Human Genetics

, Volume 130, Issue 2, pp 175–185

X-chromosome inactivation: molecular mechanisms from the human perspective

  • Christine Yang
  • Andrew G. Chapman
  • Angela D. Kelsey
  • Jakub Minks
  • Allison M. Cotton
  • Carolyn J. Brown
Review Paper

Abstract

X-chromosome inactivation is an epigenetic process whereby one X chromosome is silenced in mammalian female cells. Since it was first proposed by Lyon in 1961, mouse models have been valuable tools to uncover the molecular mechanisms underlying X inactivation. However, there are also inherent differences between mouse and human X inactivation, ranging from sequence content of the X inactivation center to the phenotypic outcomes of X-chromosome abnormalities. X-linked gene dosage in males, females, and individuals with X aneuploidies and X/autosome translocations has demonstrated that many human genes escape X inactivation, implicating cis-regulatory elements in the spread of silencing. We discuss the potential nature of these elements and also review the elements in the X inactivation center involved in the early events in X-chromosome inactivation.

References

  1. Acar M, Pando BF, Arnold FH, Elowitz MB, van Oudenaarden A (2010) A general mechanism for network-dosage compensation in gene circuits. Science 329(5999):1656–1660PubMedCrossRefGoogle Scholar
  2. Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE, Longshore J, Willard HF (2006) X chromosome-inactivation patterns of 1, 005 phenotypically unaffected females. Am J Hum Genet 79(3):493–499PubMedCrossRefGoogle Scholar
  3. Augui S, Filion GJ, Huart S, Nora E, Guggiari M, Maresca M, Stewart AF, Heard E (2007) Sensing X chromosome pairs before X inactivation via a novel X-pairing region of the Xic. Science 318(5856):1632–1636PubMedCrossRefGoogle Scholar
  4. Bacher CP, Guggiari M, Brors B, Augui S, Clerc P, Avner P, Eils R, Heard E (2006) Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation. Nat Cell Biol 8(3):293–299PubMedCrossRefGoogle Scholar
  5. Barakat TS, Gunhanlar N, Gontan Pardo C, Achame EM, Ghazvini M, Boers R, Kenter A, Rentmeester E, Grootegoed JA, Gribnau J (2011) RNF12 activates Xist and is essential for X chromosome inactivation. PLoS Genet 7(1):e1002001PubMedCrossRefGoogle Scholar
  6. Barr ML, Bertram EG (1949) A morphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature 163:676–677PubMedCrossRefGoogle Scholar
  7. Barr ML, Shaver EL, Carr DH, Plunkett ER (1959) An unusual sex chromatin pattern in three mentally deficient subjects. J Ment Defic Res 3:78–87PubMedGoogle Scholar
  8. Berletch JB, Yang F, Disteche CM (2010) Escape from X inactivation in mice and humans. Genome Biol 11(6):213PubMedGoogle Scholar
  9. Bolduc V, Chagnon P, Provost S, Dube M-P, Belisle C, Gingras M, Mollica L, Busque L (2008) No evidence that skewing of X-chromosome inactivation patterns is transmitted to offspring in humans. J Clin Invest 118:333–341Google Scholar
  10. Bondy CA, Matura LA, Wooten N, Troendle J, Zinn AR, Bakalov VK (2007) The physical phenotype of girls and women with Turner syndrome is not X-imprinted. Hum Genet 121(3–4):469–474PubMedCrossRefGoogle Scholar
  11. Brown CJ, Willard HF (1993) Molecular and genetic studies of human X chromosome inactivation. Adv Dev Biol 2:37–72CrossRefGoogle Scholar
  12. Brown CJ, Willard HF (1994) The human X inactivation center is not required for maintenance of X inactivation. Nature 368:154–156PubMedCrossRefGoogle Scholar
  13. Brown CJ, Ballabio A, Rupert JL, Lafreniere RG, Grompe M, Tonlorenzi R, Willard HF (1991a) A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Nature 349:38–44PubMedCrossRefGoogle Scholar
  14. Brown CJ, Lafreniere RG, Powers VE, Sebastio G, Ballabio A, Pettigrew AL, Ledbetter DH, Levy E, Craig IW, Willard HF (1991b) Localization of the X inactivation centre on the human X chromosome in Xq13. Nature 349(6304):82–84PubMedCrossRefGoogle Scholar
  15. Caiulo A, Bardoni B, Camerino G, Guioli S, Minelli A, Piantanida M, Crosato F, Dalla Fior T, Maraschio P (1989) Cytogenetic and molecular analysis of an unbalanced translocation (X;7) (q28;p15) in a dysmorphic girl. Hum Genet 84(1):51–54PubMedCrossRefGoogle Scholar
  16. Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434(7031):400–404PubMedCrossRefGoogle Scholar
  17. Carrel L, Cottle AA, Goglin KC, Willard HF (1999) A first-generation X-inactivation profile of the human X chromosome. Proc Natl Acad Sci USA 96(25):14440–14444PubMedCrossRefGoogle Scholar
  18. Cattanach BM, Issacson JH (1967) Controlling elements in the mouse X chromosome. Genetics 57:331–346PubMedGoogle Scholar
  19. Chang SC, Brown CJ (2010) Identification of regulatory elements flanking human XIST reveals species differences. BMC Mol Biol 11:20PubMedCrossRefGoogle Scholar
  20. Changolkar LN, Singh G, Cui K, Berletch JB, Zhao K, Disteche CM, Pehrson JR (2010) Genome-wide distribution of macroH2A1 histone variants in mouse liver chromatin. Mol Cell Biol 30(23):5473–5483PubMedCrossRefGoogle Scholar
  21. 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(16):2223–2237PubMedCrossRefGoogle Scholar
  22. Chow J, Heard E (2009) X inactivation and the complexities of silencing a sex chromosome. Curr Opin Cell Biol 21(3):359–366PubMedCrossRefGoogle Scholar
  23. Chow JC, Hall LL, Clemson CM, Lawrence JB, Brown CJ (2003) Characterization of expression at the human XIST locus in somatic, embryonal carcinoma, and transgenic cell lines. Genomics 82(3):309–322PubMedCrossRefGoogle Scholar
  24. Chow JC, Hall LL, Baldry SE, Thorogood NP, Lawrence JB, Brown CJ (2007) Inducible XIST-dependent X-chromosome inactivation in human somatic cells is reversible. Proc Natl Acad Sci USA 104(24):10104–10109PubMedCrossRefGoogle Scholar
  25. Chow JC, Ciaudo C, Fazzari MJ, Mise N, Servant N, Glass JL, Attreed M, Avner P, Wutz A, Barillot E, Greally JM, Voinnet O, Heard E (2010) LINE-1 activity in facultative heterochromatin formation during X chromosome inactivation. Cell 141(6):956–969PubMedCrossRefGoogle Scholar
  26. Chureau C, Prissette M, Bourdet A, Barbe V, Cattolico L, Jones L, Eggen A, Avner P, Duret L (2002) Comparative sequence analysis of the X-inactivation center region in mouse, human and bovine. Genome Res 12:894–908PubMedGoogle Scholar
  27. Chureau C, Chantalat S, Romito A, Galvani A, Duret L, Avner P, Rougeulle C (2011) Ftx is a non-coding RNA which affects Xist expression and chromatin structure within the X-inactivation center region. Hum Mol Genet 20(4):705–718PubMedCrossRefGoogle Scholar
  28. Ciccodicola A, D’Esposito M, Esposito T, Gianfrancesco F, Migliaccio C, Miano MG, Matarazzo MR, Vacca M, Franze A, Cuccurese M, Cocchia M, Curci A, Terracciano A, Torino A, Cocchia S et al (2000) Differentially regulated and evolved genes in the fully sequenced Xq/Yq pseudoautosomal region. Hum Mol Genet 9:395–401PubMedCrossRefGoogle Scholar
  29. Craig IW, Mill J, Craig GM, Loat C, Schalkwyk LC (2004) Application of microarrays to the analysis of the inactivation status of human X-linked genes expressed in lymphocytes. Eur J Hum Genet 12(8):639–646PubMedCrossRefGoogle Scholar
  30. Davidson RG, Nitowsky HM, Childs B (1963) Demonstration of two populations of cells in the human female heterozygous for glucose-6-phosphate dehydrogenase variants. Proc Natl Acad Sci USA 50:481–485PubMedCrossRefGoogle Scholar
  31. Davies W, Isles A, Smith R, Karunadasa D, Burrmann D, Humby T, Ojarikre O, Biggin C, Skuse D, Burgoyne P, Wilkinson L (2005) Xlr3b is a new imprinted candidate for X-linked parent-of-origin effects on cognitive function in mice. Nat Genet 37(6):625–629PubMedCrossRefGoogle Scholar
  32. Debrand E, Chureau C, Arnaud D, Avner P, Heard E (1999) Functional analysis of the DXPas34 locus, a 3′ regulator of Xist expression. Mol Cell Biol 19:8513–8525PubMedGoogle Scholar
  33. Dobrovolny R, Dvorakova L, Ledvinova J, Magage S, Bultas J, Lubanda JC, Elleder M, Karetova D, Pavlikova M, Hrebicek M (2005) Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population. J Mol Med 83(8):647–654PubMedCrossRefGoogle Scholar
  34. Donohoe ME, Zhang LF, Xu N, Shi Y, Lee JT (2007) Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch. Mol Cell 25(1):43–56PubMedCrossRefGoogle Scholar
  35. Donohoe ME, Silva SS, Pinter SF, Xu N, Lee JT (2009) The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting. Nature 460(7251):128–132PubMedCrossRefGoogle Scholar
  36. Dvash T, Lavon N, Fan G (2010) Variations of X chromosome inactivation occur in early passages of female human embryonic stem cells. PLoS One 5(6):e11330PubMedCrossRefGoogle Scholar
  37. Ellison JW, Wardak Z, Young MF, Gehron Robey P, Laig-Webster M, Chiong W (1997) PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet 6(8):1341–1347PubMedCrossRefGoogle Scholar
  38. Epstein CJ (1969) Mammalian oocytes: X chromosome activity. Science 163(871):1078–1079PubMedCrossRefGoogle Scholar
  39. Filippova GN, Cheng MK, Moore JM, Truong JP, Hu YJ, Nguyen DK, Tsuchiya KD, Disteche CM (2005) Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development. Dev Cell 8(1):31–42PubMedCrossRefGoogle Scholar
  40. Ford CE, Jones KW, Polani PE, De Almeida JC, Briggs JH (1959) A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome). Lancet 1(7075):711–713PubMedCrossRefGoogle Scholar
  41. Gartler SM, Riggs AD (1983) Mammalian X-chromosome inactivation. Ann Rev Genet 17:155–190PubMedCrossRefGoogle Scholar
  42. Giorda R, Bonaglia MC, Milani G, Baroncini A, Spada F, Beri S, Menozzi G, Rusconi M, Zuffardi O (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(8):897–905PubMedCrossRefGoogle Scholar
  43. Goto Y, Kimura H (2009) Inactive X chromosome-specific histone H3 modifications and CpG hypomethylation flank a chromatin boundary between an X-inactivated and an escape gene. Nucleic Acids Res 37(22):7416–7428PubMedCrossRefGoogle Scholar
  44. Goto Y, Takagi N (1999) Maternaly inherited X chromosome is not inactivated in mouse blastocysts due to parental imprinting. Chromosome Res 7:101–109Google Scholar
  45. Graves JA (2006) Sex chromosome specialization and degeneration in mammals. Cell 124(5):901–914PubMedCrossRefGoogle Scholar
  46. Graves JA, Koina E, Sankovic N (2006) How the gene content of human sex chromosomes evolved. Curr Opin Genet Dev 16(3):219–224PubMedCrossRefGoogle Scholar
  47. Hall LL, Byron M, Sakai K, Carrel L, Willard HF, Lawrence JB (2002a) An ectopic human XIST gene can induce chromosome inactivation in postdifferentiation human HT-1080 cells. Proc Natl Acad Sci USA 99(13):8677–8682PubMedCrossRefGoogle Scholar
  48. Hall LL, Clemson CM, Byron M, Wydner K, Lawrence JB (2002b) Unbalanced X;autosome translocations provide evidence for sequence specificity in the association of XIST RNA with chromatin. Hum Mol Genet 11:3157–3165PubMedCrossRefGoogle Scholar
  49. Hall H, Hunt P, Hassold T (2006) Meiosis and sex chromosome aneuploidy: how meiotic errors cause aneuploidy; how aneuploidy causes meiotic errors. Curr Opin Genet Dev 16(3):323–329PubMedCrossRefGoogle Scholar
  50. Hall LL, Byron M, Butler J, Becker KA, Nelson A, Amit M, Itskovitz-Eldor J, Stein J, Stein G, Ware C, Lawrence JB (2008) X-inactivation reveals epigenetic anomalies in most hESC but identifies sublines that initiate as expected. J Cell Physiol 216(2):445–452PubMedCrossRefGoogle Scholar
  51. Hoffman LM, Hall L, Batten JL, Young H, Pardasani D, Baetge EE, Lawrence J, Carpenter MK (2005) X-inactivation status varies in human embryonic stem cell lines. Stem Cells 23(10):1468–1478PubMedCrossRefGoogle Scholar
  52. Jacobs PA, Baikie AG, Brown WM, Macgregor TN, Maclean N, Harnden DG (1959) Evidence for the existence of the human “super female”. Lancet 2(7100):423–425PubMedCrossRefGoogle Scholar
  53. Jacobs PA, Melville M, Ratcliffe S, Keay AJ, Syme J (1974) A cytogenetic survey of 11,680 newborn infants. Ann Hum Genet 37(4):359–376PubMedCrossRefGoogle Scholar
  54. Jacobs PA, Matsuyama AM, Buchanan IM, Wilson C (1979) Late replicating X chromosomes in human triploidy. Am J Hum Genet 31:446–457PubMedGoogle Scholar
  55. Jacobs PA, Hunt PA, Mayer M, Bart RD (1981) Duchenne muscular dystrophy (DMD) in a female with an X/autosome translocation: further evidence that the DMD locus is at Xp21. Am J Hum Genet 33:513–518PubMedGoogle Scholar
  56. Jegalian K, Page DC (1998) A proposed path by which genes common to mammalian X and Y chromosomes evolve to become X inactivated. Nature 394(6695):776–780PubMedCrossRefGoogle Scholar
  57. Jeppesen P, Turner B (1993) The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression. Cell 74:281–289PubMedCrossRefGoogle Scholar
  58. Johnston CM, Lovell FL, Leongamornlert DA, Stranger BE, Dermitzakis ET, Ross MT (2008) Large-scale population study of human cell lines indicates that dosage compensation is virtually complete. PLoS Genet 4(1):e9PubMedCrossRefGoogle Scholar
  59. Jonkers I, Barakat TS, Achame EM, Monkhorst K, Kenter A, Rentmeester E, Grosveld F, Grootegoed JA, Gribnau J (2009) RNF12 is an X-encoded dose-dependent activator of X chromosome inactivation. Cell 139(5):999–1011PubMedCrossRefGoogle Scholar
  60. Keohane AM, Barlow AL, Waters J, Bourn D, Turner BM (1999) H4 acetylation, XIST RNA and replication timing are coincident and define X;autosome boundaries in two abnormal X chromosomes. Hum Mol Genet 8:377–383PubMedCrossRefGoogle Scholar
  61. Klinefelter HF, Reifenstein EC, Albright F (1942) Syndrome characterized by gynecomastia, aspermatogenesis without A-Leydigism, and increased excretion of follicle-stimulating hormone. J Clin Endocrinol Metab 2(11):615–627CrossRefGoogle Scholar
  62. Lafreniere RG, Brown CJ, Rider S, Chelly J, Taillon-Miller P, Chinault AC, Monaco AP, Willard HF (1993) 2.6 Mb YAC contig of the human X inactivation center region in Xq13: physical linkage of the RPS4X, PHKA1, XIST and DXS128E genes. Hum Mol Genet 2(8):1105–1115PubMedCrossRefGoogle Scholar
  63. Leal CA, Ayala-Madrigal ML, Figuera LE, Medina C (1998) Histone H4 acetylation analyses in patients with polysomy X: implications for the mechanisms of X inactivation. Hum Genet 103:29–33PubMedCrossRefGoogle Scholar
  64. Lee JT, Davidow LS, Warshawsky D (1999) Tsix, a gene antisense to Xist at the X-inactivation center. Nat Genet 21:400–404PubMedCrossRefGoogle Scholar
  65. Lengner CJ, Gimelbrant AA, Erwin JA, Cheng AW, Guenther MG, Welstead GG, Alagappan R, Frampton GM, Xu P, Muffat J, Santagata S, Powers D, Barrett CB, Young RA, Lee JT et al (2010) Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations. Cell 141(5):872–883PubMedCrossRefGoogle Scholar
  66. Leppig KA, Brown CJ, Bressler SL, Gustashaw K, Pagon RA, Willard HF, Disteche CM (1993) Mapping of the distal boundary of the X-inactivation center in a rearranged X chromosome from a female expressing XIST. Hum Mol Genet 2(7):883–888PubMedCrossRefGoogle Scholar
  67. Li N, Carrel L (2008) Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus. Proc Natl Acad Sci USA 105(44):17055–17060PubMedCrossRefGoogle Scholar
  68. Lopes AM, Burgoyne PS, Ojarikre A, Bauer J, Sargent CA, Amorim A, Affara NA (2010) Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome. BMC Genomics 11:82PubMedCrossRefGoogle Scholar
  69. Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190:372–373PubMedCrossRefGoogle Scholar
  70. Lyon MF (1962) Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet 14:135–145PubMedGoogle Scholar
  71. Lyon MF (1998) X-chromosome inactivation: a repeat hypothesis. Cytogenet Cell Genet 80:133–137PubMedCrossRefGoogle Scholar
  72. Marahrens Y, Panning B, Dausman J, Strauss W, Jaenisch R (1997) Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev 11:156–166PubMedCrossRefGoogle Scholar
  73. Marioni JC, Mason CE, Mane SM, Stephens M, Gilad Y (2008) RNA-seq: an assessment of technical reproducibility and comparison with gene expression arrays. Genome Res 18(9):1509–1517PubMedCrossRefGoogle Scholar
  74. McFadden DE, Robinson WP (2006) Phenotype of triploid embryos. J Med Genet 43(7):609–612PubMedCrossRefGoogle Scholar
  75. McNeil JA, Johnson CV, Carter KC, Singer RH, Lawrence JB (1991) Localizing DNA and RNA within nuclei and chromosomes by fluorescence in situ hybridization. GATA 8(2):41–58Google Scholar
  76. Migeon BR (2003) Is Tsix repression of Xist specific to mouse? Nat Genet 33:337PubMedCrossRefGoogle Scholar
  77. Migeon BR, Luo S, Stasiowski BA, Jani M, Axelman J, Van Dyke DL, Weiss L, Jacobs PA, Yang-Feng TL, Wiley JE (1993) Deficient transcription of XIST from tiny ring X chromosomes in females with severe phenotypes. Proc Natl Acad Sci USA 90(24):12025–12029PubMedCrossRefGoogle Scholar
  78. Migeon BR, Kazi E, Haisley-Royster C, Hu J, Reeves R, Call L, Lawler A, Moore CS, Morrison H, Jeppesen P (1999) Human X inactivation center induces random X chromosome inactivation in male transgenic mice. Genomics 59(2):113–121PubMedCrossRefGoogle Scholar
  79. Migeon BR, Chowdury AK, Dunston JA, McIntosh I (2001) Identification of TSIX, encoding an RNA antisense to human XIST, reveals differences from its murine counterpart: implications for X inactivation. Am J Hum Genet 69:951–960PubMedCrossRefGoogle Scholar
  80. Migeon BR, Pappas K, Stetten G, Trunca C, Jacobs PA (2008) X inactivation in triploidy and trisomy: the search for autosomal transfactors that choose the active X. Eur J Hum Genet 16(2):153–162PubMedCrossRefGoogle Scholar
  81. Minks J, Brown CJ (2009) Getting to the center of X-chromosome inactivation: the role of transgenes. Biochem Cell Biol 87(5):759–766PubMedCrossRefGoogle Scholar
  82. Moreira de Mello JC, de Araujo ES, Stabellini R, Fraga AM, de Souza JE, Sumita DR, Camargo AA, Pereira LV (2010) Random X inactivation and extensive mosaicism in human placenta revealed by analysis of allele-specific gene expression along the X chromosome. PLoS One 5(6):e10947PubMedCrossRefGoogle Scholar
  83. Morris JK, Alberman E, Scott C, Jacobs P (2008) Is the prevalence of Klinefelter syndrome increasing? Eur J Hum Genet 16(2):163–170PubMedCrossRefGoogle Scholar
  84. Muller HJ (1932) Further studies on the nature and causes of gene mutations. Proc Sixth Intern Congr Genet 1:213–255Google Scholar
  85. Nakagawa S, Prasanth KV (2011) eXIST with matrix-associated proteins. Trends Cell Biol. doi:10.1016/j.tcb.2011.02.001
  86. Navarro P, Chambers I, Karwacki-Neisius V, Chureau C, Morey C, Rougeulle C, Avner P (2008) Molecular coupling of Xist regulation and pluripotency. Science 321(5896):1693–1695PubMedCrossRefGoogle Scholar
  87. Nguyen DK, Disteche CM (2006) Dosage compensation of the active X chromosome in mammals. Nat Genet 38(1):47–53PubMedCrossRefGoogle Scholar
  88. Nussbaum RL, McInnes RR, Willard HF (2001) Thompson & Thompson genetics in medicine, 6th edn. W.B. Saunders Co., PhiladelphiaGoogle Scholar
  89. Ogawa Y, Lee JT (2003) Xite, X-inactivation intergenic transcription elements that regulate the probability of choice. Mol Cell 11:731–743PubMedCrossRefGoogle Scholar
  90. Paterno GD, McBurney MW (1985) X chromosome inactivation during induced differentiation of a female mouse embryonal carcinoma cell line. J Cell Sci 75:149–163PubMedGoogle Scholar
  91. Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379:131–137PubMedCrossRefGoogle Scholar
  92. Plagnol V, Uz E, Wallace C, Stevens H, Clayton D, Ozcelik T, Todd JA (2008) Extreme clonality in lymphoblastoid cell lines with implications for allele specific expression analyses. PLoS One 3(8):e2966PubMedCrossRefGoogle Scholar
  93. Plenge RM, Hendrich BD, Schwartz C, Arena JF, Naumova A, Sapienza C, Winter RM, Willard HF (1997) A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nat Genet 17:353–356PubMedCrossRefGoogle Scholar
  94. Rack KA, Chelly J, Gibbons RJ, Rider S, Benjamin D, Lafreniere RG, Oscier D, Hendriks RW, Craig IW, Willard HF, Monaco AP, Buckle VJ (1994) Absence of the XIST gene from late-replicating isodicentric X chromosomes in leukemia. Hum Mol Genet 3(7):1053–1059PubMedCrossRefGoogle Scholar
  95. Raefski AS, O’Neill MJ (2005) Identification of a cluster of X-linked imprinted genes in mice. Nat Genet 37(6):620–624PubMedCrossRefGoogle Scholar
  96. Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, Muroya K, Binder G, Kirsch S, Winkelmann M, Nordsiek G, Heinrich U, Breuning MH, Ranke MB, Rosenthal A et al (1997) Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16(1):54–63PubMedCrossRefGoogle Scholar
  97. Rastan S, Robertson EJ (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
  98. Reinius B, Shi C, Hengshuo L, Sandhu KS, Radomska KJ, Rosen GD, Lu L, Kullander K, Williams RW, Jazin E (2010) Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse. BMC Genomics 11:614PubMedCrossRefGoogle Scholar
  99. Riggs AD (1975) X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet 14:9–25PubMedCrossRefGoogle Scholar
  100. Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL, Howe KL, Ashurst JL, Fulton RS et al (2005) The DNA sequence of the human X chromosome. Nature 434(7031):325–337PubMedCrossRefGoogle Scholar
  101. Ross NL, Wadekar R, Lopes A, Dagnall A, Close J, Delisi LE, Crow TJ (2006) Methylation of two Homo sapiens-specific X-Y homologous genes in Klinefelter’s syndrome (XXY). Am J Med Genet B Neuropsychiatr Genet 141B(5):544–548PubMedCrossRefGoogle Scholar
  102. Russell LB (1963) Mammalian X-chromosome action: inactivation limited in spread and in region of origin. Science 140:976–978PubMedCrossRefGoogle Scholar
  103. Schmidt M, Du Sart D (1992) Functional disomies of the X chromosome influence the cell selection and hence the inactivation pattern in females with balanced X;autosome translocations: a review of 122 cases. Am J Med Genet 42:161–169PubMedCrossRefGoogle Scholar
  104. Shapiro LJ, Mohandas T, Weiss R, Romeo G (1979) Non-inactivation of an x-chromosome locus in man. Science 204(4398):1224–1226PubMedCrossRefGoogle Scholar
  105. Sharp A, Robinson DO, Jacobs P (2001) Absence of correlation between late-replication and spreading of X inactivation in an X;autosome translocation. Hum Genet 109(3):295–302PubMedCrossRefGoogle Scholar
  106. Sharp AJ, Spotswood HT, Robinson DO, Turner BM, Jacobs PA (2002) Molecular and cytogenetic analysis of the spreading of X inactivation in X;autosome translocations. Hum Mol Genet 11(25):3145–3156PubMedCrossRefGoogle Scholar
  107. Shen Y, Matsuno Y, Fouse SD, Rao N, Root S, Xu R, Pellegrini M, Riggs AD, Fan G (2008) X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations. Proc Natl Acad Sci USA 105(12):4709–4714PubMedCrossRefGoogle Scholar
  108. Shin J, Bossenz M, Chung Y, Ma H, Byron M, Taniguchi-Ishigaki N, Zhu X, Jiao B, Hall LL, Green MR, Jones SN, Hermans-Borgmeyer I, Lawrence JB, Bach I (2010) Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice. Nature 467(7318):977–981PubMedCrossRefGoogle Scholar
  109. 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(12):4820–4825PubMedCrossRefGoogle Scholar
  110. Skuse DH, James RS, Bishop DVM, Coppin B, Dalton P, Aamodt-Leeper G, Bacaress-Hamilton M, Creswell C, McGurk R, Jacobs PA (1997) Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature 387:705–708PubMedCrossRefGoogle Scholar
  111. Solari AJ, Rahn IM, Ferreyra ME, Carballo MA (2001) The behavior of sex chromosomes in two human X-autosome translocations: failure of extensive X-inactivation spreading. Biocell 25(2):155–166PubMedGoogle Scholar
  112. Stabellini R, de Mello JC, Hernandes LM, Pereira LV (2009) MAOA and GYG2 are submitted to X chromosome inactivation in human fibroblasts. Epigenetics 4(6):388–393PubMedCrossRefGoogle Scholar
  113. Stadtfeld M, Maherali N, Breault DT, Hochedlinger K (2008) Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2(3):230–240PubMedCrossRefGoogle Scholar
  114. Stochholm K, Juul S, Gravholt CH (2010) Mortality and incidence in women with 47, XXX and variants. Am J Med Genet A 152A(2):367–372PubMedCrossRefGoogle Scholar
  115. Sun S, Fukue Y, Nolen L, Sadreyev RI, Lee JT (2010) Characterization of Xpr (Xpct) reveals instability but no effects on X-chromosome pairing or Xist expression. Transcription 1(1):46–56PubMedCrossRefGoogle Scholar
  116. Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA (2005a) Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab 90(12):6516–6522PubMedCrossRefGoogle Scholar
  117. Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA (2005b) Mortality and cancer incidence in women with extra X chromosomes: a cohort study in Britain. Hum Genet 118(2):255–260PubMedCrossRefGoogle Scholar
  118. Talebizadeh Z, Simon SD, Butler MG (2006) X chromosome gene expression in human tissues: male and female comparisons. Genomics 88(6):675–681PubMedCrossRefGoogle Scholar
  119. Tchieu J, Kuoy E, Chin MH, Trinh H, Patterson M, Sherman SP, Aimiuwu O, Lindgren A, Hakimian S, Zack JA, Clark AT, Pyle AD, Lowry WE, Plath K (2010) Female human iPSCs retain an inactive X chromosome. Cell Stem Cell 7(3):329–342PubMedCrossRefGoogle Scholar
  120. Tian D, Sun S, Lee JT (2010) The long noncoding RNA, Jpx, is a molecular switch for X chromosome inactivation. Cell 143(3):390–403PubMedCrossRefGoogle Scholar
  121. Tomkins DJ, McDonald HL, Farrell SA, Brown CJ (2002) Lack of expression of XIST from a small ring X chromosome containing the XIST locus in a girl with short stature, facial dysmorphism and developmental delay. Eur J Hum Genet 10(1):44–51PubMedCrossRefGoogle Scholar
  122. van den Berg IM, Laven JS, Stevens M, Jonkers I, Galjaard RJ, Gribnau J, van Doorninck JH (2009) X chromosome inactivation is initiated in human preimplantation embryos. Am J Hum Genet 84(6):771–779PubMedCrossRefGoogle Scholar
  123. Wang Z, Willard HF, Mukherjee S, Furey TS (2006) Evidence of influence of genomic DNA sequence on human X chromosome inactivation. PLoS Comput Biol 2(9):e113PubMedCrossRefGoogle Scholar
  124. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10(1):57–63PubMedCrossRefGoogle Scholar
  125. 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 63:20–28PubMedCrossRefGoogle Scholar
  126. Wutz A (2007) Xist function: bridging chromatin and stem cells. Trends Genet 23(9):457–464PubMedCrossRefGoogle Scholar
  127. Xiong Y, Chen X, Chen Z, Wang X, Shi S, Zhang J, He X (2010) RNA sequencing shows no dosage compensation of the active X-chromosome. Nat Genet 42(12):1043–1047PubMedCrossRefGoogle Scholar
  128. Xu N, Tsai CL, Lee JT (2006) Transient homologous chromosome pairing marks the onset of X inactivation. Science 311(5764):1149–1152PubMedCrossRefGoogle Scholar
  129. Yang F, Babak T, Shendure J, Disteche CM (2010) Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res 20(5):614–622PubMedCrossRefGoogle Scholar
  130. Yasukochi Y, Maruyama O, Mahajan MC, Padden C, Euskirchen GM, Schulz V, Hirakawa H, Kuhara S, Pan XH, Newburger PE, Snyder M, Weissman SM (2010) X chromosome-wide analyses of genomic DNA methylation states and gene expression in male and female neutrophils. Proc Natl Acad Sci USA 107(8):3704–3709PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Christine Yang
    • 1
  • Andrew G. Chapman
    • 1
  • Angela D. Kelsey
    • 1
  • Jakub Minks
    • 1
  • Allison M. Cotton
    • 1
  • Carolyn J. Brown
    • 1
  1. 1.Department of Medical Genetics, Molecular Epigenetics Group, Life Sciences InstituteUniversity of British ColumbiaVancouverCanada

Personalised recommendations