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Genome Res. 2015 Apr;25(4):488-503. doi: 10.1101/gr.185926.114. Epub 2015 Feb 4.

The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.

Author information

1
Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3215, Institut Curie, 75248 Paris Cedex 05, France; Institut National de la Santé et de la Recherche Médicale U934, Institut Curie, 75248 Paris Cedex 05, France; Equipe Labellisée Ligue Contre le Cancer, UMR3215, 75248 Paris Cedex 05, France;
2
Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France; Institut National de la Santé et de la Recherche Médicale U830, Institut Curie, 75248 Paris Cedex 05, France;
3
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Equipe Labellisée Ligue Contre le Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, University of Strasbourg, 67404 Illkirch Cedex, France;
4
Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France; Department of Tumor Biology, Institut Curie, 75248 Paris Cedex 05, France;
5
Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France; Plate-forme d'Imagerie Cellulaire et Tissulaire at BDD (Pict@BDD), Institut Curie, 75248 Paris Cedex 05, France.
6
Department of Tumor Biology, Institut Curie, 75248 Paris Cedex 05, France;
7
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Equipe Labellisée Ligue Contre le Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, University of Strasbourg, 67404 Illkirch Cedex, France; Edith.Heard@curie.fr Anne.Salomon@curie.fr marc-henri.stern@curie.fr hg@igbmc.fr.
8
Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France; Equipe Labellisée Ligue Contre le Cancer, UMR3215, 75248 Paris Cedex 05, France; Institut National de la Santé et de la Recherche Médicale U830, Institut Curie, 75248 Paris Cedex 05, France; Department of Tumor Biology, Institut Curie, 75248 Paris Cedex 05, France; Edith.Heard@curie.fr Anne.Salomon@curie.fr marc-henri.stern@curie.fr hg@igbmc.fr.
9
Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France; Institut National de la Santé et de la Recherche Médicale U830, Institut Curie, 75248 Paris Cedex 05, France; Department of Tumor Biology, Institut Curie, 75248 Paris Cedex 05, France; Edith.Heard@curie.fr Anne.Salomon@curie.fr marc-henri.stern@curie.fr hg@igbmc.fr.
10
Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3215, Institut Curie, 75248 Paris Cedex 05, France; Institut National de la Santé et de la Recherche Médicale U934, Institut Curie, 75248 Paris Cedex 05, France; Equipe Labellisée Ligue Contre le Cancer, UMR3215, 75248 Paris Cedex 05, France; Edith.Heard@curie.fr Anne.Salomon@curie.fr marc-henri.stern@curie.fr hg@igbmc.fr.

Abstract

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.

PMID:
25653311
PMCID:
PMC4381521
DOI:
10.1101/gr.185926.114
[Indexed for MEDLINE]
Free PMC Article

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