title: The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.
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.
authors: 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;
authors: Ronan
authors: R
authors: Chaligné
authors: 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;
authors: Tatiana
authors: T
authors: Popova
authors: 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;
authors: Marco-Antonio
authors: MA
authors: Mendoza-Parra
authors: 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;
authors: Mohamed-Ashick M
authors: MA
authors: Saleem
authors: Centre de Recherche, Institut Curie, 75248 Paris Cedex 05, France; Department of Tumor Biology, Institut Curie, 75248 Paris Cedex 05, France;
authors: David
authors: D
authors: Gentien
authors: 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;
authors: Kristen
authors: K
authors: Ban
authors: 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.
authors: Tristan
authors: T
authors: Piolot
authors: 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.
authors: Olivier
authors: O
authors: Leroy
authors: Department of Tumor Biology, Institut Curie, 75248 Paris Cedex 05, France;
authors: Odette
authors: O
authors: Mariani
authors: 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.
authors: Hinrich
authors: H
authors: Gronemeyer
authors: 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.
authors: Anne
authors: A
authors: Vincent-Salomon
authors: 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.
authors: Marc-Henri
authors: MH
authors: Stern
authors: 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.
authors: Edith
authors: E
authors: Heard
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000473:pathology; D041321:Chromosomes, Human, X / Q000235:genetics*; D004265:DNA Helicases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics*; D006655:Histone Deacetylases / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D012728:Sex Chromatin / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015293:Transducin / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D049951:X Chromosome Inactivation / Q000235:genetics*; D000075924:X-linked Nuclear Protein
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D006657:Histones; C095203:MAGEA6 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; C119542:TBL1X protein, human; D025521:Tumor Suppressor Proteins; C077885:XIST non-coding RNA; D056466:Histone Demethylases; C086877:KDM5C protein, human; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein; D015293:Transducin
references: Cell. 2001 Dec 14;107(6):727-38
references: 11747809
references: Nat Genet. 2002 Jan;30(1):73-6
references: 11740495
references: Nat Genet. 2002 Feb;30(2):167-74
references: 11780141
references: Cell. 2002 Nov 1;111(3):393-405
references: 12419249
references: Mol Cancer Ther. 2002 Aug;1(10):769-76
references: 12492109
references: Clin Cancer Res. 2009 Jan 1;15(1):91-9
references: 19118036
references: Cancer Res. 2009 May 1;69(9):3802-9
references: 19366799
references: Oncogene. 2009 Jun 25;28(25):2370-82
references: 19430493
references: Proc Can Cancer Conf. 1957;2:3-16
references: 13437159
references: Nature. 1961 Apr 22;190:372-3
references: 13764598
references: Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17450-5
references: 15574503
references: J Cell Biol. 2004 Dec 20;167(6):1025-35
references: 15596546
references: Nature. 2005 Mar 17;434(7031):400-4
references: 15772666
references: Genome Res. 2009 Aug;19(8):1361-73
references: 19581487
references: Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13493-8
references: 19651608
references: EMBO Mol Med. 2010 Jan;2(1):6-15
references: 20043281
references: PLoS Biol. 2010 Jan;8(1):e1000276
references: 20052282
references: Genome Biol. 2009;10(11):R128
references: 19903341
references: Carcinogenesis. 2010 Jun;31(6):961-7
references: 20400477
references: Cell. 2010 Jun 11;141(6):956-69
references: 20550932
references: Cell Mol Life Sci. 2010 Oct;67(20):3499-510
references: 20473547
references: Nat Biotechnol. 2010 Oct;28(10):1057-68
references: 20944598
references: Cold Spring Harb Perspect Biol. 2010 Nov;2(11):a000604
references: 20943757
references: Oncol Rep. 2011 Jun;25(6):1677-81
references: 21455583
references: Nature. 2011 Apr 21;472(7343):370-4
references: 21471966
references: Genes Dev. 2011 Jul 1;25(13):1371-83
references: 21690198
references: Hum Mol Genet. 2011 Oct 15;20(20):3964-73
references: 21791549
references: Nature. 2012 Jan 19;481(7381):329-34
references: 22237022
references: Nat Med. 2012 Apr;18(4):605-11
references: 22406747
references: Cancer Cell. 2012 May 15;21(5):655-67
references: 22624715
references: Nature. 2012 Jun 21;486(7403):395-9
references: 22495314
references: Nature. 2012 Sep 6;489(7414):57-74
references: 22955616
references: Cancer Res. 2012 Nov 1;72(21):5454-62
references: 22933060
references: Cytogenet Genome Res. 2002;99(1-4):75-84
references: 12900548
references: Nat Rev Cancer. 2004 Aug;4(8):617-29
references: 15286741
references: Oncogene. 2004 Aug 12;23(36):6163-9
references: 15195139
references: Nat Rev Cancer. 2004 Sep;4(9):677-87
references: 15343274
references: Br J Surg. 1972 Sep;59(9):731-4
references: 5070138
references: J Endocrinol Invest. 1981 Oct-Dec;4(4):455-7
references: 7334186
references: Dev Biol. 1996 Dec 15;180(2):618-30
references: 8954732
references: J Cell Biol. 1997 Jun 2;137(5):965-74
references: 9166399
references: Nat Genet. 1999 Aug;22(4):323-4
references: 10431231
references: Cancer Res. 2005 Mar 15;65(6):2139-46
references: 15781624
references: Mod Pathol. 2005 Dec;18(12):1623-31
references: 16258515
references: Cancer Cell. 2006 Feb;9(2):121-32
references: 16473279
references: Cell. 2006 Apr 21;125(2):315-26
references: 16630819
references: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7688-93
references: 16682630
references: Genes Dev. 2006 Aug 15;20(16):2223-37
references: 16912274
references: Oncogene. 2006 Sep 25;25(43):5846-53
references: 16998499
references: Science. 2007 Feb 2;315(5812):642-5
references: 17204608
references: Cell. 2007 Mar 9;128(5):977-89
references: 17350580
references: Cell. 2007 Mar 9;128(5):991-1002
references: 17350581
references: Chromosoma. 2007 Apr;116(2):147-57
references: 17103221
references: Cancer Res. 2007 Jun 1;67(11):5134-40
references: 17545591
references: Nat Rev Cancer. 2007 Aug;7(8):628-33
references: 17611545
references: Oncol Rep. 2007 Oct;18(4):769-74
references: 17786334
references: Science. 2007 Nov 16;318(5853):1136-40
references: 18006746
references: Mol Carcinog. 2008 Feb;47(2):137-47
references: 17849419
references: Methods Mol Biol. 2008;463:297-308
references: 18951174
references: Cell. 2013 Feb 14;152(4):727-42
references: 23415223
references: Cell. 2013 Mar 28;153(1):38-55
references: 23540689
references: Semin Cancer Biol. 2013 Apr;23(2):99-108
references: 22722067
references: BMC Cancer. 2013;13:215
references: 23627572
references: Mol Cell Biol. 2013 Aug;33(16):3150-65
references: 23754746
references: Nature. 2013 Dec 19;504(7480):465-9
references: 24162848
references: Dev Cell. 2005 Jan;8(1):31-42
references: 15669143
references: Hum Mol Genet. 2014 Mar 1;23(5):1211-23
references: 24158853
references: Tumour Biol. 2014 Jul;35(7):7097-103
references: 24760274
references: Genome Biol. 2013;14(11):R122
references: 24176135
references: Nature. 2000 Aug 17;406(6797):747-52
references: 10963602
references: Nat Genet. 2001 Jan;27(1):20-1
references: 11137993
references: J Cell Biol. 2001 May 14;153(4):773-84
references: 11352938