Virchows Archiv

, Volume 456, Issue 1, pp 13–21 | Cite as

Genome-scale approaches to the epigenetics of common human disease

Review and Perspective


Traditionally, the pathology of human disease has been focused on microscopic examination of affected tissues, chemical and biochemical analysis of biopsy samples, other available samples of convenience, such as blood, and noninvasive or invasive imaging of varying complexity, in order to classify disease and illuminate its mechanistic basis. The molecular age has complemented this armamentarium with gene expression arrays and selective analysis of individual genes. However, we are entering a new era of epigenomic profiling, i.e., genome-scale analysis of cell-heritable nonsequence genetic change, such as DNA methylation. The epigenome offers access to stable measurements of cellular state and to biobanked material for large-scale epidemiological studies. Some of these genome-scale technologies are beginning to be applied to create the new field of epigenetic epidemiology.


Epigenetics Epidemiology DNA methylation 


  1. 1.
    Van Speybroeck L (2002) From epigenesis to epigenetics: the case of C. H. Waddington. Ann N Y Acad Sci 981:61–81PubMedCrossRefGoogle Scholar
  2. 2.
    Feinberg AP, Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4:143–153CrossRefPubMedGoogle Scholar
  3. 3.
    Poirier LA (2002) The effects of diet, genetics and chemicals on toxicity and aberrant DNA methylation: an introduction. J Nutr 132:2336S–2339SPubMedGoogle Scholar
  4. 4.
    Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 196:261–282CrossRefPubMedGoogle Scholar
  5. 5.
    Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321:209–213CrossRefPubMedGoogle Scholar
  6. 6.
    Riggs AD, Pfeifer GP (1992) X-chromosome inactivation and cell memory. Trends Genet 8:169–174PubMedGoogle Scholar
  7. 7.
    Strichman-Almashanu LZ, Lee RS, Onyango PO et al (2002) A genome-wide screen for normally methylated human CpG islands that can identify novel imprinted genes. Genome Res 12:543–554PubMedGoogle Scholar
  8. 8.
    Song F, Smith JF, Kimura MT et al (2005) Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc Natl Acad Sci USA 102:3336–3341CrossRefPubMedGoogle Scholar
  9. 9.
    Shiota K, Kogo Y, Ohgane J et al (2002) Epigenetic marks by DNA methylation specific to stem, germ and somatic cells in mice. Genes Cells 7:961–969CrossRefPubMedGoogle Scholar
  10. 10.
    Eckhardt F, Lewin J, Cortese R et al (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38:1378–1385CrossRefPubMedGoogle Scholar
  11. 11.
    Hark AT, Schoenherr CJ, Katz DJ et al (2000) CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405:486–489CrossRefPubMedGoogle Scholar
  12. 12.
    Cui H, Niemitz EL, Ravenel JD et al (2001) Loss of imprinting of insulin-like growth factor-II in Wilms’ tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Res 61:4947–4950PubMedGoogle Scholar
  13. 13.
    Silva AJ, White R (1988) Inheritance of allelic blueprints for methylation patterns. Cell 54:145–152CrossRefPubMedGoogle Scholar
  14. 14.
    Sandovici I, Naumova AK, Leppert M et al (2004) A longitudinal study of X-inactivation ratio in human females. Hum Genet 115:387–392CrossRefPubMedGoogle Scholar
  15. 15.
    Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447(7143):433–440CrossRefPubMedGoogle Scholar
  16. 16.
    Feinberg AP, Vogelstein B (1983) Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun 111:47–54CrossRefPubMedGoogle Scholar
  17. 17.
    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
  18. 18.
    Sakatani T, Kaneda A, Iacobuzio-Donahue CA et al (2005) Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307:1976–1978CrossRefPubMedGoogle Scholar
  19. 19.
    Kaneda A, Wang CJ, Cheong R, et al (2007) Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proc Natl Acad Sci USA 104:20926–20931CrossRefPubMedGoogle Scholar
  20. 20.
    Horsthemke B, Buiting K (2008) Genomic imprinting and imprinting defects in humans. Adv Genet 61:225–246CrossRefPubMedGoogle Scholar
  21. 21.
    Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9:2395–2402CrossRefPubMedGoogle Scholar
  22. 22.
    Petronis A, Gottesman II, Crow TJ et al (2000) Psychiatric epigenetics: a new focus for the new century. Mol Psychiatry 5:342–346CrossRefPubMedGoogle Scholar
  23. 23.
    Bjornsson HT, Fallin MD, Feinberg AP (2004) An integrated epigenetic and genetic approach to common human disease. Trends Genet 20:350–358CrossRefPubMedGoogle Scholar
  24. 24.
    Weaver IC, Cervoni N, Champagne FA et al (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854CrossRefPubMedGoogle Scholar
  25. 25.
    Tsankova NM, Berton O, Renthal W et al (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525CrossRefPubMedGoogle Scholar
  26. 26.
    Shimabukuro M, Jinno Y, Fuke C et al (2006) Haloperidol treatment induces tissue- and sex-specific changes in DNA methylation: a control study using rats. Behav Brain Funct 2:37CrossRefPubMedGoogle Scholar
  27. 27.
    McMahon FJ, Stine OC, Meyers DA et al (1995) Patterns of maternal transmission in bipolar affective disorder. Am J Hum Genet 56:1277–1286PubMedGoogle Scholar
  28. 28.
    Skuse DH, James RS, Bishop DV et al (1997) Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature 387:705–708CrossRefPubMedGoogle Scholar
  29. 29.
    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 USA 96:14412–14417CrossRefPubMedGoogle Scholar
  30. 30.
    Sutcliffe JS, Nelson DL, Zhang F et al (1992) DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet 1:397–400CrossRefPubMedGoogle Scholar
  31. 31.
    Amir RE, Van den Veyver IB, Wan M et al (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188CrossRefPubMedGoogle Scholar
  32. 32.
    Fan G, Beard C, Chen RZ et al (2001) DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J Neurosci 21:788–797PubMedGoogle Scholar
  33. 33.
    Nelson ED, Kavalali ET, Monteggia LM (2008) Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J Neurosci 28:395–406CrossRefPubMedGoogle Scholar
  34. 34.
    Roohi J, Montagna C, Tegay DH et al (2008) Disruption of contactin 4 in 3 subjects with autism spectrum disorder. J Med Genet 46(3):176–182CrossRefPubMedGoogle Scholar
  35. 35.
    Bakkaloglu B, O’Roak BJ, Louvi A et al (2008) Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82:165–173CrossRefPubMedGoogle Scholar
  36. 36.
    Arking DE, Cutler DJ, Brune CW et al (2008) A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82:160–164CrossRefPubMedGoogle Scholar
  37. 37.
    Alarcon M, Abrahams BS, Stone JL et al (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82:150–159CrossRefPubMedGoogle Scholar
  38. 38.
    Strauss KA, Puffenberger EG, Huentelman MJ et al (2006) Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354:1370–1377CrossRefPubMedGoogle Scholar
  39. 39.
    Wareham KA, Lyon MF, Glenister PH et al (1987) Age related reactivation of an X-linked gene. Nature 327:725–727CrossRefPubMedGoogle Scholar
  40. 40.
    Brown S, Rastan S (1988) Age-related reactivation of an X-linked gene close to the inactivation centre in the mouse. Genet Res 52:151–154CrossRefPubMedGoogle Scholar
  41. 41.
    Bennett-Baker PE, Wilkowski J, Burke DT (2003) Age-associated activation of epigenetically repressed genes in the mouse. Genetics 165:2055–2062PubMedGoogle Scholar
  42. 42.
    Bandeen-Roche K, Xue QL, Ferrucci L et al (2006) Phenotype of frailty: characterization in the women’s health and aging studies. J Gerontol A Biol Sci Med Sci 61:262–266PubMedGoogle Scholar
  43. 43.
    Fraga MF, Ballestar E, Paz MF et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609CrossRefPubMedGoogle Scholar
  44. 44.
    Feinberg AP (2001) Methylation meets genomics. Nat Genet 27:9–10CrossRefPubMedGoogle Scholar
  45. 45.
    Fazzari MJ, Greally JM (2004) Epigenomics: beyond CpG islands. Nat Rev Genet 5:446–455CrossRefPubMedGoogle Scholar
  46. 46.
    Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298CrossRefPubMedGoogle Scholar
  47. 47.
    Illingworth RS, Bird AP (2009) CpG islands—‘a rough guide’. FEBS Lett 583:1713–1720CrossRefPubMedGoogle Scholar
  48. 48.
    Bibikova M, Fan JB (2009) GoldenGate assay for DNA methylation profiling. Methods Mol Biol 507:149–163CrossRefPubMedGoogle Scholar
  49. 49.
    Clark SJ, Harrison J, Paul CL et al (1994) High sensitivity mapping of methylated cytosines. Nucleic Acids Res 22:2990–2997CrossRefPubMedGoogle Scholar
  50. 50.
    Bibikova M, Lin Z, Zhou L et al (2006) High-throughput DNA methylation profiling using universal bead arrays. Genome Res 16:383–393CrossRefPubMedGoogle Scholar
  51. 51.
    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
  52. 52.
    Irizarry RA, Ladd-Acosta C, Carvalho B et al (2008) Comprehensive high-throughput arrays for relative methylation (CHARM). Genome Res 18:780–790CrossRefPubMedGoogle Scholar
  53. 53.
    Irizarry RA, Ladd-Acosta C, Wen B et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41:178–186CrossRefPubMedGoogle Scholar
  54. 54.
    Costello JF, Smiraglia DJ, Plass C (2002) Restriction landmark genome scanning. Methods 27:144–149CrossRefPubMedGoogle Scholar
  55. 55.
    Jorgensen HF, Adie K, Chaubert P et al (2006) Engineering a high-affinity methyl-CpG-binding protein. Nucleic Acids Res 34:e96CrossRefPubMedGoogle Scholar
  56. 56.
    Illingworth R, Kerr A, Desousa D et al (2008) A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol 6:e22CrossRefPubMedGoogle Scholar
  57. 57.
    Khulan B, Thompson RF, Ye K et al (2006) Comparative isoschizomer profiling of cytosine methylation: the HELP assay. Genome Res 16:1046–1055CrossRefPubMedGoogle Scholar
  58. 58.
    Oda M, Glass JL, Thompson RF et al (2009) High-resolution genome-wide cytosine methylation profiling with simultaneous copy number analysis and optimization for limited cell numbers. Nucleic Acids Res 37(12):3829–3839CrossRefPubMedGoogle Scholar
  59. 59.
    Yamada Y, Watanabe H, Miura F et al (2004) A comprehensive analysis of allelic methylation status of CpG islands on human chromosome 21q. Genome Res 14:247–266CrossRefPubMedGoogle Scholar
  60. 60.
    Ordway JM, Bedell JA, Citek RW et al (2006) Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets. Carcinogenesis 27:2409–2423CrossRefPubMedGoogle Scholar
  61. 61.
    Margulies M, Egholm M, Altman WE et al (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437:376–380PubMedGoogle Scholar
  62. 62.
    Shendure J, Porreca GJ, Reppas NB et al (2005) Accurate multiplex polony sequencing of an evolved bacterial genome. Science 309:1728–1732CrossRefPubMedGoogle Scholar
  63. 63.
    Meissner A, Gnirke A, Bell GW et al (2005) Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res 33:5868–5877CrossRefPubMedGoogle Scholar
  64. 64.
    Frazer KA, Ballinger DG, Cox DR et al (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861CrossRefPubMedGoogle Scholar
  65. 65.
    Manolio TA, Brooks LD, Collins FS (2008) A HapMap harvest of insights into the genetics of common disease. J Clin Invest 118:1590–1605CrossRefPubMedGoogle Scholar
  66. 66.
    Cooper GM, Nickerson DA, Eichler EE (2007) Mutational and selective effects on copy-number variants in the human genome. Nat Genet 39:S22–S29CrossRefPubMedGoogle Scholar
  67. 67.
    Sutherland JE, Costa M (2003) Epigenetics and the environment. Ann N Y Acad Sci 983:151–160CrossRefPubMedGoogle Scholar
  68. 68.
    Van den Veyver IB (2002) Genetic effects of methylation diets. Annu Rev Nutr 22:255–282CrossRefPubMedGoogle Scholar
  69. 69.
    Pogribny IP, Basnakian AG, Miller BJ et al (1995) Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res 55:1894–1901PubMedGoogle Scholar
  70. 70.
    Pogribny IP, Miller BJ, James SJ (1997) Alterations in hepatic p53 gene methylation patterns during tumor progression with folate/methyl deficiency in the rat. Cancer Lett 115:31–38CrossRefPubMedGoogle Scholar
  71. 71.
    Wainfan E, Poirier LA (1992) Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Res 52:2071s–2077sPubMedGoogle Scholar
  72. 72.
    Jhaveri MS, Wagner C, Trepel JB (2001) Impact of extracellular folate levels on global gene expression. Mol Pharmacol 60:1288–1295PubMedGoogle Scholar
  73. 73.
    Fowler BM, Giuliano AR, Piyathilake C et al (1998) Hypomethylation in cervical tissue: is there a correlation with folate status? Cancer Epidemiol Biomarkers Prev 7:901–906PubMedGoogle Scholar
  74. 74.
    Jacob RA, Gretz DM, Taylor PC et al (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J Nutr 128:1204–1212PubMedGoogle Scholar
  75. 75.
    Rampersaud GC, Kauwell GP, Hutson AD et al (2000) Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. Am J Clin Nutr 72:998–1003PubMedGoogle Scholar
  76. 76.
    DeBaun MR, Niemitz EL, Feinberg AP (2003) Association of in vitro fertilization with Beckwith–Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 72:156–160CrossRefPubMedGoogle Scholar
  77. 77.
    Gicquel C, Gaston V, Mandelbaum J et al (2003) In vitro fertilization may increase the risk of Beckwith–Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet 72:1338–1341CrossRefPubMedGoogle Scholar
  78. 78.
    Niemitz EL, Feinberg AP (2004) Epigenetics and assisted reproductive technology: a call for investigation. Am J Hum Genet 74:599–609CrossRefPubMedGoogle Scholar
  79. 79.
    Bjornsson HT, Cui H, Gius D et al (2004) The new field of epigenomics: implications for cancer and other common disease research. Cold Spring Harb Symp Quant Biol 69:447–456CrossRefPubMedGoogle Scholar
  80. 80.
    Harris TB, Launer LJ, Eiriksdottir G et al (2007) Age, gene/environment susceptibility—Reykjavik study: multidisciplinary applied phenomics. Am J Epidemiol 165:1076–1087CrossRefPubMedGoogle Scholar
  81. 81.
    Bjornsson HT, Sigurdsson MI, Fallin MD et al (2008) Intra-individual change in DNA methylation over time with familial clustering. JAMA 299(24):2877–2883CrossRefPubMedGoogle Scholar
  82. 82.
    Boks MP, Derks EM, Weisenberger DJ et al (2009) The relationship of DNA methylation with age, gender and genotype in twins and healthy controls. PLoS ONE 4:e6767CrossRefPubMedGoogle Scholar
  83. 83.
    Zilliox MJ, Irizarry RA (2007) A gene expression bar code for microarray data. Nat Methods 4:911–913CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Center for Epigenetics and Department of MedicineJohns Hopkins University School of MedicineBaltimoreUSA

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