Widespread overexpression from the four DNA hypermethylated HOX clusters in aggressive (IDHwt) glioma is associated with H3K27me3 depletion and alternative promoter usage.

Autor: Le Boiteux E; CNRS, Inserm, GReD, Université Clermont Auvergne, Clermont-Ferrand, France., Court F; CNRS, Inserm, GReD, Université Clermont Auvergne, Clermont-Ferrand, France., Guichet PO; INSERM-U1084, Poitiers, France.; Poitiers University, France.; Department of Cancer Biology, Poitiers Hospital, France., Vaurs-Barrière C; CNRS, Inserm, GReD, Université Clermont Auvergne, Clermont-Ferrand, France., Vaillant I; CNRS, Inserm, GReD, Université Clermont Auvergne, Clermont-Ferrand, France., Chautard E; Pathology Department, Jean Perrin Center, Clermont-Ferrand, France.; INSERM, U1240 IMoST, Université Clermont Auvergne, Clermont-Ferrand, France., Verrelle P; CIMB, INSERM U1196 CNRS UMR9187, Curie Institute, Orsay, France.; Radiotherapy Department, Curie Institute, Paris, France.; Université Clermont Auvergne, Clermont-Ferrand, France., Costa BM; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal., Karayan-Tapon L; INSERM-U1084, Poitiers, France.; Poitiers University, France.; Department of Cancer Biology, Poitiers Hospital, France., Fogli A; CNRS, Inserm, GReD, Université Clermont Auvergne, Clermont-Ferrand, France.; Biochemistry and Molecular Biology Department, Clermont-Ferrand Hospital, France., Arnaud P; CNRS, Inserm, GReD, Université Clermont Auvergne, Clermont-Ferrand, France.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2021 Aug; Vol. 15 (8), pp. 1995-2010. Date of Electronic Publication: 2021 May 02.
DOI: 10.1002/1878-0261.12944
Abstrakt: 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.
(© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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