The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer
- Ronan Chaligné1,2,3,4,
- Tatiana Popova1,5,
- Marco-Antonio Mendoza-Parra6,
- Mohamed-Ashick M. Saleem6,
- David Gentien1,7,
- Kristen Ban1,2,3,4,
- Tristan Piolot1,8,
- Olivier Leroy1,8,
- Odette Mariani7,
- Hinrich Gronemeyer6,
- Anne Vincent-Salomon1,4,5,7,
- Marc-Henri Stern1,5,7 and
- Edith Heard1,2,3,4
- 1Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France;
- 2Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3215, Institut Curie, 75248 Paris Cedex 05, France;
- 3Institut National de la Santé et de la Recherche Médicale U934, Institut Curie, Paris, France;
- 4Equipe Labellisée Ligue Contre le Cancer, UMR3215, 75248 Paris Cedex 05, France;
- 5Institut National de la Santé et de la Recherche Médicale U830, Institut Curie, 75248 Paris Cedex 05, France;
- 6Institut 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;
- 7Department of Tumor Biology, Institut Curie, 75248 Paris Cedex 05, France;
- 8Plate-forme d'Imagerie Cellulaire et Tissulaire at BDD (Pict@BDD), Institut Curie, 75248 Paris Cedex 05, France
- Corresponding authors: Edith.Heard{at}curie.fr, Anne.Salomon{at}curie.fr, marc-henri.stern{at}curie.fr, hg{at}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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.185926.114.
Freely available online through the Genome Research Open Access option.
- Received October 28, 2014.
- Accepted January 28, 2015.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
