The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.
Fiche publication
Date publication
avril 2015
Journal
Genome research
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GRONEMEYER Hinrich
Tous les auteurs :
Chaligné R, Popova T, Mendoza-Parra MA, Saleem MA, Gentien D, Ban K, Piolot T, Leroy O, Mariani O, Gronemeyer H, Vincent-Salomon A, Stern MH, Heard E
Lien Pubmed
Résumé
Disappearance of the Barr body is considered a hallmark of cancer, although whether this corresponds to genetic loss or to epigenetic instability and transcriptional reactivation is unclear. Here we show that breast tumors and cell lines frequently display major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin, including gain of euchromatic marks and aberrant distributions of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells and a significant degree of aberrant gene activity from the inactive X chromosome, including several genes involved in cancer promotion. We demonstrate that many of these genes are aberrantly reactivated in primary breast tumors, and we further demonstrate that epigenetic instability of the inactive X can lead to perturbed dosage of X-linked factors. Taken together, our study provides the first integrated analysis of the inactive X chromosome in the context of breast cancer and establishes that epigenetic erosion of the inactive X can lead to the disappearance of the Barr body in breast cancer cells. This work offers new insights and opens up the possibility of exploiting the inactive X chromosome as an epigenetic biomarker at the molecular and cytological levels in cancer.
Mots clés
Antigens, Neoplasm, metabolism, Biomarkers, Tumor, genetics, Breast Neoplasms, genetics, Cell Line, Tumor, Cell Nucleus, pathology, Chromosomes, Human, X, genetics, DNA Helicases, metabolism, DNA Methylation, genetics, Epigenesis, Genetic, genetics, Female, Genes, X-Linked, genetics, Histone Deacetylases, metabolism, Histone Demethylases, genetics, Histones, genetics, Humans, Neoplasm Proteins, metabolism, Nuclear Proteins, metabolism, Promoter Regions, Genetic, genetics, RNA, Long Noncoding, genetics, Repressor Proteins, metabolism, Sex Chromatin, genetics, Transcription, Genetic, genetics, Transducin, metabolism, Ubiquitin-Protein Ligases, genetics, X Chromosome Inactivation, genetics
Référence
Genome Res.. 2015 Apr;25(4):488-503