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X Chromosome Inactivation and Autoimmunity

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Abstract

Autoimmune diseases appear to have multiple contributing factors including genetics, epigenetics, environmental factors, and aging. The predominance of females among patients with autoimmune diseases suggests possible involvement of the X chromosome and X chromosome inactivation. X chromosome inactivation is an epigenetic event resulting in multiple levels of control for modulation of the expression of X-linked genes in normal female cells such that there remains only one active X chromosome in the cell. The extent of this control is unique among the chromosomes and has the potential for problems when regulation is disrupted. Here we discuss the X chromosome inactivation process and how the X chromosome and X chromosome inactivation may be involved in development of autoimmune disorders.

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Abbreviations

dcSAM:

Decarboxylated S-adenosylmethionine

EBV:

Epstein–Barr virus

LINE:

Long interspersed nuclear element

MS:

Multiple sclerosis

PAD:

Peptidyl arginine deiminase

PAR1, PAR2:

Pseudo-autosomal regions of the X chromosome

SAF:

Scaffold attachment factor

SAM:

S-adenosylmethionine, the cellular methyl group donor

SAMDC:

SAM decarboxylase, a key, initial enzyme in polyamine synthesis

SAT1:

Spermidine/spermine-N1-acetyltransferase, an enzyme in polyamine recycling

SMS:

Spermine synthase, an enzyme in polyamine synthesis

TSIX:

An anti-sense gene to the XIST gene, involved in initiation of XCI

Xa:

The active X chromosome

XAR:

X-added region

XCI:

X chromosome inactivation, epigenetic silencing of X chromosomes

XCR:

X-conserved region

Xi:

The inactive X chromosome

XIC:

X-inactivation center, locus of genes involved in initiating XCI

XIST:

X-inactivation specific transcript, a key gene in initiating XCI

X-CGD:

X-linked chronic granulomatous disease

Xp:

X chromosome short arm

Xq:

X chromosome long arm

References

  1. Migeon BR (2007) Females are mosaics: X inactivation and sex differences in disease. Oxford University Press, New York

    Google Scholar 

  2. Kelley RL, Kuroda MI (1995) Equality for X chromosomes. Science 270:1607–1610

    Article  PubMed  CAS  Google Scholar 

  3. Jacobson L, Gange SJ, Rose NR, Graham NMH (1997) Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 84:223–242

    Article  PubMed  CAS  Google Scholar 

  4. Scofield RH, Bruner GR, Namjou N et al (2008) 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 58:2511–2517

    Article  PubMed  Google Scholar 

  5. Kantarci OH, Barcellos LF, Atkinson EJ et al (2006) Men transmit MS more often to their children vs women: the Carter effect. Neurology 67:305–310

    Article  PubMed  CAS  Google Scholar 

  6. Ross MT, Grafham DV, Coffey AJ et al (2005) The DNA sequence of the human X chromosome. Nature 434:325–337

    Article  PubMed  CAS  Google Scholar 

  7. Ohno S, Becak W, Becak ML (1964) X-autosome ratio and the behavior pattern of individual X-chromosomes in placental mammals. Chromosoma 15:14–30

    Article  PubMed  CAS  Google Scholar 

  8. Huebner K, Croce CM (2001) FRA3B and other common fragile sites: the weakest links. Nat Rev Cancer 1:214–221

    Article  PubMed  CAS  Google Scholar 

  9. Thorland EC, Myers SL, Persing DH et al (2000) Human papillomavirus type 16 integrations in cervical tumors frequently occur in common fragile sites. Cancer Res 60:5916–5921

    PubMed  CAS  Google Scholar 

  10. Glover TW, Arit MF, Casper AM, Durkin SG (2005) Mechanisms of common fragile site instability. Hum Mol Genet 14:R197–R205

    Article  PubMed  CAS  Google Scholar 

  11. Glover TW, Stein CK (1987) Induction of sister chromatid exchanges at common fragile sites. Am J Hum Genet 41:882–890

    PubMed  CAS  Google Scholar 

  12. Chatila TA, Blaeser F, Ho N et al (2000) JM2, a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106:R75–R81

    Article  PubMed  CAS  Google Scholar 

  13. Heard E, Clerc P, Avner P (1997) X-chromosome inactivation in mammals. Annu Rev Genet 31:571–610

    Article  PubMed  CAS  Google Scholar 

  14. Carrel L, Willard HF (1999) Heterogeneous gene expression from the inactive X chromosome: an X-linked gene that escapes X inactivation in some human cell lines but is inactivated in others. Proc Natl Acad Sci U S A 96:7364–7369

    Article  PubMed  CAS  Google Scholar 

  15. Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434:400–404

    Article  PubMed  CAS  Google Scholar 

  16. Lyon MF (1962) Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet 14:135–148

    PubMed  CAS  Google Scholar 

  17. Lyon MF (2000) LINE-1 elements and X chromosome inactivation: a function for “junk” DNA? Proc Natl Acad Sci U S A 97:6248–6249

    Article  PubMed  CAS  Google Scholar 

  18. Plath K, Mlynarczyk-Evans SK, Nusinow DA, Panning B (2002) Xist RNA and the mechanism of X chromosome inactivation. Annu Rev Genet 36:233–278

    Article  PubMed  CAS  Google Scholar 

  19. Navarro P, Pichard S, Ciaudo C, Avner P, Rougeulle C (2005) Tsix transcription across the Xist gene alters chromatin conformation without affecting Xist transcription: implications for X-chromosome inactivation. Genes Dev 19:1474–1484

    Article  PubMed  CAS  Google Scholar 

  20. Tsai CL, Rowntree RK, Cohen DE, Lee JT (2008) Higher order chromatin structure at the X-inactivation center via looping DNA. Dev Biol 319:416–425

    Article  PubMed  CAS  Google Scholar 

  21. Xu N, Tsai CL, Lee JT (2006) Transient homologous chromosome pairing marks the onset of X inactivation. Science 311:1149–1152

    Article  PubMed  CAS  Google Scholar 

  22. Shibata S, Lee JT (2009) MacroRNAs in the epigenetic control of X-chromosome inactivation. Epigenomics 2009:187–214

    Article  Google Scholar 

  23. Navarro P, Page DR, Avner P, Rougeulle C (2006) Tsix-mediated epigenetic switch of a CTCF-flanked region of the Xist promoter determines the Xist transcription program. Genes Dev 20:2787–2792

    Article  PubMed  CAS  Google Scholar 

  24. Boumil RM, Ogawa Y, Sun BK, Huynh KD, Lee JT (2006) Differential methylation of Xite and CTCF sites in Tsix mirrors the pattern of X-inactivation choice in mice. Mol Cell Biol 26:2109–2117

    Article  PubMed  CAS  Google Scholar 

  25. Rasmussen TP, Wutz A, Pehrson JR, Jaenisch R (2001) Expression of Xist RNA is sufficient to initiate macrochromatin body formation. Chromosoma 110:411–420

    Article  PubMed  CAS  Google Scholar 

  26. Brown CJ, Willard HF (1994) The human X-inactivation centre is not required for maintenance of X-chromosome inactivation. Nature 368:154–156

    Article  PubMed  CAS  Google Scholar 

  27. Hansen RS (2003) X inactivation-specific methylation of LINE-1 elements by DNMT3B: implications for the Lyon repeat hypothesis. Hum Mol Genet 12:2559–2567

    Article  PubMed  CAS  Google Scholar 

  28. Boggs BA, Cheung P, Heard E, Spector DL, Chinault AC, Allis CD (2002) Differentially methylated forms of histone H3 show unique association patterns with inactive human X chromosomes. Nat Genet 30:73–76

    Article  PubMed  CAS  Google Scholar 

  29. Ng K, Pullirsch D, Leeb M, Wutz A (2007) Xist and the order of silencing. EMBO Reports 8:34–39

    Article  PubMed  CAS  Google Scholar 

  30. Changolkar LN, Pehrson JR (2006) MacroH2A1 histone variants are depleted on active genes but concentrated on the inactive X chromosome. Mol Cell Biol 26:4410–4420

    Article  PubMed  CAS  Google Scholar 

  31. Pehrson JR, Fried VA (1992) MacroH2A, a core histone containing a large non-histone region. Science 257:1398–1400

    Article  PubMed  CAS  Google Scholar 

  32. Chadwick BP, Valley CM, Willard HF (2001) Histone variant macroH2A contains two distinct macrochromatin domains capable of directing macroH2A to the inactive X chromosome. Nuc Acids Res 29:2699–2705

    Article  CAS  Google Scholar 

  33. Chadwick BP, Willard HF (2001) A novel chromatin protein, distantly related to histone H2A, is largely excluded from the inactive X chromosome. J Cell Biol 152:375–384

    Article  PubMed  CAS  Google Scholar 

  34. Fackelmayer FO (2005) A stable proteinaceous structure in the territory of inactive X chromosomes. J Biol Chem 280:1720–1723

    Article  PubMed  CAS  Google Scholar 

  35. Barr ML, Carr DH (1960) Sex chromatin, sex chromosomes and sex anomalies. Can Med Assoc J 83:979–986

    PubMed  CAS  Google Scholar 

  36. Rego A, Sinclair PB, Tao W, Kireev I, Belmont AS (2008) The facultative heterochromatin of the inactive X chromosome has a distinctive condensed ultrastructure. J Cell Sci 121:1119–1127

    Article  PubMed  CAS  Google Scholar 

  37. Clemson CM, Hall LL, Byron M, McNeil J, Lawrence JB (2006) The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences. Proc Natl Acad Sci U S A 103:7688–7693

    Article  PubMed  CAS  Google Scholar 

  38. Zhang LF, 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

    Article  PubMed  CAS  Google Scholar 

  39. Kawakami T, Zhang C, Taniguchi T, Kim et al (2004) Characterization of loss-of-inactive X in Klinefelter syndrome and female-derived cancer cells. Oncogene 23:6163–6169

    Article  PubMed  CAS  Google Scholar 

  40. Ganesan S, Silver DP, Greenberg RA et al (2002) BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell 111:393–405

    Article  PubMed  CAS  Google Scholar 

  41. Stone C, McCabe N, Ashworth A (2003) X-chromosome inactivation: X marks the spot for BRCA1. Curr Biol 13:R63–R64

    Article  PubMed  CAS  Google Scholar 

  42. Bolduc V, Chagnon P, Provost S et al (2008) No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans. J Clin Invest 118:333–341

    Article  PubMed  CAS  Google Scholar 

  43. Knudsen GP, Pedersen J, Klingenberg O, Lygren I, Ørstavik KH (2007) Increased skewing of X chromosome inactivation with age in both blood and buccal cells. Cytogenet Genome Res 116:24–28

    Article  PubMed  CAS  Google Scholar 

  44. Devriendt K, Matthijs G, Legius E et al (1997) Skewed X-chromosome inactivation in female carriers of dyskeratosis congenita. Am J Hum Genet 60:581–587

    PubMed  CAS  Google Scholar 

  45. Knudsen GP, Neilson TC, Pedersen J et al (2006) Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers. Eur J Hum Genet 14:1189–1194

    Article  PubMed  CAS  Google Scholar 

  46. Köker MY, Sanal O, de Boer M et al (2006) Skewing of X-chromosome inactivation in three generations of carriers with X-linked chronic granulomatous disease within one family. Eur J Clin Invest 36:257–264

    Article  PubMed  Google Scholar 

  47. Stewart JJ (1998) The female X-inactivation mosaic in systemic lupus erythematosus. Immunol Today 19:352–357

    Article  PubMed  CAS  Google Scholar 

  48. Chitnis S, Monteiro J, Glass D et al (2000) The role of X-chromosome inactivation in female predisposition to autoimmunity. Arthritis Res 2:399–406

    Article  PubMed  CAS  Google Scholar 

  49. Knudsen GP, Harbo HF, Smestad C et al (2007) X chromosome inactivation in females with multiple sclerosis. Eur J Neurol 14:1392–1396

    Article  PubMed  CAS  Google Scholar 

  50. Özbalkan Z, Bağişlar S, Kiraz S et al (2005) Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum 52:1564–1570

    Article  PubMed  CAS  Google Scholar 

  51. Chagnon P, Schneider R, Hébert J et al (2006) Identification and characterization of an Xp22.33;Yp11.2 translocation causing triplication of genes in pseudoautosomal region 1 in an XX male with severe systemic lupus erythematosus. Arthritis Rheum 54:1270–1278

    Article  PubMed  CAS  Google Scholar 

  52. Lu Q, Wu A, Tesmer L, Ray D, Yousif N, Richardson B (2007) Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol 179:6352–6358

    PubMed  CAS  Google Scholar 

  53. Brix TH, Knudsen GPS, Kristiansen M, Kyvik KO, Ørstavik KH, Hegedüs L (2005) High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity. J Clin Endrocrinol Metab 90:5949–5953

    Article  CAS  Google Scholar 

  54. D'Alessandro E, Cola MD, Lo Re ML et al (1990) Nonrandom chromosome changes in multiple sclerosis. Am J Med Genet 37:406–411

    Article  PubMed  Google Scholar 

  55. Brandrup F, Koch C, Petri M, Schiodt M, Johansen KS (1981) Discoid lupus erythematosus-like lesions and stomatitis in female carriers of X-linked chronic granulomatosus disease. Br J Dermatol 104:495–505

    Article  PubMed  CAS  Google Scholar 

  56. Ortiz-Romero P, Corell-Almuzara A, Lopez-Estebaranz J, Arranz F, Ruiz-Contreras J (1997) Lupus like lesions in a patient with X-linked chronic granulomatous disease and recombinant X chromosome. Dermatology 195:280–283

    Article  PubMed  CAS  Google Scholar 

  57. Richardson AL, Wang ZC, De Nicolo A et al (2006) X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9:121–132

    Article  PubMed  CAS  Google Scholar 

  58. van’t Veer LJ, Dal H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536

    Article  Google Scholar 

  59. Javierre BM, Esteller M, Ballestar E (2008) Epigenetic connections between autoimmune disorders and haematological malignancies. Trends Immunol 29:615–623

    Article  CAS  Google Scholar 

  60. Puri H, Campbell R, Puri-Harner V et al (1978) Serum-free polyamines in children with systemic lupus erythematosus. Adv Polyamine Res 2:359–367

    Google Scholar 

  61. Wallace HM, Fraser AV, Hughes A (2003) A perspective of polyamine metabolism. Biochem J 376:1–14

    Article  PubMed  CAS  Google Scholar 

  62. Casero RA, Marton LJ (2007) Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discovery 6:373–390

    Article  CAS  Google Scholar 

  63. Hobbs CA, Gilmour SK (2000) High levels of intracellular polyamines promote histone acetyltransferase activity results in chromatin hyperacetylation. J Cell Biochem 77:345–360

    Article  PubMed  CAS  Google Scholar 

  64. Poduslo JF, Curran GL (1996) Polyamine modification increases the permeability of proteins at the blood-nerve and blood-brain barriers. J Neurochem 66:1599–1609

    PubMed  CAS  Google Scholar 

  65. Williams K (1997) Modulation and block of ion channels: a new biology of polyamines. Cell Signal 9:1–13

    Article  PubMed  CAS  Google Scholar 

  66. Maeda Y, Rachez C, Hawel L, Byus CV, Freedman LP, Sladek FM (2002) Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein. Mol Endocrinol 16:1502–1510

    Article  PubMed  CAS  Google Scholar 

  67. Thomas T, Kiang DT (1988) A twenty-two-fold increase in relative affinity of estrogen receptor to poly(dA-dC) poly(dG-dT) in the presence of polyamines. Nuc Acids Res 16:4705–4720

    Article  CAS  Google Scholar 

  68. Kleppe K, Osland A, Fosse V et al (1981) Effect of polyamines on enzymes involved in DNA repair. Med Biol 59:374–380

    PubMed  CAS  Google Scholar 

  69. Hasan R, Moinuddin AK, Ali R (1995) Polyamine induced Z-conformation of native calf thymus DNA. FEBS Lett 368:27–30

    Article  PubMed  CAS  Google Scholar 

  70. Brooks WH (2000) Autoimmune diseases may result from inappropriate RNA polymerase III transcription: comment on the article by Neidhart et al. Arthritis Rheum 46:1412–1413

    Article  Google Scholar 

  71. Brooks WH (2005) Autoimmune disorders result from loss of epigenetic control following chromosome damage. Med Hypotheses 64:590–598

    Article  PubMed  CAS  Google Scholar 

  72. Brooks WH (2002) Systemic lupus erythematosus and related autoimmune diseases are antigen-driven, epigenetic diseases. Med Hypotheses 59:736–741

    Article  PubMed  CAS  Google Scholar 

  73. Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, why. Mol Cell 33:1–13

    Article  PubMed  CAS  Google Scholar 

  74. Herrmann F, Bossert M, Schwander A, Akgün E, Fackelmayer FO (2004) Arginine methylation of scaffold attachment factor A by heterogeneous nuclear ribonucleoprotein particle-associated PRMT1. J Biol Chem 279:48774–48779

    Article  PubMed  CAS  Google Scholar 

  75. Nakashima K, Hagiwara T, Yamada M (2002) Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J Biol Chem 277:49562–49568

    Article  PubMed  CAS  Google Scholar 

  76. Szekanecz Z, Soos L, Szabo Z et al (2008) Anti-citrullinated protein antibodies in rheumatoid arthritis: as good as it gets? Clin Rev Allerg Immunol 34:26–31

    Article  Google Scholar 

  77. Pavlova BG, Muhlberger HH, Stobl H et al (1995) B lymphocytes with latent EBV infection appearing in long-term bone marrow cultures (HLTBMCs) from haematological patients induce lysis of stromal microenvironment. Br J Haematology 89:704–711

    Article  CAS  Google Scholar 

  78. Drotar ME, Silva S, Barone E et al (2003) Epstein-Barr virus nuclear antigen-1 and Myc cooperate in lymphomagenesis. Int J Cancer 106:388–395

    Article  PubMed  CAS  Google Scholar 

  79. Arnheim N, Calabrese P (2009) Understanding what determines the frequency and pattern of human germline mutations. Nat Rev Genet 10:478–488

    Article  PubMed  CAS  Google Scholar 

  80. Barros SP, Offenbacher S (2009) Epigenetics: connecting environment and genotype to phenotype and disease. J Dent Res 88:400–408

    Article  PubMed  CAS  Google Scholar 

  81. Figueiredo LM, Cross GA, Janzen CJ (2009) Epigenetic regulation in African trypanosomes: a new kid on the block. Nat Rev Microbiol 7:504–513

    Article  PubMed  CAS  Google Scholar 

  82. Hewagama A, Richardson B (2009) The genetics and epigenetics of autoimmune diseases. J Autoimmun 33:3–11

    Article  PubMed  CAS  Google Scholar 

  83. Invernizzi P (2009) Future directions in genetic for autoimmune diseases. J Autoimmun 33:1–2

    Article  PubMed  CAS  Google Scholar 

  84. Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M (2009) Female predominance and X chromosome defects in autoimmune diseases. J Autoimmun 33:12–16

    Article  PubMed  CAS  Google Scholar 

  85. Larizza D, Calcaterra V, Martinetti M (2009) Autoimmune stigmata in Turner syndrome: when lacks an X chromosome. J Autoimmun 33:25–30

    Article  PubMed  CAS  Google Scholar 

  86. Persani L, Rossetti R, Cacciatore C, Bonomi M (2009) Primary Ovarian Insufficiency: X chromosome defects and autoimmunity. J Autoimmun 33:35–41

    Article  PubMed  CAS  Google Scholar 

  87. Sawalha AH, Harley JB, Scofield RH (2009) Autoimmunity and Klinefelter's syndrome: when men have two X chromosomes. J Autoimmun 33:31–34

    Article  PubMed  CAS  Google Scholar 

  88. Wells AD (2009) New, insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol 182:7331–7341

    Article  PubMed  CAS  Google Scholar 

  89. Zernicka-Goetz M, Morris SA, Bruce AW (2009) Making a firm decision: multifaceted regulation of cell fate in the early mouse embryo. Nat Rev Genet 10:467–477

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The author would like to thank Dr. Yves Renaudineau (University of Brest, Brest, France) for his kind advice in the preparation of this manuscript. The author would also like to thank Dr. Thomas Yang (University of Florida, Gainesville, Florida, USA) for providing the cell lines and facilities used in preparing Fig. 2. The author would also like to thank Dr. Missag Parseghian (Peregrine Pharmaceuticals, Inc., Tustin, California, USA) for providing the anti-histone H1 antibodies used in Fig. 2.

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Authors and Affiliations

  1. Experimental HTS, Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612-9416, USA

    Wesley H. Brooks

  2. Drug Discovery, SRB-3, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612-9416, USA

    Wesley H. Brooks

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  1. Wesley H. Brooks
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Correspondence to Wesley H. Brooks.

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This work is supported by the NIH (P30-CA76292-11; SP01CA118210; W81XWH-08-2-0101; CA067771-14) through funding awarded to H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612-9416 USA

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Brooks, W.H. X Chromosome Inactivation and Autoimmunity. Clinic Rev Allerg Immunol 39, 20–29 (2010). https://doi.org/10.1007/s12016-009-8167-5

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