Advertisement

Epigenetics of Complex Diseases: From General Theory to Laboratory Experiments

  • A. Schumacher
  • A. PetronisEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 310)

Abstract

Despite significant effort, understanding the causes and mechanisms of complex non-Mendelian diseases remains a key challenge. Although numerous molecular genetic linkage and association studies have been conducted in order to explain the heritable predisposition to complex diseases, the resulting data are quite often inconsistent and even controversial. In a similar way, identification of environmental factors causal to a disease is difficult. In this article, a new interpretation of the paradigm of “genes plus environment” is presented in which the emphasis is shifted to epigenetic misregulation as a major etiopathogenic factor. Epigenetic mechanisms are consistent with various non-Mendelian irregularities of complex diseases, such as the existence of clinically indistinguishable sporadic and familial cases, sexual dimorphism, relatively late age of onset and peaks of susceptibility to some diseases, discordance of monozygotic twins and major fluctuations on the course of disease severity. It is also suggested that a substantial portion of phenotypic variance that traditionally has been attributed to environmental effects may result from stochastic epigenetic events in the cell. It is argued that epigenetic strategies, when applied in parallel with the traditional genetic ones, may significantly advance the discovery of etiopathogenic mechanisms of complex diseases. The second part of this chapter is dedicated to a review of laboratory methods for DNA methylation analysis, which may be useful in the study of complex diseases. In this context, epigenetic microarray technologies are emphasized, as it is evident that such technologies will significantly advance epigenetic analyses in complex diseases.

Keywords

Complex Disease Monozygotic Twin Angelman Syndrome Epigenetic Difference Restriction Landmark Genomic Scanning 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abkevich V, Camp NJ, Hensel CH, et al (2003) Predisposition locus for major depression at chromosome 12q22–12q23.2. Am J Hum Genet 73:1271–1281PubMedGoogle Scholar
  2. Adorjan P, Distler J, Lipscher E, et al (2002) Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids Res 30:e21PubMedGoogle Scholar
  3. Akey DT, Akey JM, Zhang K, Jin L (2002) Assaying DNA methylation based on high-throughput melting curve approaches. Genomics 80:376–384PubMedGoogle Scholar
  4. Allen ND, Norris ML, Surani MA (1990) Epigenetic control of transgene expression and imprinting by genotype-specific modifiers. Cell 61:853–861PubMedGoogle Scholar
  5. Allen ND, Logan K, Lally G, et al (1995) Distribution of parthenogenetic cells in the mouse brain and their influence on brain development and behavior. Proc Natl Acad Sci U S A 92:10782–10786PubMedGoogle Scholar
  6. 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 23:185–188PubMedGoogle Scholar
  7. Balog RP, de Souza YE, Tang HM, et al (2002) Parallel assessment of CpG methylation by two-color hybridization with oligonucleotide arrays. Anal Biochem 309:301–310PubMedGoogle Scholar
  8. Barlow DP (1995) Gametic imprinting in mammals. Science 270:1610–1613PubMedGoogle Scholar
  9. Baumer A, Wiedemann U, Hergersberg M, Schinzel A (2001) A novel MSP/DHPLC method for the investigation of the methylation status of imprinted genes enables the molecular detection of low cell mosaicisms. Hum Mutat 17:423–430PubMedGoogle Scholar
  10. Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168–174PubMedGoogle Scholar
  11. Beck S, Olek A, Walter J (1999) From genomics to epigenomics: a loftier view of life. Nat Biotechnol 17:1144PubMedGoogle Scholar
  12. Bertelsen A, Harvald B, Hauge M (1977) A Danish twin study of manic-depressive disorders. Br J Psychiatry 130:330–351PubMedGoogle Scholar
  13. Bestor TH, Chandler VL, Feinberg AP (1994) Epigenetic effects in eukaryotic gene expression. Dev Genet 15:458PubMedGoogle Scholar
  14. Brock GJ, Huang TH, Chen CM, Johnson KJ (2001) A novel technique for the identification of CpG islands exhibiting altered methylation patterns (ICEAMP). Nucleic Acids Res 29:E123PubMedGoogle Scholar
  15. Cardno AG, Gottesman II (2000) Twin studies of schizophrenia: from bow-and-arrow concordances to Star Wars Mx and functional genomics. Am J Med Genet 97:12–17PubMedGoogle Scholar
  16. Chotai KA, Payne SJ (1998) A rapid, PCR based test for differential molecular diagnosis of Prader-Willi and Angelman syndromes. J Med Genet 35:472–475PubMedGoogle Scholar
  17. Clement G, Benhattar J (2005) A methylation sensitive dot blot assay (MS-DBA) for the quantitative analysis of DNA methylation in clinical samples. J Clin Pathol 58:155–158PubMedGoogle Scholar
  18. Constancia M, Pickard B, Kelsey G, Reik W (1998) Imprinting mechanisms. Genome Res 8:881–900PubMedGoogle Scholar
  19. 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
  20. Cottrell SE, Distler J, Goodman NS, et al (2004) A real-time PCR assay for DNA methylation using methylation-specific blockers. Nucleic Acids Res 32:e10PubMedGoogle Scholar
  21. Cross SH, Charlton JA, Nan X, Bird AP (1994) Purification of CpG islands using a methylated DNA binding column. Nat Genet 6:236–244PubMedGoogle Scholar
  22. Crow TJ, DeLisi LE, Johnstone EC (1989) Concordance by sex in sibling pairs with schizophrenia is paternally inherited. Evidence for a pseudoautosomal locus. Br J Psychiatry 155:92–97PubMedGoogle Scholar
  23. Csordas A, Puschendorf B, Grunicke H (1986) Increased acetylation of histones at an early stage of oestradiol-mediated gene activation in the liver of immature chicks. J Steroid Biochem 24:437–442PubMedGoogle Scholar
  24. Cui H, Cruz-Correa M, Giardiello FM, et al (2003) Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299:1753–1755PubMedGoogle Scholar
  25. Cyranowski JM, Frank E, Young E, Shear MK (2000) Adolescent onset of the gender difference in lifetime rates of major depression: a theoretical model. Arch Gen Psychiatry 57:21–27PubMedGoogle Scholar
  26. Dahl C, Guldberg P (2003) DNA methylation analysis techniques. Biogerontology 4:233–250PubMedGoogle Scholar
  27. Deb-Rinker P, Klempan TA, O’Reilly RL, et al (1999) Molecular characterization of a MSRV-like sequence identified by RDA from monozygotic twin pairs discordant for schizophrenia. Genomics 61:133–144PubMedGoogle Scholar
  28. Deb-Rinker P, O’Reilly RL, Torrey EF, Singh SM (2002) Molecular characterization of a 2.7 kb, 12q13-specific, retroviral related sequence isolated by RDA from monozygotic twins discordant for schizophrenia. Genome 45:1–10Google Scholar
  29. Dobrovic A, Bianco T, Tan LW, et al (2002) Screening for and analysis of methylation differences using methylation-sensitive single-strand conformation analysis. Methods 27:134–138PubMedGoogle Scholar
  30. Dupont JM, Tost J, Jammes H, Gut IG (2004) De novo quantitative bisulfite sequencing using the pyrosequencing technology. Anal Biochem 333:119–127PubMedGoogle Scholar
  31. Eads CA, Danenberg KD, Kawakami K, et al (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28:E32PubMedGoogle Scholar
  32. Ehrlich M, Ehrlich K (1993) Effect of DNA methylation and the binding of vertebrate and plant proteins to DNA. In: Jost J, Saluz P (eds) DNA methylation: molecular biology and biological significance. Birkhauser Verlag, Basel, 145–168Google Scholar
  33. Feinberg AP (1999) Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction. Cancer Res 59:1743s–1746sPubMedGoogle Scholar
  34. Fraga MF, Uriol E, Borja Diego L, et al (2002) High-performance capillary electrophoretic method for the quantification of 5-methyl 2′-deoxycytidine in genomic DNA: application to plant, animal and human cancer tissues. Electrophoresis 23:1677–1681PubMedGoogle Scholar
  35. Frigola J, Ribas M, Risques RA, Peinado MA (2002) Methylome profiling of cancer cells by amplification of inter-methylated sites (AIMS). Nucleic Acids Res 30:e28PubMedGoogle Scholar
  36. Frommer M, McDonald LE, Millar DS, et al (1992) A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci U S A 89:1827–1831PubMedGoogle Scholar
  37. Fuke C, Shimabukuro M, Petronis A, et al (2004) Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet 68:196–204PubMedGoogle Scholar
  38. Galm O, Rountree MR, Bachman KE, et al (2002) Enzymatic regional methylation assay: a novel method to quantify regional CpG methylation density. Genome Res 12:153–157PubMedGoogle Scholar
  39. Gitan RS, Shi H, Chen CM, et al (2002) Methylation-specific oligonucleotide microarray: a new potential for high-throughput methylation analysis. Genome Res 12:158–164PubMedGoogle Scholar
  40. Gonzalgo ML, Jones PA (2002) Quantitative methylation analysis using methylationsensitive single-nucleotide primer extension (Ms-SNuPE). Methods 27:128–133PubMedGoogle Scholar
  41. Gonzalgo ML, Liang G, Spruck CH 3rd, et al (1997) Identification and characterization of differentially methylated regions of genomic DNA by methylation-sensitive arbitrarily primed PCR. Cancer Res 57:594–599PubMedGoogle Scholar
  42. Guldberg P, Worm J, Gronbaek K (2002) Profiling DNA methylation by melting analysis. Methods 27:121–127PubMedGoogle Scholar
  43. Hall JG (1990) Genomic imprinting: review and relevance to human diseases. Am J Hum Genet 46:857–873PubMedGoogle Scholar
  44. Hatada I, Kato A, Morita S, et al (2002) A microarray-based method for detecting methylated loci. J Hum Genet 47:448–451PubMedGoogle Scholar
  45. Hayashizaki Y, Hatada I, Hirotsune S, et al (1993) Restriction landmark genomic scanning (RLGS) method and its application (in Japanese). Seikagaku 65:109–115PubMedGoogle Scholar
  46. Heiman GA, Hodge SE, Wickramaratne P, Hsu H (1996) Age-at-interview bias in anticipation studies: computer simulations and an example with panic disorder. Psychiatr Genet 6:61–66PubMedGoogle Scholar
  47. Henikoff S, Matzke MA (1997) Exploring and explaining epigenetic effects. Trends Genet 13:293–295PubMedGoogle Scholar
  48. Herman JG, Graff JR, Myohanen S, et al (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93:9821–9826PubMedGoogle Scholar
  49. Hodge SE, Wickramaratne P (1995) Statistical pitfalls in detecting age-of-onset anticipation: the role of correlation in studying anticipation and detecting ascertainment bias. Psychiatr Genet 5:43–47PubMedGoogle Scholar
  50. Hou P, Ji M, Ge C, et al (2003a) Detection of methylation of human p16(Ink4a) gene 5′-CpG islands by electrochemical method coupled with linker-PCR. Nucleic Acids Res 31:e92PubMedGoogle Scholar
  51. Hou P, Ji M, Liu Z, et al (2003b) A microarray to analyze methylation patterns of p16(Ink4a) gene 5′-CpG islands. Clin Biochem 36:197–202PubMedGoogle Scholar
  52. Hou P, Ji M, Li S, et al (2004) High-throughput method for detecting DNA methylation. J Biochem Biophys Methods 60:139–150PubMedGoogle Scholar
  53. Howard R, Rabins PV, Seeman MV, Jeste DV (2000) Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. The International Late-Onset Schizophrenia Group. Am J Psychiatry 157:172–178PubMedGoogle Scholar
  54. Huang TH, Laux DE, Hamlin BC, et al (1997) Identification of DNA methylation markers for human breast carcinomas using the methylation-sensitive restriction fingerprinting technique. Cancer Res 57:1030–1034PubMedGoogle Scholar
  55. Huang TH, Perry MR, Laux DE (1999) Methylation profiling of CpG islands in human breast cancer cells. Hum Mol Genet 8:459–470PubMedGoogle Scholar
  56. Hubrich-Kuhner K, Buhk HJ, Wagner H, et al (1989) Non-C-G recognition sequences of DNA cytosine-5-methyltransferase from rat liver. Biochem Biophys Res Commun 160:1175–1182PubMedGoogle Scholar
  57. Ingrosso D, Cimmino A, Perna AF, et al (2003) Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 361:1693–1699PubMedGoogle Scholar
  58. Jablonka E, Lamb M (1995) Epigenetic inheritance and evolution. Oxford University Press, New York, pp 1–360Google Scholar
  59. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33Suppl:245–254PubMedGoogle Scholar
  60. Jantzen K, Fritton HP, Igo-Kemenes T, et al (1987) Partial overlapping of binding sequences for steroid hormone receptors and DNaseI hypersensitive sites in the rabbit uteroglobin gene region. Nucleic Acids Res 15:4535–4552PubMedGoogle Scholar
  61. Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167PubMedGoogle Scholar
  62. Jones PL, Veenstra GJ, Wade PA, et al (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187–191PubMedGoogle Scholar
  63. Kaminsky ZA, Assadzadeh A, Flanagan J, Petronis A (2005) Single nucleotide extension technology for quantitative site-specific evaluation of metC/C in GC-rich regions. Nucleic Acids Res 33:e95PubMedGoogle Scholar
  64. Kapranov P, Cawley SE, Drenkow J, et al (2002) Large-scale transcriptional activity in chromosomes 21 and 22. Science 296:916–919PubMedGoogle Scholar
  65. Kendler KS, Prescott CA (1999) A population-based twin study of lifetime major depression in men and women. Arch Gen Psychiatry 56:39–44PubMedGoogle Scholar
  66. Keverne EB (1997) Genomic imprinting in the brain. Curr Opin Neurobiol 7:463–468PubMedGoogle Scholar
  67. Kuo KC, McCune RA, Gehrke CW, et al (1980) Quantitative reversed-phase high performance liquid chromatographic determination of major and modified deoxyribonucleosides in DNA. Nucleic Acids Res 8:4763–4776PubMedGoogle Scholar
  68. Lavrentieva I, Broude NE, Lebedev Y, et al (1999) High polymorphism level of genomic sequences flanking insertion sites of human endogenous retroviral long terminal repeats. FEBS Lett 443:341–347PubMedGoogle Scholar
  69. Leonard CM, Williams CA, Nicholls RD, et al (1993) Angelman and Prader-Willi syndrome: a magnetic resonance imaging study of differences in cerebral structure. Am J Med Genet 46:26–33PubMedGoogle Scholar
  70. Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 3:662–673PubMedGoogle Scholar
  71. Li J, Protopopov A, Wang F, et al (2002) NotI subtraction and NotI-specific microarrays to detect copy number and methylation changes in whole genomes. Proc Natl Acad Sci U S A 99:10724–10729PubMedGoogle Scholar
  72. Liang G, Gonzalgo ML, Salem C, Jones PA (2002) Identification of DNA methylation differences during tumorigenesis by methylation-sensitive arbitrarily primed polymerase chain reaction. Methods 27:150–155PubMedGoogle Scholar
  73. Lo YM, Wong IH, Zhang J, et al (1999) Quantitative analysis of aberrant p16 methylation using real-time quantitative methylation-specific polymerase chain reaction. Cancer Res 59:3899–3903PubMedGoogle Scholar
  74. Matin MM, Baumer A, Hornby DP (2002) An analytical method for the detection of methylation differences at specific chromosomal loci using primer extension and ion pair reverse phase HPLC. Hum Mutat 20:305–311PubMedGoogle Scholar
  75. McInnis MG (1996) Anticipation: an old idea in new genes. Am J Hum Genet 59:973–979PubMedGoogle Scholar
  76. 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
  77. McMahon FJ, Hopkins PJ, Xu J, et al (1997) Linkage of bipolar affective disorder to chromosome 18 markers in a new pedigree series. Am J Hum Genet 61:1397–1404PubMedGoogle Scholar
  78. Mueller K, Doerfler W (2000) Methylation-sensitive amplicon subtraction: a novel method to isolate differentially methylated DNA sequences in complex genomes. Gene Funct Dis 1:154–160Google Scholar
  79. Nan X, Ng HH, Johnson CA, et al (1998) Transcriptional repression by themethyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389PubMedGoogle Scholar
  80. Nicholls RD (2000) The impact of genomic imprinting for neurobehavioral and developmental disorders. J Clin Invest 105:413–418PubMedGoogle Scholar
  81. Nicholls RD, Knepper JL (2001) Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet 2:153–175PubMedGoogle Scholar
  82. Numachi Y, Yoshida S, Yamashita M, et al (2004) Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain. Ann N Y Acad Sci 1025:102–109PubMedGoogle Scholar
  83. Oakeley EJ, Podesta A, Jost JP (1997) Developmental changes in DNA methylation of the two tobacco pollen nuclei during maturation. Proc Natl Acad Sci U S A 94:11721–11725PubMedGoogle Scholar
  84. Oakeley EJ, Schmitt F, Jost JP (1999) Quantification of 5-methylcytosine in DNA by the chloroacetaldehyde reaction. Biotechniques 27:744–746, 748–750, 752PubMedGoogle Scholar
  85. Ohara K, Xu HD, Mori N, et al (1997) Anticipation and imprinting in schizophrenia. Biol Psychiatry 42:760–766PubMedGoogle Scholar
  86. Pasqualini JR, Mercat P, Giambiagi N (1989) Histone acetylation decreased by estradiol in the MCF-7 human mammary cancer cell line. Breast Cancer Res Treat 14:101–105PubMedGoogle Scholar
  87. Peoples R, Wood M, Van Atta R (2004) Photocrosslinking oligonucleotide hybridization assay for concurrent gene dosage and CpG methylation analysis. Methods Mol Biol 287:233–249PubMedGoogle Scholar
  88. Petronis A (1996) Genomic imprinting in unstable DNA diseases. Bioessays 18:587–590PubMedGoogle Scholar
  89. Petronis A (2004) The origin of schizophrenia: genetic thesis, epigenetic antithesis, and resolving synthesis. Biol Psychiatry 55:965–970PubMedGoogle Scholar
  90. Petronis A, Kennedy JL (1995) Unstable genes—unstable mind? Am J Psychiatry 152:164–172PubMedGoogle Scholar
  91. Petronis A, Popendikyte V, Kan P, Sasaki T (2002) Major psychosis and chromosome 22: genetics meets epigenetics. CNS Spectr 7:209–214PubMedGoogle Scholar
  92. 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
  93. Pfeifer GP, Steigerwald SD, Mueller PR, et al (1989) Genomic sequencing and methylation analysis by ligation mediated PCR. Science 246:810–813PubMedGoogle Scholar
  94. Pfeifer K (2000) Mechanisms of genomic imprinting. Am J Hum Genet 67:777–787PubMedGoogle Scholar
  95. Piccinelli M, Wilkinson G (2000) Gender differences in depression. Critical review. Br J Psychiatry 177:486–492PubMedGoogle Scholar
  96. Polymeropoulos MH, Xiao H, Torrey EF, et al (1993) Search for a genetic event in monozygotic twins discordant for schizophrenia. Psychiatry Res 48:27–36PubMedGoogle Scholar
  97. Rakyan V, Whitelaw E (2003) Transgenerational epigenetic inheritance. Curr Biol 13:R6PubMedGoogle Scholar
  98. Rakyan VK, Preis J, Morgan HD, Whitelaw E (2001) The marks, mechanisms and memory of epigenetic states in mammals. Biochem J 356:1–10PubMedGoogle Scholar
  99. Rakyan VK, Blewitt ME, Druker R, et al (2002) Metastable epialleles in mammals. Trends Genet 18:348–351PubMedGoogle Scholar
  100. Rakyan VK, Hildmann T, Novik KL, et al (2004) DNA methylation profiling of the humanmajor histocompatibility complex: a pilot study for the human epigenome project. PLoS Biol 2:e405PubMedGoogle Scholar
  101. Rand K, Qu W, Ho T, et al (2002) Conversion-specific detection of DNA methylation using real-time polymerase chain reaction (ConLight-MSP) to avoid false positives. Methods 27:114–120PubMedGoogle Scholar
  102. Razin A, Shemer R (1999) Epigenetic control of gene expression. Results Probl Cell Differ 25:189–204PubMedGoogle Scholar
  103. Rein T, De Pamphilis ML, Zorbas H (1998) Identifying 5-methylcytosine and related modifications in DNA genomes. Nucleic Acids Res 26:2255–2264PubMedGoogle Scholar
  104. Reiss D, Plomin R, Hetherington EM (1991) Genetics and psychiatry: an unheralded window on the environment. Am J Psychiatry 148:283–291PubMedGoogle Scholar
  105. Riggs A, Porter T (1996) Overview of epigenetic mechanisms. In: Russo VEA MR, Riggs AD (eds) Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 29–45Google Scholar
  106. Riggs A, Xiong Z, Wang L, JM L (1998) Methylation dynamics, epigenetic fidelity and X chromosome structure. In: Wolffe A (ed) Epigenetics. John Wiley and Sons, Chichester, pp 214–227Google Scholar
  107. Risch N (1990) Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet Epidemiol 7:3–16; discussion 17–45PubMedGoogle Scholar
  108. Ross SA (2003) Diet and DNA methylation interactions in cancer prevention. Ann N Y Acad Sci 983:197–207PubMedGoogle Scholar
  109. Rother KI, Silke J, Georgiev O, et al (1995) Influence of DNA sequence and methylation status on bisulfite conversion of cytosine residues. Anal Biochem 231:263–265PubMedGoogle Scholar
  110. Saluz HP, Jiricny J, Jost JP (1986) Genomic sequencing reveals a positive correlation between the kinetics of strand-specific DNA demethylation of the overlapping estradiol/glucocorticoid-receptor binding sites and the rate of avian vitellogenin mRNA synthesis. Proc Natl Acad Sci U S A 83:7167–7171PubMedGoogle Scholar
  111. Schatz P, Dietrich D, Schuster M (2004) Rapid analysis of CpG methylation patterns using RNase T1 cleavage and MALDI-TOF. Nucleic Acids Res 32:e167PubMedGoogle Scholar
  112. Schmitt F, Oakeley EJ, Jost JP (1997) Antibiotics induce genome-wide hypermethylation in cultured Nicotiana tabacum plants. J Biol Chem 272:1534–1540PubMedGoogle Scholar
  113. Schulze TG, Chen YS, Badner JA, et al (2003) Additional, physically ordered markers increase linkage signal for bipolar disorder on chromosome 18q22. Biol Psychiatry 53:239–243PubMedGoogle Scholar
  114. Schumacher A (2001) Mechanisms and brain specific consequences of genomic imprinting in Prader-Willi and Angelman syndromes. Gene Funct Dis 1:7–25Google Scholar
  115. Schumacher A, Kapranov P, Kaminsky Z, Flanagan J, Assadzadeh A, Yau P, Virtanen C, Winegarden N, Cheng J, Gingeras T, Petronis A (2006) Microarray-based DNA methylation profiling: technology and applications. Nucleic Acids Res 34:528–542PubMedGoogle Scholar
  116. Shi H, Maier S, Nimmrich I, et al (2003a) Oligonucleotide-based microarray for DNA methylation analysis: principles and applications. J Cell Biochem 88:138–143PubMedGoogle Scholar
  117. Shi H, Wei SH, Leu YW, et al (2003b) Triple analysis of the cancer epigenome: an integrated microarray system for assessing gene expression, DNA methylation, and histone acetylation. Cancer Res 63:2164–2171PubMedGoogle Scholar
  118. Siegfried Z, Eden S, Mendelsohn M, et al (1999) DNA methylation represses transcription in vivo. Nat Genet 22:203–206PubMedGoogle Scholar
  119. Stach D, Schmitz OJ, Stilgenbauer S, et al (2003) Capillary electrophoretic analysis of genomic DNA methylation levels. Nucleic Acids Res 31:E2PubMedGoogle Scholar
  120. Sutherland E, Coe L, Raleigh EA (1992) McrBC: a multisubunit GTP-dependent restriction endonuclease. J Mol Biol 225:327–348PubMedGoogle Scholar
  121. Sutherland JE, Costa M (2003) Epigenetics and the environment. Ann N Y Acad Sci 983:151–160PubMedGoogle Scholar
  122. Taubes G (1995) Epidemiology faces its limits. Science 269:164–169PubMedGoogle Scholar
  123. Thomassin H, Oakeley EJ, Grange T (1999) Identification of 5-methylcytosine in complex genomes. Methods 19:465–475PubMedGoogle Scholar
  124. Thomassin H, Kress C, Grange T (2004) MethylQuant: a sensitive method for quantifying methylation of specific cytosines within the genome. Nucleic Acids Res 32:e168PubMedGoogle Scholar
  125. Tompa R, McCallum CM, Delrow J, et al (2002) Genome-wide profiling of DNA methylation reveals transposon targets of CHROMOMETHYLASE3. Curr Biol 12:65–68PubMedGoogle Scholar
  126. Tost J, Schatz P, Schuster M, et al (2003) Analysis and accurate quantification of CpG methylation by MALDI mass spectrometry. Nucleic Acids Res 31:e50PubMedGoogle Scholar
  127. Toyota M, Ho C, Ahuja N, et al (1999) Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res 59:2307–2312PubMedGoogle Scholar
  128. Truss M, Chalepakis G, Pina B, et al (1992) Transcriptional control by steroid hormones. J Steroid Biochem Mol Biol 41:241–248PubMedGoogle Scholar
  129. Tsujita T, Niikawa N, Yamashita H, et al (1998) Genomic discordance between monozygotic twins discordant for schizophrenia. Am J Psychiatry 155:422–424PubMedGoogle Scholar
  130. Uhlmann K, Brinckmann A, Toliat MR, et al (2002) Evaluation of a potential epigenetic biomarker by quantitativemethyl-single nucleotide polymorphism analysis. Electrophoresis 23:4072–4079PubMedGoogle Scholar
  131. Ushijima T, Morimura K, Hosoya Y, et al (1997) Establishment of methylation-sensitive-representational difference analysis and isolation of hypo-and hypermethylated genomic fragments in mouse liver tumors. ProcNatl Acad Sci U S A 94:2284–2289Google Scholar
  132. Veldic M, Caruncho HJ, Liu WS, et al (2004) DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proc Natl Acad Sci U S A 101:348–353PubMedGoogle Scholar
  133. Vincent JB, Kalsi G, Klempan T, et al (1998) No evidence of expansion of CAG or GAA repeats in schizophrenia families and monozygotic twins. Hum Genet 103:41–47PubMedGoogle Scholar
  134. Walter J, Paulsen M (2003) Imprinting and disease. Semin Cell Dev Biol 14:101–110PubMedGoogle Scholar
  135. Warren MP, Brooks-Gunn J (1989) Mood and behavior at adolescence: evidence for hormonal factors. J Clin Endocrinol Metab 69:77–83PubMedGoogle Scholar
  136. Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23:5293–5300PubMedGoogle Scholar
  137. Weaver IC, Cervoni N, Champagne FA, et al (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854PubMedGoogle Scholar
  138. Weissman MM, Olfson M (1995) Depression in women: implications for health care research. Science 269:799–801PubMedGoogle Scholar
  139. 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 11:1317–1325PubMedGoogle Scholar
  140. Weksberg R, Smith AC, Squire J, Sadowski P (2003) Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet 12 Spec No 1:R61–68PubMedGoogle Scholar
  141. Williams CA, Hendrickson JE, Cantu ES, Donlon TA (1989) Angelman syndrome in a daughter with del(15) (q11q13) associated with brachycephaly, hearing loss, enlarged foramen magnum, and ataxia in themother. Am J Med Genet 32:333–338PubMedGoogle Scholar
  142. 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
  143. Worm J, Aggerholm A, Guldberg P (2001) In-tube DNA methylation profiling by fluorescence melting curve analysis. Clin Chem 47:1183–1189PubMedGoogle Scholar
  144. Wu J, Issa JP, Herman J, et al (1993) Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. Proc Natl Acad Sci U S A 90:8891–8895PubMedGoogle Scholar
  145. Xiong LZ, Xu CG, Saghai Maroof MA, Zhang Q (1999) Patterns of cytosine methylation in an elite rice hybrid and its parental lines, detected by a methylation-sensitive amplification polymorphism technique. Mol Gen Genet 261:439–446PubMedGoogle Scholar
  146. Xiong Z, Laird PW (1997) COBRA: a sensitive and quantitative DNA methylation assay. Nucleic Acids Res 25:2532–2534PubMedGoogle Scholar
  147. Yamamoto F, Yamamoto M (2004) A DNA microarray-based methylation-sensitive (MS)-AFLP hybridization method for genetic and epigenetic analyses. Mol Genet Genomics 271:678–686PubMedGoogle Scholar
  148. Yamamoto T, Nagasaka T, Notohara K, et al (2004) Methylation assay by nucleotide incorporation: a quantitative assay for regional CpG methylation density. Biotechniques 36:846–850, 852, 854PubMedGoogle Scholar
  149. Yan PS, Efferth T, Chen HL, et al (2002) Use of CpG island microarrays to identify colorectal tumors with a high degree of concurrent methylation. Methods 27:162–169PubMedGoogle Scholar
  150. Yang AS JP, Shibata A (1996) The mutational burden of 5-methylcytosine. In: Russo V, Riggs A (eds) Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 77–94Google Scholar
  151. Yokomori N, Moore R, Negishi M (1995) Sexually dimorphic DNA demethylation in the promoter of the Slp (sex-limited protein) gene in mouse liver. Proc Natl Acad Sci U S A 92:1302–1306PubMedGoogle Scholar
  152. Zeschnigk M, Bohringer S, Price EA, et al (2004) A novel real-time PCR assay for quantitative analysis of methylated alleles (QAMA): analysis of the retinoblastoma locus. Nucleic Acids Res 32:e125PubMedGoogle Scholar
  153. Zhang Z, Chen CQ, Manev H (2004) Enzymatic regional methylation assay for determination of CpG methylation density. Anal Chem 76:6829–6832PubMedGoogle Scholar
  154. Zubenko GS, Maher B, Hughes HB 3rd, et al (2003) Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression. Am J Med Genet 123B:1–18Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  1. 1.The Krembil Family Epigenetics LaboratoryCentre for Addiction and Mental HealthTorontoCanada

Personalised recommendations