Understanding the Complex Circuitry of lncRNAs at the X-inactivation Center and Its Implications in Disease Conditions

  • John Lalith Charles Richard
  • Yuya OgawaEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 394)


Balanced gene expression is a high priority in order to maintain optimal functioning since alterations and variations could result in acute consequences. X chromosome inactivation (X-inactivation) is one such strategy utilized by mammalian species to silence the extra X chromosome in females to uphold a similar level of expression between the two sexes. A functionally versatile class of molecules called long noncoding RNA (lncRNA) has emerged as key regulators of gene expression and plays important roles during development. An lncRNA that is indispensable for X-inactivation is X-inactive specific transcript (Xist), which induces a repressive epigenetic landscape and creates the inactive X chromosome (Xi). With recent advents in the field of X-inactivation, novel positive and negative lncRNA regulators of Xist such as Jpx and Tsix, respectively, have broadened the regulatory network of X-inactivation. Xist expression failure or dysregulation has been implicated in producing developmental anomalies and disease states. Subsequently, reactivation of the Xi at a later stage of development has also been associated with certain tumors. With the recent influx of information about lncRNA biology and advancements in methods to probe lncRNA, we can now attempt to understand this complex network of Xist regulation in development and disease. It has become clear that the presence of an extra set of genes could be fatal for the organism. Only by understanding the precise ways in which lncRNAs function can treatments be developed to bring aberrations under control. This chapter summarizes our current understanding and knowledge with regard to how lncRNAs are orchestrated at the X-inactivation center (Xic), with a special focus on how genetic diseases come about as a consequence of lncRNA dysregulation.


Down Syndrome Membranous Nephropathy Rett Syndrome Monoallelic Expression Xist Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Long noncoding RNA


X-inactive specific transcript


X-inactivation center

ES cells

Embryonic stem cells


Histone H3 tri-methylated lysine 27


Long interspersed nuclear element


Yin Yang 1


Heterogenous nuclear ribonucleoprotein U


Inactive X chromosome


Active X chromosome


Methyl-CpG binding protein 2


Myeloproliferative neoplasm and myelodysplastic syndrome


11 Zinc finger protein/CCCTF binding factor


Human induced pluripotent stem cells



The authors wish to thank members of the Ogawa Lab for helpful comments and Serenity Curtis for editing the manuscript. This work was supported by grant from the NIH (RO1-GM102184) and the March of Dimes Research Foundation (#6-FY12-337) to Y.O.


  1. Amir RE, Van den Veyver IB, Wan M et al (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188. doi: 10.1038/13810 PubMedCrossRefGoogle Scholar
  2. Anguera MC, Ma W, Clift D et al (2011) Tsx produces a long noncoding RNA and has general functions in the germline, stem cells, and brain. PLoS Genet 7:e1002248. doi: 10.1371/journal.pgen.1002248 PubMedPubMedCentralCrossRefGoogle Scholar
  3. Anguera MC, Sadreyev R, Zhang Z et al (2012) Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes. Cell Stem Cell 11:75–90. doi: 10.1016/j.stem.2012.03.008 PubMedPubMedCentralCrossRefGoogle Scholar
  4. Belmont JW (1996) Genetic control of X inactivation and processes leading to X-inactivation skewing. Am J Hum Genet 58:1101–1108PubMedPubMedCentralGoogle Scholar
  5. Bittel DC, Theodoro MF, Kibiryeva N et al (2008) Comparison of X-chromosome inactivation patterns in multiple tissues from human females. J Med Genet 45:309–313. doi: 10.1136/jmg.2007.055244 PubMedCrossRefGoogle Scholar
  6. Blewitt ME, Gendrel A-V, Pang Z et al (2008) SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nat Genet 40:663–669. doi: 10.1038/ng.142 PubMedCrossRefGoogle Scholar
  7. Bock C, Kiskinis E, Verstappen G et al (2011) Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144:439–452. doi: 10.1016/j.cell.2010.12.032 PubMedPubMedCentralCrossRefGoogle Scholar
  8. Brockdorff N, Ashworth A, Kay GF et al (1991) Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351:329–331. doi: 10.1038/351329a0 PubMedCrossRefGoogle Scholar
  9. Brown CJ, Ballabio A, Rupert JL et al (1991a) A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349:38–44. doi: 10.1038/349038a0 PubMedCrossRefGoogle Scholar
  10. Brown CJ, Lafreniere RG, Powers VE et al (1991b) Localization of the X inactivation centre on the human X chromosome in Xq13. Nature 349:82–84. doi: 10.1038/349082a0 PubMedCrossRefGoogle Scholar
  11. Brown CJ, Willard HF (1994) The human X-inactivation centre is not required for maintenance of X-chromosome inactivation. Nature 368:154–156. doi: 10.1038/368154a0 PubMedCrossRefGoogle Scholar
  12. Brown SD (1991) XIST and the mapping of the X chromosome inactivation centre. BioEssays 13:607–612. doi: 10.1002/bies.950131112 PubMedCrossRefGoogle Scholar
  13. Camus P, Abbadi N, Perrier MC et al (1996) X chromosome inactivation in 30 girls with Rett syndrome: analysis using the probe. Hum Genet 97:247–250PubMedCrossRefGoogle Scholar
  14. Carninci P, Kasukawa T, Katayama S et al (2005) The transcriptional landscape of the mammalian genome. Science 309:1559–1563. doi: 10.1126/science.1112014 PubMedCrossRefGoogle Scholar
  15. Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434:400–404. doi: 10.1038/nature03479 PubMedCrossRefGoogle Scholar
  16. Chadwick BP, Willard HF (2004) Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome. Proc Natl Acad Sci USA 101:17450–17455. doi: 10.1073/pnas.0408021101 PubMedPubMedCentralCrossRefGoogle Scholar
  17. Chaligné R, Heard E (2014) X-chromosome inactivation in development and cancer. FEBS Lett 588:2514–2522. doi: 10.1016/j.febslet.2014.06.023 PubMedCrossRefGoogle Scholar
  18. Chaumeil J, Le Baccon P, Wutz A, Heard E (2006) A novel role for Xist RNA in the formation of a repressive nuclear compartment into which genes are recruited when silenced. Genes Dev 20:2223–2237. doi: 10.1101/gad.380906 PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chaumeil J, Okamoto I, Guggiari M, Heard E (2002) Integrated kinetics of X chromosome inactivation in differentiating embryonic stem cells. Cytogenet Genome Res 99:75–84PubMedCrossRefGoogle Scholar
  20. Chow JC, Brown CJ, Hall LL et al (2003) Characterization of expression at the human XIST locus in somatic, embryonal carcinoma, and transgenic cell lines. Genomics 82:309–322PubMedCrossRefGoogle Scholar
  21. Chow JC, Ciaudo C, Fazzari MJ et al (2010) LINE-1 activity in facultative heterochromatin formation during X chromosome inactivation. Cell 141:956–969. doi: 10.1016/j.cell.2010.04.042 PubMedCrossRefGoogle Scholar
  22. Chow JC, Hall LL, Baldry SEL et al (2007) Inducible XIST-dependent X-chromosome inactivation in human somatic cells is reversible. Proc Natl Acad Sci USA 104:10104–10109. doi: 10.1073/pnas.0610946104 PubMedPubMedCentralCrossRefGoogle Scholar
  23. Chu C, Chang HY, Qu K et al (2011) Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol Cell 44:667–678. doi: 10.1016/j.molcel.2011.08.027 PubMedPubMedCentralCrossRefGoogle Scholar
  24. Chureau C, Chantalat S, Romito A et al (2011) Ftx is a non-coding RNA which affects Xist expression and chromatin structure within the X-inactivation center region. Hum Mol Genet 20:705–718. doi: 10.1093/hmg/ddq516 PubMedCrossRefGoogle Scholar
  25. Chureau C, Prissette M, Bourdet A et al (2002) Comparative sequence analysis of the X-inactivation center region in mouse, human, and bovine. Genome Res 12:894–908. doi: 10.1101/gr.152902 PubMedPubMedCentralGoogle Scholar
  26. Clemson CM, Willard HF, McNeil JA, Lawrence JB (1996) XIST RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. J Cell Biol 132:259–275PubMedCrossRefGoogle Scholar
  27. Cohen DE, Davidow LS, Erwin JA et al (2007) The DXPas34 repeat regulates random and imprinted X inactivation. Dev Cell 12:57–71. doi: 10.1016/j.devcel.2006.11.014 PubMedCrossRefGoogle Scholar
  28. Costanzi C, Pehrson J (1998) Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature 393:599–601PubMedCrossRefGoogle Scholar
  29. Csankovszki G, Nagy A, Jaenisch R (2001) Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol 153:773–784PubMedPubMedCentralCrossRefGoogle Scholar
  30. Csankovszki G, Panning B, Bates B et al (1999) Conditional deletion of Xist disrupts histone macroH2A localization but not maintenance of X inactivation. Nat Genet 22:323–324. doi: 10.1038/11887 PubMedCrossRefGoogle Scholar
  31. de Napoles M, Mermoud JE, Wakao R et al (2004) Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev Cell 7:663–676. doi: 10.1016/j.devcel.2004.10.005 PubMedCrossRefGoogle Scholar
  32. Dvash T, Fan G (2009) Epigenetic regulation of X-inactivation in human embryonic stem cells. Epigenetics (official journal of the DNA Methylation Society) 4:19–22CrossRefGoogle Scholar
  33. Engreitz JM, Pandya-Jones A, Mcdonel P et al (2013) The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341:1237973. doi: 10.1126/science.1237973 PubMedPubMedCentralCrossRefGoogle Scholar
  34. Fang J, Chen T, Chadwick BP et al (2004) Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation. J Biol Chem 279:52812–52815. doi: 10.1074/jbc.C400493200 PubMedCrossRefGoogle Scholar
  35. Gafni O, Weinberger L, Mansour AA et al (2013) Derivation of novel human ground state naive pluripotent stem cells. Nature 504:282–286. doi: 10.1038/nature12745 PubMedCrossRefGoogle Scholar
  36. Gardiner KJ (2010) Molecular basis of pharmacotherapies for cognition in down syndrome. Trends Pharmacol Sci 31:66–73. doi: 10.1016/ PubMedPubMedCentralCrossRefGoogle Scholar
  37. Gendrel A-V, Apedaile A, Coker H et al (2012) Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. Dev Cell 23:265–279. doi: 10.1016/j.devcel.2012.06.011 PubMedPubMedCentralCrossRefGoogle Scholar
  38. Giacometti E, Luikenhuis S, Beard C, Jaenisch R (2007) Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc Natl Acad Sci USA 104:1931–1936. doi: 10.1073/pnas.0610593104 PubMedPubMedCentralCrossRefGoogle Scholar
  39. Giorda R, Bonaglia MC, Milani G et al (2008) Molecular and cytogenetic analysis of the spreading of X inactivation in a girl with microcephaly, mild dysmorphic features and t(X;5)(q22.1;q31.1). Eur J Hum Genet 16:897–905. doi: 10.1038/ejhg.2008.28 PubMedCrossRefGoogle Scholar
  40. Gore A, Li Z, Fung H-L et al (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471:63–67. doi: 10.1038/nature09805 PubMedPubMedCentralCrossRefGoogle Scholar
  41. Groth KA, Skakkebæk A, Høst C et al (2013) Clinical review: Klinefelter syndrome–a clinical update. J Clin Endocrinol Metab 98:20–30. doi: 10.1210/jc.2012-2382 PubMedCrossRefGoogle Scholar
  42. Guy J, Gan J, Selfridge J et al (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315:1143–1147. doi: 10.1126/science.1138389 PubMedCrossRefGoogle Scholar
  43. Hafner M, Landthaler M, Burger L et al (2010) PAR-CliP–a method to identify transcriptome-wide the binding sites of RNA binding proteins. J Vis Exp. doi: 10.3791/2034 PubMedPubMedCentralGoogle Scholar
  44. Happle R (2006) X-chromosome inactivation: role in skin disease expression. Acta Paediatr 95:16–23. doi: 10.1111/j.1651-2227.2006.tb02384.x CrossRefGoogle Scholar
  45. Happle R, Frosch PJ (1985) Manifestation of the lines of Blaschko in women heterozygous for X-linked hypohidrotic ectodermal dysplasia. Clin Genet 27:468–471Google Scholar
  46. Hasegawa Y, Brockdorff N, Kawano S et al (2010) The matrix protein hnRNP U is required for chromosomal localization of Xist RNA. Dev Cell 19:469–476. doi: 10.1016/j.devcel.2010.08.006 PubMedCrossRefGoogle Scholar
  47. Hatakeyama C, Anderson CL, Beever CL et al (2004) The dynamics of X-inactivation skewing as women age. Clin Genet 66:327–332. doi: 10.1111/j.1399-0004.2004.00310.x PubMedCrossRefGoogle Scholar
  48. Hayes J, Peruzzi PP, Lawler S (2014) MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol Med 20:460–469. doi: 10.1016/j.molmed.2014.06.005 PubMedCrossRefGoogle Scholar
  49. Heard E, Disteche CM (2006) Dosage compensation in mammals: fine-tuning the expression of the X chromosome. Genes Dev 20:1848–1867. doi: 10.1101/gad.1422906 PubMedCrossRefGoogle Scholar
  50. Heard E, Kress C, Mongelard F et al (1996) Transgenic mice carrying an Xist-containing YAC. Hum Mol Genet 5:441–450PubMedCrossRefGoogle Scholar
  51. Heard E, Rougeulle C, Arnaud D et al (2001) Methylation of histone H3 at Lys-9 is an early mark on the X chromosome during X inactivation. Cell 107:727–738PubMedCrossRefGoogle Scholar
  52. Henry NL, Hayes DF (2012) Cancer biomarkers. Molecular Oncology 6:140–146. doi: 10.1016/j.molonc.2012.01.010 PubMedCrossRefGoogle Scholar
  53. Huang Y-S, Hsieh H-Y, Shih H-M et al (2014) Urinary Xist is a potential biomarker for membranous nephropathy. Biochem Biophys Res Commun 452:415–421. doi: 10.1016/j.bbrc.2014.08.077 PubMedCrossRefGoogle Scholar
  54. Huynh KD, Lee JT (2003) Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos. Nature 426:857–862PubMedCrossRefGoogle Scholar
  55. Jeon Y, Lee JT (2011) YY1 tethers Xist RNA to the inactive X nucleation center. Cell 146:119–133. doi: 10.1016/j.cell.2011.06.026 PubMedPubMedCentralCrossRefGoogle Scholar
  56. Jiang J, Brown CJ, Jing Y et al (2013) Translating dosage compensation to trisomy 21. Nature. doi: 10.1038/nature12394 Google Scholar
  57. Johnston CM, Newall AET, Brockdorff N, Nesterova TB (2002) Enox, a novel gene that maps 10 kb upstream of Xist and partially escapes X inactivation. Genomics 80:236–244PubMedCrossRefGoogle Scholar
  58. Kawakami T, Okamoto K, Ogawa O, Okada Y (2004a) XIST unmethylated DNA fragments in male-derived plasma as a tumour marker for testicular cancer. Lancet 363:40–42. doi: 10.1016/S0140-6736(03)15170-7 PubMedCrossRefGoogle Scholar
  59. Kawakami T, Okamoto K, Sugihara H et al (2003) The roles of supernumerical X chromosomes and XIST expression in testicular germ cell tumors. J Urol 169:1546–1552. doi: 10.1097/01.ju.0000044927.23323.5a PubMedCrossRefGoogle Scholar
  60. Kawakami T, Zhang C, Taniguchi T et al (2004b) Characterization of loss-of-inactive X in Klinefelter syndrome and female-derived cancer cells. Oncogene 23:6163–6169. doi: 10.1038/sj.onc.1207808 PubMedCrossRefGoogle Scholar
  61. Keer JT, Hamvas RM, Brockdorff N et al (1990) Genetic mapping in the region of the mouse X-inactivation center. Genomics 7:566–572PubMedCrossRefGoogle Scholar
  62. Keohane AM, O’neill LP, Belyaev ND et al (1996) X-inactivation and histone H4 acetylation in embryonic stem cells. Dev Biol 180:618–630. doi: 10.1006/dbio.1996.0333 PubMedCrossRefGoogle Scholar
  63. Kim K, Doi A, Wen B (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467:285–290. doi: 10.1038/nature09342 PubMedPubMedCentralCrossRefGoogle Scholar
  64. Kobayashi S, Totoki Y, Soma M et al (2013) Identification of an imprinted gene cluster in the X-inactivation center. PLoS ONE 8:e71222. doi: 10.1371/journal.pone.0071222 PubMedPubMedCentralCrossRefGoogle Scholar
  65. Kohlmaier A, Savarese F, Lachner M et al (2004) A chromosomal memory triggered by Xist regulates histone methylation in X inactivation. PLoS Biol 2:e171. doi: 10.1371/journal.pbio.0020171 PubMedPubMedCentralCrossRefGoogle Scholar
  66. König J, Zarnack K, Rot G et al (2010) iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 17:909–915. doi: 10.1038/nsmb.1838 PubMedPubMedCentralCrossRefGoogle Scholar
  67. Krepischi AC, Kok F, Otto PG (1998) X chromosome-inactivation patterns in patients with Rett syndrome. Hum Genet 102:319–321PubMedCrossRefGoogle Scholar
  68. Kristiansen M, Knudsen GPS, Maguire P et al (2005) High incidence of skewed X chromosome inactivation in young patients with familial non-BRCA1/BRCA2 breast cancer. J Med Genet 42:877–880. doi: 10.1136/jmg.2005.032433 PubMedPubMedCentralCrossRefGoogle Scholar
  69. Kristiansen M, Langerød A, Knudsen GP et al (2002) High frequency of skewed X inactivation in young breast cancer patients. J Med Genet 39:30–33. doi: 10.1136/jmg.39.1.30 PubMedPubMedCentralCrossRefGoogle Scholar
  70. Lam MTY, Li W, Rosenfeld MG, Glass CK (2014) Enhancer RNAs and regulated transcriptional programs. Trends Biochem Sci 39:170–182. doi: 10.1016/j.tibs.2014.02.007 PubMedPubMedCentralCrossRefGoogle Scholar
  71. Lee JT (2000) Disruption of imprinted X inactivation by parent-of-origin effects at Tsix. Cell 103:17–27PubMedCrossRefGoogle Scholar
  72. Lee JT, Bartolomei MS (2013) X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152:1308–1323. doi: 10.1016/j.cell.2013.02.016 PubMedCrossRefGoogle Scholar
  73. Lee JT, Davidow LS, Warshawsky D (1999a) Tsix, a gene antisense to Xist at the X-inactivation centre. Nat Genet 21:400–404. doi: 10.1038/7734 PubMedCrossRefGoogle Scholar
  74. Lee JT, Jaenisch R (1997) Long-range cis effects of ectopic X-inactivation centres on a mouse autosome. Nature 386:275–279. doi: 10.1038/386275a0 PubMedCrossRefGoogle Scholar
  75. Lee JT, Lu N (1999) Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 99:47–57PubMedCrossRefGoogle Scholar
  76. Lee JT, Lu N, Han Y (1999b) Genetic analysis of the mouse X inactivation center defines an 80-kb multifunction domain. Proc Natl Acad Sci U S A 96:3836–3841PubMedPubMedCentralCrossRefGoogle Scholar
  77. Lee JT, Strauss WM, Dausman J, Jaenisch R (1996) A 450 kb transgene displays properties of the mammalian X-inactivation center. Cell 86:83–94PubMedCrossRefGoogle Scholar
  78. Lessing D, Anguera MC, Lee JT (2013) X chromosome inactivation and epigenetic responses to cellular reprogramming. Annu Rev Genomics Hum Genet. doi: 10.1146/annurev-genom-091212-153530 PubMedGoogle Scholar
  79. Liang F, Holt I, Pertea G et al (2000) Gene index analysis of the human genome estimates approximately 120,000 genes. Nat Genet 25:239–240. doi: 10.1038/76126 PubMedCrossRefGoogle Scholar
  80. Liao DJ, Du Q-Q, Yu BW et al (2003) Novel perspective: focusing on the X chromosome in reproductive cancers. Cancer Invest 21:641–658PubMedCrossRefGoogle Scholar
  81. Lieberman-Aiden E, van Berkum NL, Williams L et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326:289–293. doi: 10.1126/science.1181369 PubMedPubMedCentralCrossRefGoogle Scholar
  82. Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373PubMedCrossRefGoogle Scholar
  83. Lyon MF (2000) LINE-1 elements and X chromosome inactivation: a function for “junk” DNA? Proc Natl Acad Sci USA 97:6248–6249PubMedPubMedCentralCrossRefGoogle Scholar
  84. Maass PG, Luft FC, Bahring S (2014) Long non-coding RNA in health and disease. J Mol Med 92:337–346. doi: 10.1007/s00109-014-1131-8 PubMedCrossRefGoogle Scholar
  85. Mak W, Nesterova TB, de Napoles M et al (2004) Reactivation of the paternal X chromosome in early mouse embryos. Science 303:666–669. doi: 10.1126/science.1092674 PubMedCrossRefGoogle Scholar
  86. Mak W, Silva J, Baxter J et al (2002) Mitotically stable association of polycomb group proteins eed and enx1 with the inactive X chromosome in trophoblast stem cells. Curr Biol 12:1016–1020PubMedCrossRefGoogle Scholar
  87. Marahrens Y, Panning B, Dausman J et al (1997) Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev 11:156–166PubMedCrossRefGoogle Scholar
  88. Martinez-Pomar N, Munoz-Saa I, Heine-Suner D et al (2005) A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency. Hum Genet 118:458–465. doi: 10.1007/s00439-005-0068-y PubMedCrossRefGoogle Scholar
  89. Mégarbané A, Ravel A, Mircher C et al (2009) The 50th anniversary of the discovery of trisomy 21: the past, present, and future of research and treatment of Down syndrome. Genet Med 11:611–616. doi: 10.1097/GIM.0b013e3181b2e34c PubMedCrossRefGoogle Scholar
  90. Migeon BR (2006) The role of X inactivation and cellular mosaicism in women’s health and sex-specific diseases. JAMA 295:1428–1433. doi: 10.1001/jama.295.12.1428 PubMedCrossRefGoogle Scholar
  91. Minks J, Robinson WP, Brown CJ (2008) A skewed view of X chromosome inactivation. J Clin Invest 118:20–23. doi: 10.1172/JCI34470 PubMedPubMedCentralCrossRefGoogle Scholar
  92. Monk M, Harper MI (1979) Sequential X chromosome inactivation coupled with cellular differentiation in early mouse embryos. Nature 281:311–313PubMedCrossRefGoogle Scholar
  93. Natoli G, Andrau J-C (2012) Noncoding transcription at enhancers: general principles and functional models. Annu Rev Genet 46:1–19. doi: 10.1146/annurev-genet-110711-155459 PubMedCrossRefGoogle Scholar
  94. Navarro P (2005) Tsix transcription across the Xist gene alters chromatin conformation without affecting Xist transcription: implications for X-chromosome inactivation. Genes Dev 19:1474–1484. doi: 10.1101/gad.341105 PubMedPubMedCentralCrossRefGoogle Scholar
  95. Norris DP, Brockdorff N, Rastan S (1991) Methylation status of CpG-rich islands on active and inactive mouse X chromosomes. Mamm Genome 1:78–83PubMedCrossRefGoogle Scholar
  96. Nozawa R-S, Nagao K, Igami K-T et al (2013) Human inactive X chromosome is compacted through a PRC2-independent SMCHD1-HBiX1 pathway. Nat Struct Mol Biol. doi: 10.1038/nsmb.2532 PubMedGoogle Scholar
  97. Ogawa Y, Lee JT (2003) Xite, X-inactivation intergenic transcription elements that regulate the probability of choice. Mol Cell 11:731–743PubMedCrossRefGoogle Scholar
  98. Ohhata T, Hoki Y, Sasaki H, Sado T (2008) Crucial role of antisense transcription across the Xist promoter in Tsix-mediated Xist chromatin modification. Development 135:227–235. doi: 10.1242/dev.008490 PubMedCrossRefGoogle Scholar
  99. Ohhata T, Wutz A (2013) Reactivation of the inactive X chromosome in development and reprogramming. Cell Mol Life Sci 70:2443–2461. doi: 10.1007/s00018-012-1174-3 PubMedPubMedCentralCrossRefGoogle Scholar
  100. Okamoto I, Otte AP, Allis CD et al (2004) Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 303:644–649. doi: 10.1126/science.1092727 PubMedCrossRefGoogle Scholar
  101. Orazi A, Germing U (2008) The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22:1308–1319. doi: 10.1038/leu.2008.119 PubMedCrossRefGoogle Scholar
  102. Pageau G, Hall LL, Ganesan S et al (2007) The disappearing Barr body in breast and ovarian cancers. Nat Rev Cancer 7:628–633. doi: 10.1038/nrc2172 PubMedCrossRefGoogle Scholar
  103. Payer B, Lee JT (2008) X chromosome dosage compensation: how mammals keep the balance. Annu Rev Genet 42:733–772. doi: 10.1146/annurev.genet.42.110807.091711 PubMedCrossRefGoogle Scholar
  104. Penny GD, Kay GF, Sheardown SA et al (1996) Requirement for Xist in X chromosome inactivation. Nature 379:131–137. doi: 10.1038/379131a0 PubMedCrossRefGoogle Scholar
  105. Peschansky VJ, Wahlestedt C (2014) Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics (official journal of the DNA Methylation Society) 9:3–12. doi: 10.4161/epi.27473 CrossRefGoogle Scholar
  106. Pinter SF, Sadreyev R, Yildirim E et al (2012) Spreading of X chromosome inactivation via a hierarchy of defined Polycomb stations. Genome Res 22:1864–1876. doi: 10.1101/gr.133751.111 PubMedPubMedCentralCrossRefGoogle Scholar
  107. Plath K, Fang J, Mlynarczyk-Evans SK et al (2003) Role of histone H3 lysine 27 methylation in X inactivation. Science 300:131–135. doi: 10.1126/science.1084274 PubMedCrossRefGoogle Scholar
  108. Plath K, Talbot D, Hamer KM et al (2004) Developmentally regulated alterations in Polycomb repressive complex 1 proteins on the inactive X chromosome. J Cell Biol 167:1025–1035. doi: 10.1083/jcb.200409026 PubMedPubMedCentralCrossRefGoogle Scholar
  109. Puck JM, Nussbaum RL, Conley ME (1987) Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation. J Clin Invest 79:1395–1400. doi: 10.1172/JCI112967 PubMedPubMedCentralCrossRefGoogle Scholar
  110. Pullirsch D, Härtel R, Kishimoto H et al (2010) The Trithorax group protein Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation. Development 137:935–943. doi: 10.1242/dev.035956 PubMedPubMedCentralCrossRefGoogle Scholar
  111. Rastan S (1983) Non-random X-chromosome inactivation in mouse X-autosome translocation embryos–location of the inactivation centre. J Embryol Exp Morphol 78:1–22. doi: 10.1016/s0065-2660(08)60074-7 PubMedGoogle Scholar
  112. Rastan S, Brown SD (1990) The search for the mouse X-chromosome inactivation centre. Genet Res 56:99–106PubMedCrossRefGoogle Scholar
  113. Rastan S, Robertson E (1985) X-chromosome deletions in embryo-derived (EK) cell lines associated with lack of X-chromosome inactivation. J Embryol Exp Morphol 90:379–388PubMedGoogle Scholar
  114. Richardson A, Wang Z, de Nicolo A et al (2006) X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9:121–132PubMedCrossRefGoogle Scholar
  115. Rogner UC, Wilke K, Steck E et al (1995) The melanoma antigen gene (MAGE) family is clustered in the chromosomal band Xq28. Genomics 29:725–731. doi: 10.1006/geno.1995.9945 PubMedCrossRefGoogle Scholar
  116. Sado T, Brockdorff N (2013) Advances in understanding chromosome silencing by the long non-coding RNA Xist. Philos Trans R Soc Lond B Biol Sci 368:20110325. doi: 10.1098/rstb.2011.0325 PubMedPubMedCentralCrossRefGoogle Scholar
  117. Sado T, Fenner MH, Tan SS et al (2000) X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev Biol 225:294–303. doi: 10.1006/dbio.2000.9823 PubMedCrossRefGoogle Scholar
  118. Sado T, Hoki Y, Sasaki H (2005) Tsix silences Xist through modification of chromatin structure. Dev Cell 9:159–165. doi: 10.1016/j.devcel.2005.05.015 PubMedCrossRefGoogle Scholar
  119. Sado T, Wang Z, Sasaki H, Li E (2001) Regulation of imprinted X-chromosome inactivation in mice by Tsix. Development 128:1275–1286PubMedGoogle Scholar
  120. Sharp A, Robinson D, Jacobs P (2000) Age-and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 107:343–349. doi: 10.1007/s004390000382 PubMedCrossRefGoogle Scholar
  121. Sharp AJ, Stathaki E, Migliavacca E et al (2011) DNA methylation profiles of human active and inactive X chromosomes. Genome Res 21:1592–1600. doi: 10.1101/gr.112680.110 PubMedPubMedCentralCrossRefGoogle Scholar
  122. Silva J, Mak W, Zvetkova I et al (2003) Establishment of histone H3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. Dev Cell 4:481–495. doi: 10.1016/S1534-5807(03)00068-6 PubMedCrossRefGoogle Scholar
  123. Silva SS, Rowntree RK, Mekhoubad S, Lee JT (2008) X-chromosome inactivation and epigenetic fluidity in human embryonic stem cells. Proc Natl Acad Sci USA 105:4820–4825. doi: 10.1073/pnas.0712136105 PubMedPubMedCentralCrossRefGoogle Scholar
  124. Simmler MC, Cunningham DB, Clerc P et al (1996) A 94 kb genomic sequence 3’ to the murine Xist gene reveals an AT rich region containing a new testis specific gene Tsx. Hum Mol Genet 5:1713–1726PubMedCrossRefGoogle Scholar
  125. Simon MD, Pinter SF, Fang R et al (2013) High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature 504:465–469. doi: 10.1038/nature12719 PubMedPubMedCentralCrossRefGoogle Scholar
  126. Simon MD, Wang CI, Kharchenko PV et al (2011) The genomic binding sites of a noncoding RNA. Proc Natl Acad Sci 108:20497–20502. doi: 10.1073/pnas.1113536108 PubMedPubMedCentralCrossRefGoogle Scholar
  127. Sirchia SM, Ramoscelli L, Grati FR et al (2005) Loss of the inactive X chromosome and replication of the active X in BRCA1-defective and wild-type breast cancer cells. Cancer Res 65:2139–2146. doi: 10.1158/0008-5472.CAN-04-3465 PubMedCrossRefGoogle Scholar
  128. Smahi A, Courtois G, Vabres P et al (2000) Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The international incontinentia pigmenti (IP) consortium. Nature 405:466–472. doi: 10.1038/35013114 PubMedCrossRefGoogle Scholar
  129. Soma M, Fujihara Y, Okabe M et al (2014) Ftx is dispensable for imprinted X-chromosome inactivation in preimplantation mouse embryos. Scientific Reports 4:5181. doi: 10.1038/srep05181 PubMedCrossRefGoogle Scholar
  130. Spatz A, Borg C, Feunteun J (2004) X-chromosome genetics and human cancer. Nat Rev Cancer 4:617–629. doi: 10.1038/nrc1413 PubMedCrossRefGoogle Scholar
  131. Splinter E, de Wit E, Nora EP et al (2011) The inactive X chromosome adopts a unique three-dimensional conformation that is dependent on Xist RNA. Genes Dev 25:1371–1383. doi: 10.1101/gad.633311 PubMedPubMedCentralCrossRefGoogle Scholar
  132. Stavropoulos N, Rowntree RK, Lee JT (2005) Identification of developmentally specific enhancers for Tsix in the regulation of X chromosome inactivation. Mol Cell Biol 25:2757–2769. doi: 10.1128/MCB.25.7.2757-2769.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  133. Sun BK, Deaton A, Lee JT (2006) A transient heterochromatic state in Xist preempts X inactivation choice without RNA stabilization. Mol Cell 21:617–628PubMedCrossRefGoogle Scholar
  134. Sun BK, Tsao H (2008) X-chromosome inactivation and skin disease. J Investig Dermatol 128:2753–2759. doi: 10.1038/jid.2008.145 PubMedCrossRefGoogle Scholar
  135. Sun S, Del Rosario BC, Szanto A et al (2013) Jpx RNA activates Xist by evicting CTCF. Cell 153:1537–1551. doi: 10.1016/j.cell.2013.05.028 PubMedPubMedCentralCrossRefGoogle Scholar
  136. Sybert VP, McCauley E (2004) Turner’s syndrome. N Engl J Med 351:1227–1238. doi: 10.1056/NEJMra030360 PubMedCrossRefGoogle Scholar
  137. Takagi N (1980) Primary and secondary nonrandom X chromosome inactivation in early female mouse embryos carrying Searle’s translocation T(X; 16)16H. Chromosoma 81:439–459PubMedCrossRefGoogle Scholar
  138. Takagi N, Sasaki M (1975) Preferential inactivation of the paternally derived X chromosome in the extraembryonic membranes of the mouse. Nature 256:640–642PubMedCrossRefGoogle Scholar
  139. Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. doi: 10.1016/j.cell.2007.11.019 PubMedCrossRefGoogle Scholar
  140. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRefGoogle Scholar
  141. Tan SS, Williams EA, Tam PP (1993) X-chromosome inactivation occurs at different times in different tissues of the post-implantation mouse embryo. Nat Genet 3:170–174. doi: 10.1038/ng0293-170 PubMedCrossRefGoogle Scholar
  142. Thomas GA, Williams D, Williams ED (1988) The demonstration of tissue clonality by X-linked enzyme histochemistry. J Pathol 155:101–108. doi: 10.1002/path.1711550205 PubMedCrossRefGoogle Scholar
  143. Tian D, Sun S, Lee JT (2010) The long noncoding RNA, Jpx, is a molecular switch for X chromosome inactivation. Cell 143:390–403. doi: 10.1016/j.cell.2010.09.049 PubMedPubMedCentralCrossRefGoogle Scholar
  144. Tomoda K, Takahashi K, Leung K et al (2012) Derivation conditions impact X-inactivation status in female human induced pluripotent stem cells. Cell Stem Cell 11:91–99. doi: 10.1016/j.stem.2012.05.019 PubMedPubMedCentralCrossRefGoogle Scholar
  145. Torres EM, Williams BR, Amon A (2008) Aneuploidy: cells losing their balance. Genetics 179:737–746. doi: 10.1534/genetics.108.090878 PubMedPubMedCentralCrossRefGoogle Scholar
  146. Van Echten-Arends J, Coonen E, Reuters B et al (2013) Preimplantation genetic diagnosis for X;autosome translocations: lessons from a case of misdiagnosis. Hum Reprod 28:3141–3145. doi: 10.1093/humrep/det362 PubMedCrossRefGoogle Scholar
  147. Viggiano E, Picillo E, Cirillo A, Politano L (2013) Comparison of X-chromosome inactivation in Duchenne muscle/myocardium-manifesting carriers, non-manifesting carriers and related daughters. Clin Genet 84:265–270. doi: 10.1111/cge.12048 PubMedCrossRefGoogle Scholar
  148. Vigneau S, Augui S, Navarro P et al (2006) An essential role for the DXPas34 tandem repeat and Tsix transcription in the counting process of X chromosome inactivation. Proc Natl Acad Sci USA 103:7390–7395. doi: 10.1073/pnas.0602381103 PubMedPubMedCentralCrossRefGoogle Scholar
  149. Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43:904–914. doi: 10.1016/j.molcel.2011.08.018 PubMedPubMedCentralCrossRefGoogle Scholar
  150. Wapinski OL, Chang HY (2011) Long noncoding RNAs and human disease. Trends Cell Biol 21:354–361. doi: 10.1016/j.tcb.2011.04.001 PubMedCrossRefGoogle Scholar
  151. Weaving LS, Ellaway CJ, Gécz J, Christodoulou J (2005) Rett syndrome: clinical review and genetic update. J Med Genet 42:1–7. doi: 10.1136/jmg.2004.027730 PubMedPubMedCentralCrossRefGoogle Scholar
  152. Weaving LS, Williamson SL, Bennetts B et al (2003) Effects ofMECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype. Am J Med Genet 118A:103–114. doi: 10.1002/ajmg.a.10053 PubMedCrossRefGoogle Scholar
  153. White WM, Willard HF, van Dyke DL, Wolff DJ (1998) The spreading of X inactivation into autosomal material of an x;autosome translocation: evidence for a difference between autosomal and X-chromosomal DNA. Am J Hum Genet 63:20–28. doi: 10.1086/301922 PubMedPubMedCentralCrossRefGoogle Scholar
  154. Wutz A (2011) Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat Rev Genet 12:542–553. doi: 10.1038/nrg3035 PubMedCrossRefGoogle Scholar
  155. Wutz A, Jaenisch R (2000) A shift from reversible to irreversible X inactivation is triggered during ES cell differentiation. Mol Cell 5:695–705PubMedCrossRefGoogle Scholar
  156. Yildirim E, Kirby JE, Brown DE et al (2013) Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152:727–742. doi: 10.1016/j.cell.2013.01.034 PubMedCrossRefGoogle Scholar
  157. Yoshioka M, Yorifuji T, Mituyoshi I (1998) Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy. Clin Genet 53:102–107PubMedCrossRefGoogle Scholar
  158. Zhang L-F, Huynh KD, Lee JT (2007) Perinucleolar targeting of the inactive X during S phase: evidence for a role in the maintenance of silencing. Cell 129:693–706. doi: 10.1016/j.cell.2007.03.036 PubMedCrossRefGoogle Scholar
  159. Zhao J, Sun BK, Erwin JA et al (2008) Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322:750–756. doi: 10.1126/science.1163045 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Division of Reproductive Sciences, Cincinnati Children’s Hospital Medical Center; Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiUSA

Personalised recommendations