANEOUS, epigenetics, Brain Neoplasms, Genes, Homeobox, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Promoter, [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], General Medicine, DNA Methylation, HOX genes, Isocitrate Dehydrogenase, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, embryonic structures, DNA methylation, Cancer research, glioma stem cells, Molecular Medicine, Homeobox, Research Article |
| الوصف: | In human, the 39 coding HOX genes and 18 referenced noncoding antisense transcripts are arranged in four genomic clusters named HOXA, B, C, and D. This highly conserved family belongs to the homeobox class of genes that encode transcription factors required for normal development. Therefore, HOX gene deregulation might contribute to the development of many cancer types. Here, we study HOX gene deregulation in adult glioma, a common type of primary brain tumor. We performed extensive molecular analysis of tumor samples, classified according to their isocitrate dehydrogenase (IDH1) gene mutation status, and of glioma stem cells. We found widespread expression of sense and antisense HOX transcripts only in aggressive (IDHwt) glioma samples, although the four HOX clusters displayed DNA hypermethylation. Integrative analysis of expression, DNA methylation, and histone modification signatures along the clusters revealed that HOX gene upregulation relies on canonical and alternative bivalent CpG island promoters that escape hypermethylation. H3K27me3 loss at these promoters emerges as the main cause of widespread HOX gene upregulation in IDHwt glioma cell lines and tumors. Our study provides the first comprehensive description of the epigenetic changes at HOX clusters and their contribution to the transcriptional changes observed in adult glioma. It also identified putative ‘master’ HOX proteins that might contribute to the tumorigenic potential of glioma stem cells. This study describes the epigenetic and transcriptional changes at HOX clusters in aggressive glioma. It shows how DNA hypermethylation and gene overexpression can coexist and suggest that loss of H3K27me3 along the HOX clusters is the main driving force of HOX widespread transcriptional alteration in aggressive glioma samples. It highlights the complexity of HOX gene expression pattern in patients where the usage of alternative promoters contributes to splice variant variability among samples. |
| اللغة: | English |
| تدمد: | 1574-7891 1878-0261 |
| DOI: | 10.1002/1878-0261.12944⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c663b7f53d6cfea16f45f720db7c7867 https://hal.archives-ouvertes.fr/hal-03172071/document |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c663b7f53d6cfea16f45f720db7c7867 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15747891 18780261 |
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| DOI: | 10.1002/1878-0261.12944⟩ |