Clinical Reviews in Allergy & Immunology

, Volume 39, Issue 1, pp 30–41 | Cite as

Epigenetics Lessons from Twins: Prospects for Autoimmune Disease

Article

Abstract

The existence of phenotypic differences between monozygotic (MZ) twins is a prime case where the relationship between genetic determinants and environmental factors is illustrated. Although virtually identical from a genetic point of view, MZ twins show a variable degree of discordance with respect to different features including susceptibility to disease. Discordance has frequently been interpreted in terms of the impact of the environment with genetics. In this sense, accumulated evidence supports the notion that environmental factors can have a long-term effect on epigenetic profiles and influence the susceptibility to disease. In relation with autoimmune diseases, the identification of DNA methylation changes in individuals who develop the disease, and the influence of inhibitors of DNA methyltransferases and histone modification enzymes in the development of autoimmunity are attracting the attention of researchers in the epigenetics field. In this context, the study of discordant MZ twins constitutes an attractive model to further investigate the epigenetic mechanisms involved in their development as well as to dissect the contribution of environmental traits. The implications of novel strategies to map epigenetic profiles and how the use of MZ twins can contribute to dissect the epigenetic component of autoimmune disease are discussed.

Keywords

Monozygotic twins Epigenetics DNA methylation Autoimmune Systemic lupus erythematosus Environmental effects 

Notes

Acknowledgements

EB is supported by PI081346 (FIS) grant from the Spanish Ministry of Science and Innovation (MICINN).

References

  1. 1.
    MacGillivray I, Campbell DM, Thompson B (eds) (1988) Twinning and twins. Wiley, NYGoogle Scholar
  2. 2.
    Reed TE, Chandler JH (1958) Huntington’s chorea in Michigan. I. Demography and genetics. Am J Hum Genet 10:201–225PubMedGoogle Scholar
  3. 3.
    Gibbons RJ, Higgs DR (1996) The alpha-thalassemia/mental retardation syndromes. Medicine (Baltimore) 75:45–52CrossRefGoogle Scholar
  4. 4.
    Greaves MF, Maia AT, Wiemels JL, Ford AM (2003) Leukemia in twins: lessons in natural history. Blood 102:2321–2333CrossRefPubMedGoogle Scholar
  5. 5.
    Hrubec Z, Robinette CD (1984) The study of human twins in medical research. N Engl J Med 310:435–441PubMedCrossRefGoogle Scholar
  6. 6.
    Singh SM, McDonald P, Murphy B, O’Reilly R (2004) Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development. Clin Genet 65:435–440CrossRefPubMedGoogle Scholar
  7. 7.
    Salvetti M, Ristori G, Bomprezzi R, Pozzilli P, Leslie RD (2000) Twins: mirrors of the immune system. Immunol Today 21:342–347CrossRefPubMedGoogle Scholar
  8. 8.
    Yamagishi H, Ishii C, Maeda J, Kojima Y et al (1998) Phenotypic discordance in monozygotic twins with 22q11.2 deletion. Am J Med Genet 78:319–321CrossRefPubMedGoogle Scholar
  9. 9.
    Hillebrand G, Siebert R, Simeoni E, Santer R (2000) DiGeorge syndrome with discordant phenotype in monozygotic twins. J Med Genet 37:E23CrossRefPubMedGoogle Scholar
  10. 10.
    Ballestar E, Esteller M (2008) Epigenetic gene regulation in cancer. Adv Genet 61:247–267CrossRefPubMedGoogle Scholar
  11. 11.
    Weksberg R, Shuman C, Caluseriu O et al (2002) Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum Mol Genet 11:1317–1325CrossRefPubMedGoogle Scholar
  12. 12.
    Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188CrossRefPubMedGoogle Scholar
  13. 13.
    Hansen RS, Wijmenga C, Luo P et al (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A 96:14412–14417CrossRefPubMedGoogle Scholar
  14. 14.
    Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463CrossRefPubMedGoogle Scholar
  15. 15.
    Fisher AG (2002) Cellular identity and lineage choice. Nat Rev Immunol 2:977–982CrossRefPubMedGoogle Scholar
  16. 16.
    Miller OJ, Schnedl W, Allen J, Erlanger BF (1974) 5-Methylcytosine localised in mammalian constitutive heterochromatin. Nature 251:636–637CrossRefPubMedGoogle Scholar
  17. 17.
    Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 196:261–282CrossRefPubMedGoogle Scholar
  18. 18.
    Aissani B, Bernardi G (1991) CpG islands: features and distribution in the genomes of vertebrates. Gene 106:173–183CrossRefPubMedGoogle Scholar
  19. 19.
    Keshet I, Lieman-Hurwitz J, Cedar H (1986) DNA methylation affects the formation of active chromatin. Cell 44:535–543CrossRefPubMedGoogle Scholar
  20. 20.
    Reik W, Collick A, Norris ML, Barton SC, Surani MA (1987) Genomic imprinting determines methylation of parental alleles in transgenic mice. Nature 328:248–251CrossRefPubMedGoogle Scholar
  21. 21.
    Wolf SF, Migeon BR (1982) Studies of X chromosome DNA methylation in normal human cells. Nature 295:667–671CrossRefPubMedGoogle Scholar
  22. 22.
    Ezhkova E, Pasolli HA, Parker JS et al (2009) Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136:1122–1135CrossRefPubMedGoogle Scholar
  23. 23.
    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45CrossRefPubMedGoogle Scholar
  24. 24.
    Wang Y, Fischle W, Cheung W, Jacobs S, Khorasanizadeh S, Allis CD (2004) Beyond the double helix: writing and reading the histone code. Novartis Found Symp 259:3–17CrossRefPubMedGoogle Scholar
  25. 25.
    Chahal SS, Matthews HR, Bradbury EM (1980) Acetylation of histone H4 and its role in chromatin structure and function. Nature 287:76–79CrossRefPubMedGoogle Scholar
  26. 26.
    Rundlett SE, Carmen AA, Suka N, Turner BM, Grunstein M (1998) Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3. Nature 392:831–835CrossRefPubMedGoogle Scholar
  27. 27.
    Santos-Rosa H, Schneider R, Bannister AJ et al (2002) Active genes are tri-methylated at K4 of histone H3. Nature 419:407–411CrossRefPubMedGoogle Scholar
  28. 28.
    Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T (2001) Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410:116–120CrossRefPubMedGoogle Scholar
  29. 29.
    Schotta G, Lachner M, Sarma K et al (2004) A silencing pathway to induce H3–K9 and H4–K20 trimethylation at constitutive heterochromatin. Genes Dev 18:1251–1262CrossRefPubMedGoogle Scholar
  30. 30.
    Bauer UM, Daujat S, Nielsen SJ, Nightingale K, Kouzarides T (2002) Methylation at arginine 17 of histone H3 is linked to gene activation. EMBO Rep 3:39–44CrossRefPubMedGoogle Scholar
  31. 31.
    de la Cruz X, Lois S, Sanchez-Molina S, Martinez-Balbas MA (2005) Do protein motifs read the histone code? BioEssays 27:164–175CrossRefPubMedGoogle Scholar
  32. 32.
    Schlesinger Y, Straussman R, Keshet I et al (2007) Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 39:232–236CrossRefPubMedGoogle Scholar
  33. 33.
    Widschwendter M, Fiegl H, Egle D et al (2007) Epigenetic stem cell signature in cancer. Nat Genet 39:157–158CrossRefPubMedGoogle Scholar
  34. 34.
    Ballestar E, Wolffe AP (2001) Methyl-CpG-binding proteins: targeting specific gene repression. Eur J Biochem 268:1–6CrossRefPubMedGoogle Scholar
  35. 35.
    Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J (2003) N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol Cell 12:723–734CrossRefPubMedGoogle Scholar
  36. 36.
    Nakayama J, Rice JC, Strahl BD, Allis CD, Grewal SI (2001) Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292:110–113CrossRefPubMedGoogle Scholar
  37. 37.
    Espada J, Ballestar E, Fraga MF et al (2004) Human DNMT1 is essential to maintain the histone H3 modification pattern. J Biol Chem 279:37175–37184CrossRefPubMedGoogle Scholar
  38. 38.
    Thorne JL, Campbell MJ, Turner BM (2008) Transcription factors, chromatin and cancer. Int J Biochem Cell Biol 41:164–175CrossRefPubMedGoogle Scholar
  39. 39.
    McEwan IJ (2009) Nuclear receptors: one big family. Methods Mol Biol 505:3–18CrossRefPubMedGoogle Scholar
  40. 40.
    Wilson VL, Jones PA (1983) DNA methylation decreases in aging but not in immortal cells. Science 220:1055–1057CrossRefPubMedGoogle Scholar
  41. 41.
    Mays-Hoopes L, Chao W, Butcher HC, Huang RC (1986) Decreased methylation of the major mouse long interspersed repeated DNA during aging and in myeloma cells. Dev Genet 7:65–73CrossRefPubMedGoogle Scholar
  42. 42.
    Friso S, Choi SW, Girelli D et al (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci U S A 99:5606–5611CrossRefPubMedGoogle Scholar
  43. 43.
    Millar SE, Miller MW, Stevens ME, Barsh GS (1995) Expression and transgenic studies of the mouse agouti gene provide insight into the mechanisms by which mammalian coat color patterns are generated. Development 121:3223–3232PubMedGoogle Scholar
  44. 44.
    Michaud EJ, van Vugt MJ, Bultman SJ, Sweet HO, Davisson MT, Woychik RP (1994) Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. Genes Dev 8:1463–1472CrossRefPubMedGoogle Scholar
  45. 45.
    Wolff GL, Kodell RL, Moore SR, Cooney CA (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12:949–957PubMedGoogle Scholar
  46. 46.
    Cooney CA, Dave AA, Wolff GL (2002) Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr 132:2393S–2400SPubMedGoogle Scholar
  47. 47.
    Doherty AS, Mann MR, Tremblay KD, Bartolomei MS, Schultz RM (2000) Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod 62:1526–1535CrossRefPubMedGoogle Scholar
  48. 48.
    Mann MR, Lee SS, Doherty AS et al (2004) Selective loss of imprinting in the placenta following preimplantation development in culture. Development 131:3727–3735CrossRefPubMedGoogle Scholar
  49. 49.
    Lumey LH, Stein AD, Kahn HS et al (2007) Cohort profile: the Dutch Hunger Winter families study. Int J Epidemiol 36:1196–1204CrossRefPubMedGoogle Scholar
  50. 50.
    Smith FM, Garfield AS, Ward A (2006) Regulation of growth and metabolism by imprinted genes. Cytogenet Genome Res 113:279–291CrossRefPubMedGoogle Scholar
  51. 51.
    Cui H, Cruz-Correa M, Giardiello FM et al (2003) Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299:1753–1755CrossRefPubMedGoogle Scholar
  52. 52.
    Heijmans BT, Kremer D, Tobi EW, Boomsma DI, Slagboom PE (2007) Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Hum Mol Genet 16:547–554CrossRefPubMedGoogle Scholar
  53. 53.
    Heijmans BT, Tobi EW, Stein AD et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105:17046–17049CrossRefPubMedGoogle Scholar
  54. 54.
    Petronis A (2001) Human morbid genetics revisited: relevance of epigenetics. Trends Genet 17:142–146CrossRefPubMedGoogle Scholar
  55. 55.
    Tremolizzo L, Carboni G, Ruzicka WB et al (2002) An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc Natl Acad Sci U S A 99:17095–17100CrossRefPubMedGoogle Scholar
  56. 56.
    Petronis A, Gottesman II, Kan P et al (2003) Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr Bull 29:169–178PubMedGoogle Scholar
  57. 57.
    Mill J, Dempster E, Caspi A, Williams B, Moffitt T, Craig I (2006) Evidence for monozygotic twin (MZ) discordance in methylation level at two CpG sites in the promoter region of the catechol-O-methyltransferase (COMT) gene. Am J Med Genet B Neuropsychiatr Genet 141B:421–425CrossRefPubMedGoogle Scholar
  58. 58.
    Oates NA, van Vliet J, Duffy DL et al (2006) Increased DNA methylation at the AXIN1 gene in a monozygotic twin from a pair discordant for a caudal duplication anomaly. Am J Hum Genet 79:155–162CrossRefPubMedGoogle Scholar
  59. 59.
    Yamazawa K, Kagami M, Fukami M, Matsubara K, Ogata T (2008) Monozygotic female twins discordant for Silver-Russell syndrome and hypomethylation of the H19-DMR. J Hum Genet 53:950–955CrossRefPubMedGoogle Scholar
  60. 60.
    Ramagopalan SV, Dyment DA, Morrison KM et al (2008) Methylation of class II transactivator gene promoter IV is not associated with susceptibility to multiple sclerosis. BMC Med Genet 9:63CrossRefPubMedGoogle Scholar
  61. 61.
    Zhang AP, Yu J, Liu JX et al (2007) The DNA methylation profile within the 5′-regulatory region of DRD2 in discordant sib pairs with schizophrenia. Schizophr Res 90:97–103CrossRefPubMedGoogle Scholar
  62. 62.
    Fraga MF, Ballestar E, Paz MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102:10604–10609CrossRefPubMedGoogle Scholar
  63. 63.
    Bergem AL, Engedal K, Kringlen E (1997) The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch Gen Psychiatry 54:264–270PubMedGoogle Scholar
  64. 64.
    Kaprio J, Tuomilehto J, Koskenvuo M et al (1992) Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 35:1060–1067CrossRefPubMedGoogle Scholar
  65. 65.
    Kaminsky ZA, Tang T, Wang SC et al (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41:240–245CrossRefPubMedGoogle Scholar
  66. 66.
    International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN) et al (2008) Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40:204–210CrossRefGoogle Scholar
  67. 67.
    Ueda H, Howson JM, Esposito L et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511CrossRefPubMedGoogle Scholar
  68. 68.
    Leslie RDG, Elliot RB (1994) Early environmental events as a cause of IDDM. Evidence and implications. Diabetes 43:843–850CrossRefPubMedGoogle Scholar
  69. 69.
    Javierre BM, Esteller M, Ballestar E (2008) Epigenetic connections between autoimmune disorders and haematological malignancies. Trends Immunol 29:616–623CrossRefPubMedGoogle Scholar
  70. 70.
    Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33:1665–1673CrossRefPubMedGoogle Scholar
  71. 71.
    Kaplan MJ, Lu Q, Wu A, Attwood J, Richardson B (2004) Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. J Immunol 172:3652–3661PubMedGoogle Scholar
  72. 72.
    Lu Q, Wu A, Richardson BC (2005) Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. J Immunol 174:6212–6219PubMedGoogle Scholar
  73. 73.
    Lu Q, Kaplan M, Tay D et al (2002) Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheum 46:1282–1291CrossRefPubMedGoogle Scholar
  74. 74.
    Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298CrossRefPubMedGoogle Scholar
  75. 75.
    Weber M, Davies JJ, Wittig D et al (2005) Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 37:853–862CrossRefPubMedGoogle Scholar
  76. 76.
    Bibikova M, Lin Z, Zhou L et al (2006) High-throughput DNA methylation profiling using universal bead arrays. Genome Res 16:383–393CrossRefPubMedGoogle Scholar
  77. 77.
    Taylor KH, Kramer RS, Davis JW et al (2007) Ultradeep bisulfite sequencing analysis of DNA methylation patterns in multiple gene promoters by 454 sequencing. Cancer Res 67:8511–8518CrossRefPubMedGoogle Scholar
  78. 78.
    Orlando V (2000) Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation. Trends Biochem Sci 25:99–104CrossRefPubMedGoogle Scholar
  79. 79.
    Weber M, Hellmann I, Stadler MB et al (2007) Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39:457–466CrossRefPubMedGoogle Scholar
  80. 80.
    Barski A, Cuddapah S, Cui K et al (2007) High-resolution profiling of histone methylations in the human genome. Cell 129:823–837CrossRefPubMedGoogle Scholar
  81. 81.
    Ebers GC, Sadovnick AD (1994) The role of genetic factors in multiple sclerosis susceptibility. J Neuroimmunol 54:1–17CrossRefPubMedGoogle Scholar
  82. 82.
    Aho K, Koskenvuo M, Tuominen J, Kaprio J (1986) Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol 13:899–902PubMedGoogle Scholar
  83. 83.
    Järvinen P, Kaprio J, Mäkitalo R, Koskenvuo M, Aho K (1992) Systemic lupus erythematosus and related systemic diseases in a nationwide twin cohort: an increased prevalence of disease in MZ twins and concordance of disease features. J Int Med 231:67–72CrossRefGoogle Scholar
  84. 84.
    Greco L, Romino R, Coto I et al (2002) The first large population based twin study of coeliac disease. Gut 50:624–628CrossRefPubMedGoogle Scholar
  85. 85.
    Thompson NP, Driscoll R, Pounder RE et al (1996) Genetic versus environment in IBD: results of a British twin study. BMJ 312:95PubMedGoogle Scholar
  86. 86.
    Krueger GG, Duvic M (1994) Epidemiology of psoriasis: clinical issues. J Invest Dermatol 102:14S–18SCrossRefPubMedGoogle Scholar
  87. 87.
    Arnheim N, Calabrese P (2009) Understanding what determines the frequency and pattern of human germline mutations. Nat Rev Genet 10:478–488CrossRefPubMedGoogle Scholar
  88. 88.
    Barros SP, Offenbacher S (2009) Epigenetics: connecting environment and genotype to phenotype and disease. J Dent Res 88:400–408CrossRefPubMedGoogle Scholar
  89. 89.
    Figueiredo LM, Cross GA, Janzen CJ (2009) Epigenetic regulation in African trypanosomes: a new kid on the block. Nat Rev Microbiol 7:504–513CrossRefPubMedGoogle Scholar
  90. 90.
    Hewagama A, Richardson B (2009) The genetics and epigenetics of autoimmune diseases. J Autoimmun 33:3–11CrossRefPubMedGoogle Scholar
  91. 91.
    Invernizzi P (2009) Future directions in genetic for autoimmune diseases. J Autoimmun 33:1–2CrossRefPubMedGoogle Scholar
  92. 92.
    Invernizzi P, Pasini S, Selmi C, Gershwin ME, Podda M (2009) Female predominance and X chromosome defects in autoimmune diseases. J Autoimmun 33:12–16CrossRefPubMedGoogle Scholar
  93. 93.
    Larizza D, Calcaterra V, Martinetti M (2009) Autoimmune stigmata in Turner syndrome: when lacks an X chromosome. J Autoimmun 33:25–30CrossRefPubMedGoogle Scholar
  94. 94.
    Persani L, Rossetti R, Cacciatore C, Bonomi M (2009) Primary ovarian insufficiency: X chromosome defects and autoimmunity. J Autoimmun 33:35–41CrossRefPubMedGoogle Scholar
  95. 95.
    Sawalha AH, Harley JB, Scofield RH (2009) Autoimmunity and Klinefelter's syndrome: when men have two X chromosomes. J Autoimmun 33:31–34CrossRefPubMedGoogle Scholar
  96. 96.
    Wells AD (2009) New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol 182:7331–7341CrossRefPubMedGoogle Scholar
  97. 97.
    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 10:467–477CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  1. 1.Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC)Bellvitge Biomedical Research Institute (IDIBELL)L’Hospitalet de LlobregatSpain

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