The phenomenon of X chromosome inactivation and human diseases

  • Authors: Shevchenko A.I1,2,3
  • Affiliations:
    1. Federal Research Center Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences
    2. Institute of Chemical Biology and Fundamental Medicine, the Siberian Branch of the Russian Academy of Sciences
    3. State Research Institute of Circulation Pathology, Ministry of Healthcare of the Russian Federation
  • Issue: Vol 11, No 2 (2016)
  • Pages: 61-69
  • Section: Articles
  • URL:
  • DOI:

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In early development, one of the two X chromosomes is randomly inactivated in each somatic cell of female embryos. As a result, women are mosaics that means about a half of their cells bear the active X chromosome inherited from the father, while the genes of the maternally inherited X chromosome are expressed in the other half. Disturbance in the inactivation process during embryogenesis leads to fetal death. Reactivation of the inactive X chromosome in female cells can cause a number of diseases, including cancer and autoimmune disorders. Changes in randomness of X-chromosome inactivation and skewed choice of one of the X-chromosomes for inactivation can influence clinical manifestations of about 400 diseases associated with mutations in X-linked genes. The phenomenon of X chromosome inactivation is also an important issue for successful application of human pluripotent stem cells in biomedical research and regenerative medicine.

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About the authors

A. I Shevchenko

Federal Research Center Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences; Institute of Chemical Biology and Fundamental Medicine, the Siberian Branch of the Russian Academy of Sciences; State Research Institute of Circulation Pathology, Ministry of Healthcare of the Russian Federation

Novosibirsk, Russia


  1. Lyon M.F. X-chromosome inactivation and human genetic disease. Acta Paediatr. Suppl. 2002; 91(439): 107-12.
  2. Migeon B.R. X inactivation, female mosaicism, and sex differences in renal diseases. J. Am. Soc. Nephrol. 2008; 19(11): 2052-9.
  3. Vallot C., Huret C., Lesecque Y. et al. XACT, a long noncoding transcript coating the active X chromosome in human pluripotent cells. Nat. Genet. 2013; 45(3): 239-41.
  4. Vallot C., Ouimette J.F., Makhlouf M. et al. Erosion of X Chromosome Inactivation in Human Pluripotent Cells Initiates with XACT Coating and Depends on a Specific Heterochromatin Landscape. Cell Stem Cell 2015; 16(5): 533-46.
  5. Chadwick B.P., Willard H.F. Multiple spatially distinct types of facultative heterochromatin on the human inactive X chromosome. PNAS USA 2004; 101(50): 17450-5.
  6. Carrel L., Willard H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005; 434(7031): 400-4.
  7. Dementyeva E.V., Shevchenko A.I., Zakian S.M. X-chromosome upregulation and inactivation: two sides of the dosage compensation mechanism in mammals. Bioessays 2009; 31(1): 21-8.
  8. Schluth C., Cossée M., Girard-Lemaire F. et al. Phenotype in X chromosome rearrangements: pitfalls of X inactivation study. Pathol. Biol. 2007; 55(1): 29-36.
  9. Schmidt M., Du Sart D. Functional disomies of the X chromosome influence the cell selection and hence the X inactivation pattern in females with balanced X-autosome translocations: a review of 122 cases. Am. J. Med. Genet. 1992; 42(2): 161-9.
  10. Migeon B.R., Luo S., Jani M., Jeppesen P. The severe phenotype of females with tiny ring X chromosomes is associated with inability of these chromosomes to undergo X inactivation. Am. J. Hum. Genet. 1994; 55(3): 497-504.
  11. Leppig K.A., Disteche C.M. Ring X and other structural X chromosome abnormalities: X inactivation and phenotype. Semin. Reprod. Med. 2001; 19(2): 147-57.
  12. Van den Veyver I.B. Skewed X inactivation in X-linked disorders. Semin. Reprod. Med. 2001; 19(2): 183-91.
  13. Belmont J.W. Genetic control of X inactivation and processes leading to X-inactivation skewing. Am. J. Hum. Genet. 1996; 58(6): 1101-8.
  14. Pegoraro E., Whitaker J., Mowery-Rushton P. et al., Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28. Am. J. Hum. Genet. 1997; 61(1): 160-70.
  15. Pugacheva E.M., Tiwari V.K., Abdullaev Z. et al. Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. Hum. Mol. Genet. 2005; 14(7): 953-65.
  16. Plenge R.M., Hendrich B.D., Schwartz C. et al. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nat. Genet. 1997; 17(3): 353-6.
  17. Naumova A.K., Plenge R.M., Bird L.M. et al. Heritability of X chromosome-inactivation phenotype in a large family. Am. J. Hum. Genet. 1996; 58(6): 1111-9.
  18. Invernizzi P., Pasini S., Selmi C. et al. Female predominance and X chromosome defects in autoimmune diseases. J. Autoimmun. 2009; 33(1): 12-6.
  19. Scofield R.H., Bruner G.R., Namjou B. et al. Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008; 58(8): 2511-7.
  20. Sawalha A.H., Harley J.B., Scofield R.H. Autoimmunity and Klinefelter's syndrome: when men have two X chromosomes. J. Autoimmun. 2009; 33(1): 31-4.
  21. Forsdyke D.R. X chromosome reactivation perturbs intracellular self/not-self discrimination. Immunol. Cell Biol. 2009; 87(7): 525-8.
  22. Hitchcock D.I. Proteins and the Donnan equilibrium. Physiol. Rev. 1924; 4(3): 505-31.
  23. Kurbel S. Are extracellular osmolality and sodium concentration determined by Donnan effects of intracellular protein charges and of pumped sodium? J. Theor. Biol. 2008; 252(4): 769-72.
  24. Brooks W. A commentary on types of DNA methylation status of the interspersed repetitive sequences for LINE-1, Alu, HERV-E and HERV-K in the neutrophils from systemic lupus erythematosus patients and healthy controls. J. Hum. Genet. 2014; 59(4): 174-5.
  25. Brooks W.H., Renaudineau Y. Epigenetics and autoimmune diseases: the X chromosome-nucleolus nexus. Front Genet. 2015; 6: 22.
  26. Kaufman K.M., Zhao J., Kelly J.A. et al. Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. Ann. Rheum. Dis. 2013; 72(3): 437-44.
  27. Sawalha A.H. Overexpression of methyl-CpG-binding protein 2 and autoimmunity: evidence from MECP2 duplication syndrome, lupus, MECP2 transgenic and Mecp2 deficient mice. Lupus 2013; 22(9): 870-2.
  28. Banchereau J., Bazan F., Blanchard D. et al. The CD40 antigen and its ligand. Ann. Rev. Immunol. 1994; 12: 881-922.
  29. Lian X., Xiao R., Hu X. et al. DNA demethylation of CD40l in CD4+ T cells from women with systemic sclerosis: a possible explanation for female susceptibility. Arthritis Rheum. 2012; 64(7): 2338-45.
  30. Dekker R.J., van Soest S., Fontijn R.D. et al. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2). Blood 2002; 100(5): 1689-98.
  31. Kim H.P., Leonard W.J. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J. Exp. Med. 2007; 204(7): 1543-51.
  32. Higgins M.E., Claremont M., Major J.E. et al. CancerGenes: a gene selection resource for cancer genome projects. Nucleic Acids Res. 2007; 35(Database issue): D721-6.
  33. Spatz A., Borg C., Feunteun J. X-chromosome genetics and human cancer. Nat. Rev. Cancer 2004; 4(8): 617-29.
  34. Richardson A.L., Wang Z.C., De Nicolo A. et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 2006; 9(2): 121-32.
  35. Pageau G.J., Hall L.L., Ganesan S. et al. The disappearing Barr body in breast and ovarian cancers. Nat. Rev. Cancer. 2007; 7(8): 628-33.
  36. Rogner U.C., Wilke K., Steck E. et al. The melanoma antigen gene (MAGE) family is clustered in the chromosomal band Xq28. Genomics 1995; 29(3): 725-31.
  37. Shriver S.P., Bourdeau H.A., Gubish C.T. et al. Sex-specific expression of gastrin-releasing peptide receptor: relationship to smoking history and risk of lung cancer. J. Natl. Cancer Inst. 2000; 92(1): 24-33.
  38. Sudbrak R., Wieczorek G., Nuber U.A. et al. X chromosome-specific cDNA arrays: identification of genes that escape from X-inactivation and other applications. Hum. Mol. Genet. 2001; 10(1): 77-83.
  39. Cheng.PC., Gosewehr J.A., Kim T.M. et al. Potential role of the inactivated X chromosome in ovarian epithelial tumor development. JNCI J. Nat. Cancer Inst. 1996; 88(8): 510-8.
  40. Piao Z., Lee K.S., Kim H. et al. Identification of novel deletion regions on chromosome arms 2q and 6p in breast carcinomas by amplotype analysis. Genes Chromosomes Cancer 2001; 30(2): 113-22.
  41. Wang N., Cedrone E., Skuse G.R. et al. Two identical active X chromosomes in human mammary carcinoma cells. Cancer Genet Cytogenet. 1990; 46(2): 271-80.
  42. Muleris M., Dutrillaux A.M., Salmon R.J., Dutrillaux B. Sex chromosomes in a series of 79 colorectal cancers: Replication pattern, numerical, and structural changes. Genes Chromosomes Cancer. 1990; 1(3): 221-7.
  43. Dutrillaux B., Muleris M., Seureau M.G. Imbalance of sex chromosomes, with gain of early-replicating X, in human solid tumors. Int. J. Cancer 1986; 38(4): 475-9.
  44. Terracciano L.M., Bernasconi B., Ruck P. et al. Comparative genomic hybridization analysis of hepatoblastoma reveals high frequency of X-chromosome gains and similarities between epithelial and stromal components. Hum. Pathol. 2003; 34(9): 864-71.
  45. Kokalj-Vokac N., Saint-Ruf C., Lefrançois D. et al. A t(X;15) (q23;q25) with Xq reactivation in a lymphoblastoid cell line from Fanconi anemia. Cytogenet. Cell Genet. 1991; 57(1): 11-5.
  46. Jones C., Booth C., Rita D. et al. Bilateral retinoblastoma in a male patient with an X; 13 translocation: evidence for silencing of the RB1 gene by the spreading of X inactivation. Am. J. Hum. Genet. 1997; 60(6): 1558-62.
  47. Hake S.B., Xiao A., Allis C.D. Linking the epigenetic "language" of covalent histone modifications to cancer. Br. J. Cancer 2004; 90(4): 761-9.
  48. Lou Z., Minter-Dykhouse K., Chen J. BRCA1 participates in DNA decatenation. Nat. Struct. Mol. Biol. 2005;12(7): 589-93.
  49. Jäger N., Schlesner M., Jones D.T.W. et al. Hypermutation of the inactive X chromosome is a frequent event in cancer. Cell 2013; 155(3): 567-81.
  50. Medvedev S.P., Shevchenko A.I., Zakian S.M. Induced Pluripotent Stem Cells: Problems and Advantages when Applying them in Regenerative Medicine. Acta Naturae 2010; 2(2): 18-28.
  51. Silva S.S., Rowntree R.K., Mekhoubad S., Lee J.T. X-chromosome inactivation and epigenetic fluidity in human embryonic stem cells. PNAS USA 2008; 105(12): 4820-5.
  52. Anguera M.C., Sadreyev R., Zhang Z. et al. Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes. Cell Stem Cell 2012; 11(1): 75-90.
  53. Shen Y., Matsuno Y., Fouse S.D. et al. X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations. PNAS USA 2008; 105(12): 4709-14.
  54. Hall L.L., Byron M., Butler J. et al. X-inactivation reveals epigenetic anomalies in most hESC but identifies sublines that initiate as expected. J. Cell Physiol. 2008; 216(2): 445-52.
  55. Mekhoubad S., Bock C., de Boer A.S. et al. Erosion of dosage compensation impacts human iPSC disease modeling. Cell Stem Cell 2012; 10(5): 595-609.
  56. Tomoda K., Takahashi K., Leung K. et al. Derivation conditions impact X-inactivation status in female human induced pluripotent stem cells. Cell Stem Cell 2012; 11(1): 91-9.
  57. Hanna J., Cheng A.W., Saha K. et al. Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. PNAS USA 2010; 107(20): 9222-7.
  58. Ware C.B., Wang L., Mecham B.H. et al. Histone deacetylase inhibition elicits an evolutionarily conserved self-renewal program in embryonic stem cells. Cell Stem Cell 2009; 4(4): 359-69.
  59. Hasegawa Y., Tang D., Takahashi N. et al. CCL2 enhances pluripotency of human induced pluripotent stem cells by activating hypoxia related genes. Sci. Rep. 2014; doi: 10.1038/srep05228.
  60. Lengner C.J., Gimelbrant A.A., Erwin J.A. et al. Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations. Cell 2010; 141(5): 872-83.
  61. Shumaker D.K., Dechat T., Kohlmaier A. et al. Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. PNAS USA 2006; 103(23): 8703-8.
  62. Huang K.-C., Rao P.H., Lau C.C. et al. Relationship of XIST expression and responses of ovarian cancer to chemotherapy. Mol. Cancer Ther. 2002; 1(10): 769-76.
  63. Ji B., Higa K.K., Kelsoe J.R., Zhou X. Over-expression of XIST, the master gene for X chromosome inactivation, in females with major affective disorders. EBioMedicine 2015; 2(8): 907-16.
  64. Jiang J., Jing Y., Cost G.J. et al. Translating dosage compensation to trisomy 21. Nature 2013; 500(7462): 296-300.
  65. Tchieu J., Kuoy E., Chin M.H. et al. Female human iPSCs retain an inactive X chromosome. Cell Stem Cell 2010; 7(3): 329-42.

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