The phenomenon of X chromosome inactivation and human diseases
- Authors: Shevchenko A.I1,2,3
-
Affiliations:
- 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
- Issue: Vol 11, No 2 (2016)
- Pages: 61-69
- Section: Articles
- URL: https://genescells.ru/2313-1829/article/view/120579
- DOI: https://doi.org/10.23868/gc120579
Cite item
Abstract
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.
Full Text

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
Email: epigene@bionet.nsc.ru
Novosibirsk, Russia
References
- Lyon M.F. X-chromosome inactivation and human genetic disease. Acta Paediatr. Suppl. 2002; 91(439): 107-12.
- Migeon B.R. X inactivation, female mosaicism, and sex differences in renal diseases. J. Am. Soc. Nephrol. 2008; 19(11): 2052-9.
- 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.
- 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.
- 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.
- Carrel L., Willard H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005; 434(7031): 400-4.
- 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.
- 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.
- 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.
- 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.
- 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.
- Van den Veyver I.B. Skewed X inactivation in X-linked disorders. Semin. Reprod. Med. 2001; 19(2): 183-91.
- Belmont J.W. Genetic control of X inactivation and processes leading to X-inactivation skewing. Am. J. Hum. Genet. 1996; 58(6): 1101-8.
- 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.
- 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.
- 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.
- 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.
- Invernizzi P., Pasini S., Selmi C. et al. Female predominance and X chromosome defects in autoimmune diseases. J. Autoimmun. 2009; 33(1): 12-6.
- 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.
- 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.
- Forsdyke D.R. X chromosome reactivation perturbs intracellular self/not-self discrimination. Immunol. Cell Biol. 2009; 87(7): 525-8.
- Hitchcock D.I. Proteins and the Donnan equilibrium. Physiol. Rev. 1924; 4(3): 505-31.
- 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.
- 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.
- Brooks W.H., Renaudineau Y. Epigenetics and autoimmune diseases: the X chromosome-nucleolus nexus. Front Genet. 2015; 6: 22.
- 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.
- 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.
- Banchereau J., Bazan F., Blanchard D. et al. The CD40 antigen and its ligand. Ann. Rev. Immunol. 1994; 12: 881-922.
- 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.
- 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.
- 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.
- 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.
- Spatz A., Borg C., Feunteun J. X-chromosome genetics and human cancer. Nat. Rev. Cancer 2004; 4(8): 617-29.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Lou Z., Minter-Dykhouse K., Chen J. BRCA1 participates in DNA decatenation. Nat. Struct. Mol. Biol. 2005;12(7): 589-93.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Jiang J., Jing Y., Cost G.J. et al. Translating dosage compensation to trisomy 21. Nature 2013; 500(7462): 296-300.
- 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.
