A Summary of the Biological Processes, Disease-Associated Changes, and Clinical Applications of DNA Methylation

  • Gitte Brinch Andersen
  • Jörg TostEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1708)


DNA methylation at cytosines followed by guanines, CpGs, forms one of the multiple layers of epigenetic mechanisms controlling and modulating gene expression through chromatin structure. It closely interacts with histone modifications and chromatin remodeling complexes to form the local genomic and higher-order chromatin landscape. DNA methylation is essential for proper mammalian development, crucial for imprinting and plays a role in maintaining genomic stability. DNA methylation patterns are susceptible to change in response to environmental stimuli such as diet or toxins, whereby the epigenome seems to be most vulnerable during early life. Changes of DNA methylation levels and patterns have been widely studied in several diseases, especially cancer, where interest has focused on biomarkers for early detection of cancer development, accurate diagnosis, and response to treatment, but have also been shown to occur in many other complex diseases. Recent advances in epigenome engineering technologies allow now for the large-scale assessment of the functional relevance of DNA methylation. As a stable nucleic acid-based modification that is technically easy to handle and which can be analyzed with great reproducibility and accuracy by different laboratories, DNA methylation is a promising biomarker for many applications.

Key words

DNA methylation Nutrition Environment Complex disease Epigenetics Imprinting Development Cancer Hydroxymethylation Epidrugs Epigenetic therapy Epigenome engineering 


  1. 1.
    Waddington CH (1942) The epigenotype. Endeavour 1:18–20Google Scholar
  2. 2.
    Tost J (2008) Epigenetics. Horizon Scientific Press, Norwich, UKGoogle Scholar
  3. 3.
    Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150:12–27PubMedCrossRefGoogle Scholar
  4. 4.
    Chen T, Dent SY (2014) Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat Rev Genet 15:93–106PubMedCrossRefGoogle Scholar
  5. 5.
    Zentner GE, Henikoff S (2013) Regulation of nucleosome dynamics by histone modifications. Nat Struct Mol Biol 20:259–266PubMedCrossRefGoogle Scholar
  6. 6.
    Munshi A, Shafi G, Aliya N et al (2009) Histone modifications dictate specific biological readouts. J Genet Genomics 36:75–88PubMedCrossRefGoogle Scholar
  7. 7.
    Cedar H, Bergman Y (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 10:295–304PubMedCrossRefGoogle Scholar
  8. 8.
    Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21PubMedCrossRefGoogle Scholar
  9. 9.
    Lister R, Pelizzola M, Dowen RH et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Illingworth RS, Bird AP (2009) CpG islands—‘a rough guide’. FEBS Lett 583:1713–1720PubMedCrossRefGoogle Scholar
  11. 11.
    Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 196:261–282PubMedCrossRefGoogle Scholar
  12. 12.
    Takai D, Jones PA (2002) Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 99:3740–3745PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Shen L, Kondo Y, Guo Y et al (2007) Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters. PLoS Genet 3:2023–2036PubMedCrossRefGoogle Scholar
  14. 14.
    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:e22PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Altun G, Loring JF, Laurent LC (2010) DNA methylation in embryonic stem cells. J Cell Biochem 109:1–6PubMedPubMedCentralGoogle Scholar
  16. 16.
    Maunakea AK, Nagarajan RP, Bilenky M et al (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466:253–257PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    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 41:178–186PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Lee SM, Choi WY, Lee J et al (2015) The regulatory mechanisms of intragenic DNA methylation. Epigenomics 7:527–531PubMedCrossRefGoogle Scholar
  19. 19.
    Kulis M, Queiros AC, Beekman R et al (2013) Intragenic DNA methylation in transcriptional regulation, normal differentiation and cancer. Biochim Biophys Acta 1829:1161–1174PubMedCrossRefGoogle Scholar
  20. 20.
    Lev Maor G, Yearim A, Ast G (2015) The alternative role of DNA methylation in splicing regulation. Trends Genet 31:274–280PubMedCrossRefGoogle Scholar
  21. 21.
    Bock C, Paulsen M, Tierling S et al (2006) CpG island methylation in human lymphocytes is highly correlated with DNA sequence, repeats, and predicted DNA structure. PLoS Genet 2:e26PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Jia D, Jurkowska RZ, Zhang X et al (2007) Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449:248–251PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Ulrey CL, Liu L, Andrews LG et al (2005) The impact of metabolism on DNA methylation. Hum Mol Genet 14 Spec No 1:R139–147Google Scholar
  24. 24.
    Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97PubMedCrossRefGoogle Scholar
  25. 25.
    Cheng X, Blumenthal RM (2008) Mammalian DNA methyltransferases: a structural perspective. Structure 16:341–350PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Ludwig AK, Zhang P, Cardoso MC (2016) Modifiers and readers of DNA modifications and their impact on genome structure, expression, and stability in disease. Front Genet 7:115PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Hermann A, Goyal R, Jeltsch A (2004) The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem 279:48350–48359PubMedCrossRefGoogle Scholar
  28. 28.
    Jones PA, Liang G (2009) Rethinking how DNA methylation patterns are maintained. Nat Rev Genet 10:805–811PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Baubec T, Colombo DF, Wirbelauer C et al (2015) Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520:243–247PubMedCrossRefGoogle Scholar
  30. 30.
    Chedin F (2011) The DNMT3 family of mammalian de novo DNA methyltransferases. Prog Mol Biol Transl Sci 101:255–285PubMedCrossRefGoogle Scholar
  31. 31.
    Franchini DM, Schmitz KM, Petersen-Mahrt SK (2012) 5-Methylcytosine DNA demethylation: more than losing a methyl group. Annu Rev Genet 46:419–441PubMedCrossRefGoogle Scholar
  32. 32.
    Tahiliani M, Koh KP, Shen Y et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Tan L, Shi YG (2012) Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 139:1895–1902PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Nestor CE, Ottaviano R, Reddington J et al (2012) Tissue type is a major modifier of the 5-hydroxymethylcytosine content of human genes. Genome Res 22:467–477PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Langemeijer SM, Aslanyan MG, Jansen JH (2009) TET proteins in malignant hematopoiesis. Cell Cycle 8:4044–4048PubMedCrossRefGoogle Scholar
  36. 36.
    Pastor WA, Pape UJ, Huang Y et al (2011) Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473:394–397PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ficz G, Branco MR, Seisenberger S et al (2011) Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473:398–402PubMedCrossRefGoogle Scholar
  38. 38.
    Jin SG, Wu X, Li AX et al (2011) Genomic mapping of 5-hydroxymethylcytosine in the human brain. Nucleic Acids Res 39:5015–5024PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ono R, Taki T, Taketani T et al (2002) LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res 62:4075–4080PubMedGoogle Scholar
  40. 40.
    Mercher T, Quivoron C, Couronne L et al (2012) TET2, a tumor suppressor in hematological disorders. Biochim Biophys Acta 1825:173–177PubMedGoogle Scholar
  41. 41.
    Putiri EL, Tiedemann RL, Thompson JJ et al (2014) Distinct and overlapping control of 5-methylcytosine and 5-hydroxymethylcytosine by the TET proteins in human cancer cells. Genome Biol 15:R81PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Jin SG, Jiang Y, Qiu R et al (2011) 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res 71:7360–7365PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Wu SC, Zhang Y (2010) Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol 11:607–620PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Ito S, Shen L, Dai Q et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–1303PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Geiman TM, Robertson KD (2002) Chromatin remodeling, histone modifications, and DNA methylation-how does it all fit together? J Cell Biochem 87:117–125PubMedCrossRefGoogle Scholar
  46. 46.
    Yin Y, Morgunova E, Jolma A et al (2017) Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 356(6337).
  47. 47.
    Hu S, Wan J, Su Y et al (2013) DNA methylation presents distinct binding sites for human transcription factors. eLife 2:e00726PubMedPubMedCentralGoogle Scholar
  48. 48.
    Sasai N, Defossez PA (2009) Many paths to one goal? The proteins that recognize methylated DNA in eukaryotes. Int J Dev Biol 53:323–334PubMedCrossRefGoogle Scholar
  49. 49.
    Baubec T, Ivanek R, Lienert F et al (2013) Methylation-dependent and -independent genomic targeting principles of the MBD protein family. Cell 153:480–492PubMedCrossRefGoogle Scholar
  50. 50.
    Yildirim O, Li R, Hung JH et al (2011) Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 147:1498–1510PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Brinkman AB, Pennings SW, Braliou GG et al (2007) DNA methylation immediately adjacent to active histone marking does not silence transcription. Nucleic Acids Res 35:801–811PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Ushijima T (2005) Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer 5:223–231PubMedCrossRefGoogle Scholar
  53. 53.
    Stadler MB, Murr R, Burger L et al (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480:490–495PubMedGoogle Scholar
  54. 54.
    Hodges E, Molaro A, Dos Santos CO et al (2011) Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. Mol Cell 44:17–28PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Lippman Z, Gendrel AV, Black M et al (2004) Role of transposable elements in heterochromatin and epigenetic control. Nature 430:471–476PubMedCrossRefGoogle Scholar
  56. 56.
    Walsh CP, Chaillet JR, Bestor TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20:116–117PubMedCrossRefGoogle Scholar
  57. 57.
    Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13:335–340PubMedCrossRefGoogle Scholar
  58. 58.
    Baylin SB, Jones PA (2016) Epigenetic determinants of cancer. Cold Spring Harb Perspect Biol 8.
  59. 59.
    Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293:1089–1093PubMedCrossRefGoogle Scholar
  60. 60.
    Guibert S, Weber M (2013) Functions of DNA methylation and hydroxymethylation in mammalian development. Curr Top Dev Biol 104:47–83PubMedCrossRefGoogle Scholar
  61. 61.
    Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14:204–220PubMedCrossRefGoogle Scholar
  62. 62.
    Jackson M, Krassowska A, Gilbert N et al (2004) Severe global DNA hypomethylation blocks differentiation and induces histone hyperacetylation in embryonic stem cells. Mol Cell Biol 24:8862–8871PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Kim K, Doi A, Wen B et al (2010) Epigenetic memory in induced pluripotent stem cells. Nature 467:285–290PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Ohi Y, Qin H, Hong C et al (2011) Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol 13:541–549PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Smith ZD, Chan MM, Humm KC et al (2014) DNA methylation dynamics of the human preimplantation embryo. Nature 511:611–615PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Carrell DT (2012) Epigenetics of the male gamete. Fertil Steril 97:267–274PubMedCrossRefGoogle Scholar
  67. 67.
    Nakatani T, Yamagata K, Kimura T et al (2015) Stella preserves maternal chromosome integrity by inhibiting 5hmC-induced gammaH2AX accumulation. EMBO Rep 16:582–589PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Wang L, Zhang J, Duan J et al (2014) Programming and inheritance of parental DNA methylomes in mammals. Cell 157:979–991PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Lees-Murdock DJ, Walsh CP (2008) DNA methylation reprogramming in the germ line. Epigenetics 3:5–13PubMedCrossRefGoogle Scholar
  70. 70.
    Seisenberger S, Andrews S, Krueger F et al (2012) The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell 48:849–862PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Boissonnas CC, Abdalaoui HE, Haelewyn V et al (2010) Specific epigenetic alterations of IGF2-H19 locus in spermatozoa from infertile men. Eur J Hum Genet 18:73–80PubMedCrossRefGoogle Scholar
  72. 72.
    Gunes S, Arslan MA, Hekim GNT et al (2016) The role of epigenetics in idiopathic male infertility. J Assist Reprod Genet 33:553–569PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Hanson MA, Gluckman PD (2014) Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev 94:1027–1076PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Fauque P, Ripoche MA, Tost J et al (2010) Modulation of imprinted gene network in placenta results in normal development of in vitro manipulated mouse embryos. Hum Mol Genet 19:1779–1790PubMedCrossRefGoogle Scholar
  75. 75.
    Nelissen EC, Dumoulin JC, Daunay A et al (2013) Placentas from pregnancies conceived by IVF/ICSI have a reduced DNA methylation level at the H19 and MEST differentially methylated regions. Hum Reprod 28:1117–1126PubMedCrossRefGoogle Scholar
  76. 76.
    Castillo-Fernandez JE, Loke YJ, Bass-Stringer S et al (2017) DNA methylation changes at infertility genes in newborn twins conceived by in vitro fertilisation. Genome Med 9:28PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Uyar A, Seli E (2014) The impact of assisted reproductive technologies on genomic imprinting and imprinting disorders. Curr Opin Obstet Gynecol 26:210–221PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Chiba H, Hiura H, Okae H et al (2013) DNA methylation errors in imprinting disorders and assisted reproductive technology. Pediatr Int 55:542–549PubMedCrossRefGoogle Scholar
  79. 79.
    Feil R, Fraga MF (2012) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13:97–109PubMedGoogle Scholar
  80. 80.
    Heyn H, Li N, Ferreira HJ et al (2012) Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A 109:10522–10527PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Hannum G, Guinney J, Zhao L et al (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49:359–367PubMedCrossRefGoogle Scholar
  82. 82.
    Jones MJ, Goodman SJ, Kobor MS (2015) DNA methylation and healthy human aging. Aging Cell 14:924–932PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Fraga MF, Esteller M (2007) Epigenetics and aging: the targets and the marks. Trends Genet 23:413–418PubMedCrossRefGoogle Scholar
  84. 84.
    Issa JP (2014) Aging and epigenetic drift: a vicious cycle. J Clin Invest 124:24–29PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14:R115PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Weidner CI, Lin Q, Koch CM et al (2014) Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol 15:R24PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Marioni RE, Shah S, McRae AF et al (2015) DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol 16:25PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Zheng Y, Joyce BT, Colicino E et al (2016) Blood epigenetic age may predict cancer incidence and mortality. EBioMedicine 5:68–73PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Perna L, Zhang Y, Mons U et al (2016) Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clin Epigenetics 8:64PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Armstrong NJ, Mather KA, Thalamuthu A et al (2017) Aging, exceptional longevity and comparisons of the Hannum and Horvath epigenetic clocks. Epigenomics 9:689–700PubMedCrossRefGoogle Scholar
  91. 91.
    Reik W, Walter J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet 2:21–32PubMedCrossRefGoogle Scholar
  92. 92.
    Skaar DA, Li Y, Bernal AJ et al (2012) The human imprintome: regulatory mechanisms, methods of ascertainment, and roles in disease susceptibility. ILAR J 53:341–358PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Kelsey G, Bartolomei MS (2012) Imprinted genes ... and the number is? PLoS Genet 8:e1002601PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Barbaux S, Gascoin-Lachambre G, Buffat C et al (2012) A genome-wide approach reveals novel imprinted genes expressed in the human placenta. Epigenetics 7:1079–1090PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Bell AC, Felsenfeld G (2000) Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405:482–485PubMedCrossRefGoogle Scholar
  96. 96.
    Kurukuti S, Tiwari VK, Tavoosidana G et al (2006) CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. Proc Natl Acad Sci U S A 103:10684–10689PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Lee JT, Bartolomei MS (2013) X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 152:1308–1323PubMedCrossRefGoogle Scholar
  98. 98.
    Gendrel AV, Heard E (2014) Noncoding RNAs and epigenetic mechanisms during X-chromosome inactivation. Annu Rev Cell Dev Biol 30:561–580PubMedCrossRefGoogle Scholar
  99. 99.
    Li C, Zhao S, Zhang N et al (2013) Differences of DNA methylation profiles between monozygotic twins’ blood samples. Mol Biol Rep 40:5275–5280PubMedCrossRefGoogle Scholar
  100. 100.
    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 102:10604–10609PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Bollati V, Baccarelli A, Hou L et al (2007) Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res 67:876–880PubMedCrossRefGoogle Scholar
  102. 102.
    Xin F, Susiarjo M, Bartolomei MS (2015) Multigenerational and transgenerational effects of endocrine disrupting chemicals: a role for altered epigenetic regulation? Semin Cell Dev Biol 43:66–75PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Hanson MA, Skinner MK (2016) Developmental origins of epigenetic transgenerational inheritance. Environ Epigenet 2:dvw002PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ladd-Acosta C (2015) Epigenetic signatures as biomarkers of exposure. Curr Environ Health Rep 2:117–125PubMedCrossRefGoogle Scholar
  105. 105.
    Bohacek J, Mansuy IM (2015) Molecular insights into transgenerational non-genetic inheritance of acquired behaviours. Nat Rev Genet 16:641–652PubMedCrossRefGoogle Scholar
  106. 106.
    Kappil M, Lambertini L, Chen J (2015) Environmental influences on genomic imprinting. Curr Environ Health Rep 2:155–162PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Cuzin F, Grandjean V, Rassoulzadegan M (2008) Inherited variation at the epigenetic level: paramutation from the plant to the mouse. Curr Opin Genet Dev 18:193–196PubMedCrossRefGoogle Scholar
  108. 108.
    Heard E, Martienssen RA (2014) Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157:95–109PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Bohacek J, Mansuy IM (2017) A guide to designing germline-dependent epigenetic inheritance experiments in mammals. Nat Methods 14:243–249PubMedCrossRefGoogle Scholar
  110. 110.
    de Groote ML, Verschure PJ, Rots MG (2012) Epigenetic editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes. Nucleic Acids Res 40:10596–10613PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Carroll D (2014) Genome engineering with targetable nucleases. Annu Rev Biochem 83:409–439PubMedCrossRefGoogle Scholar
  112. 112.
    Jurkowski TP, Ravichandran M, Stepper P (2015) Synthetic epigenetics-towards intelligent control of epigenetic states and cell identity. Clin Epigenetics 7:18PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Laufer BI, Singh SM (2015) Strategies for precision modulation of gene expression by epigenome editing: an overview. Epigenetics Chromatin 8:34PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Maeder ML, Angstman JF, Richardson ME et al (2013) Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins. Nat Biotechnol 31:1137–1142PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Straubeta A, Lahaye T (2013) Zinc fingers, TAL effectors, or Cas9-based DNA binding proteins: what’s best for targeting desired genome loci? Mol Plant 6:1384–1387PubMedCrossRefGoogle Scholar
  116. 116.
    Choudhury SR, Cui Y, Lubecka K et al (2016) CRISPR-dCas9 mediated TET1 targeting for selective DNA demethylation at BRCA1 promoter. Oncotarget 7:46545–46556PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Thakore PI, Black JB, Hilton IB et al (2016) Editing the epigenome: technologies for programmable transcription and epigenetic modulation. Nat Methods 13:127–137PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Vojta A, Dobrinic P, Tadic V et al (2016) Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res 44:5615–5628PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Koferle A, Worf K, Breunig C et al (2016) CORALINA: a universal method for the generation of gRNA libraries for CRISPR-based screening. BMC Genomics 17:917PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Weng YL, An R, Shin J et al (2013) DNA modifications and neurological disorders. Neurotherapeutics 10:556–567PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Delhommeau F, Dupont S, Della Valle V et al (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301PubMedCrossRefGoogle Scholar
  122. 122.
    Leonard H, Cobb S, Downs J (2017) Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol 13:37–51PubMedCrossRefGoogle Scholar
  123. 123.
    Chiba S (2017) Dysregulation of TET2 in hematologic malignancies. Int J Hematol 105:17–22PubMedCrossRefGoogle Scholar
  124. 124.
    Ishida M, Moore GE (2013) The role of imprinted genes in humans. Mol Asp Med 34:826–840CrossRefGoogle Scholar
  125. 125.
    Elhamamsy AR (2017) Role of DNA methylation in imprinting disorders: an updated review. J Assist Reprod Genet 34:549–562PubMedCrossRefGoogle Scholar
  126. 126.
    Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92PubMedCrossRefGoogle Scholar
  127. 127.
    Gaudet F, Hodgson JG, Eden A et al (2003) Induction of tumors in mice by genomic hypomethylation. Science 300:489–492PubMedCrossRefGoogle Scholar
  128. 128.
    Ehrlich M, Lacey M (2013) DNA hypomethylation and hemimethylation in cancer. Adv Exp Med Biol 754:31–56PubMedCrossRefGoogle Scholar
  129. 129.
    Hur K, Cejas P, Feliu J et al (2014) Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis. Gut 63:635–646PubMedCrossRefGoogle Scholar
  130. 130.
    Virani S, Colacino JA, Kim JH et al (2012) Cancer epigenetics: a brief review. ILAR J 53:359–369PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
  132. 132.
    Kaneda A, Feinberg AP (2005) Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk. Cancer Res 65:11236–11240PubMedCrossRefGoogle Scholar
  133. 133.
    Clark SJ (2007) Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis. Hum Mol Genet 16 Spec No 1:R88–R95PubMedCrossRefGoogle Scholar
  134. 134.
    Frigola J, Song J, Stirzaker C et al (2006) Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nat Genet 38:540–549PubMedCrossRefGoogle Scholar
  135. 135.
    Bert SA, Robinson MD, Strbenac D et al (2013) Regional activation of the cancer genome by long-range epigenetic remodeling. Cancer Cell 23:9–22PubMedCrossRefGoogle Scholar
  136. 136.
    Berman BP, Weisenberger DJ, Aman JF et al (2011) Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat Genet 44:40–46PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Simo-Riudalbas L, Esteller M (2014) Cancer genomics identifies disrupted epigenetic genes. Hum Genet 133:713–725PubMedCrossRefGoogle Scholar
  138. 138.
    Shen H, Laird PW (2013) Interplay between the cancer genome and epigenome. Cell 153:38–55PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Plass C, Pfister SM, Lindroth AM et al (2013) Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer. Nat Rev Genet 14:765–780PubMedCrossRefGoogle Scholar
  140. 140.
    Turcan S, Rohle D, Goenka A et al (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Figueroa ME, Abdel-Wahab O, Lu C et al (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553–567PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Hedenfalk I, Duggan D, Chen Y et al (2001) Gene-expression profiles in hereditary breast cancer. N Engl J Med 344:539–548PubMedCrossRefGoogle Scholar
  143. 143.
    Nik-Zainal S, Davies H, Staaf J et al (2016) Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534:47–54PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Knudson AG (2001) Two genetic hits (more or less) to cancer. Nat Rev Cancer 1:157–162PubMedCrossRefGoogle Scholar
  145. 145.
    Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33(Suppl):238–244PubMedCrossRefGoogle Scholar
  146. 146.
    Li S, Garrett-Bakelman FE, Chung SS et al (2016) Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med 22:792–799PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Costello JF, Fruhwald MC, Smiraglia DJ et al (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24:132–138PubMedCrossRefGoogle Scholar
  148. 148.
    Goelz SE, Vogelstein B, Hamilton SR et al (1985) Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228:187–190PubMedCrossRefGoogle Scholar
  149. 149.
    Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7:21–33PubMedCrossRefGoogle Scholar
  150. 150.
    Issa JP, Ahuja N, Toyota M et al (2001) Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 61:3573–3577PubMedGoogle Scholar
  151. 151.
    Fleischer T, Frigessi A, Johnson KC et al (2014) Genome-wide DNA methylation profiles in progression to in situ and invasive carcinoma of the breast with impact on gene transcription and prognosis. Genome Biol 15:435PubMedPubMedCentralGoogle Scholar
  152. 152.
    Ohm JE, McGarvey KM, Yu X et al (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39:237–242PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    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 39:232–236PubMedCrossRefGoogle Scholar
  154. 154.
    Yang H, Liu Y, Bai F et al (2013) Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 32:663–669PubMedCrossRefGoogle Scholar
  155. 155.
    Lian CG, Xu Y, Ceol C et al (2012) Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 150:1135–1146PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Neri F, Dettori D, Incarnato D et al (2015) TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway. Oncogene 34:4168–4176PubMedCrossRefGoogle Scholar
  157. 157.
    Uribe-Lewis S, Stark R, Carroll T et al (2015) 5-Hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer. Genome Biol 16:69PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Simon R (2005) Roadmap for developing and validating therapeutically relevant genomic classifiers. J Clin Oncol 23:7332–7341PubMedCrossRefGoogle Scholar
  159. 159.
    BLUEPRINT consortium (2016) Quantitative comparison of DNA methylation assays for biomarker development and clinical applications. Nat Biotechnol 34:726–737CrossRefGoogle Scholar
  160. 160.
    Laird PW (2003) Early detection: the power and the promise of DNA methylation markers. Nat Rev Cancer 3:253–266PubMedCrossRefGoogle Scholar
  161. 161.
    Silva JM, Dominguez G, Garcia JM et al (1999) Presence of tumor DNA in plasma of breast cancer patients: clinicopathological correlations. Cancer Res 59:3251–3256PubMedGoogle Scholar
  162. 162.
    Akhavan-Niaki H, Samadani AA (2013) DNA methylation and cancer development: molecular mechanism. Cell Biochem Biophys 67:501–513PubMedCrossRefGoogle Scholar
  163. 163.
    Warton K, Mahon KL, Samimi G (2016) Methylated circulating tumor DNA in blood: power in cancer prognosis and response. Endocr Relat Cancer 23:R157–R171PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Lamb YN, Dhillon S (2017) Epi proColon(R) 2.0 CE: a blood-based screening test for colorectal cancer. Mol Diagn Ther 21:225–232PubMedCrossRefGoogle Scholar
  165. 165.
    Church TR, Wandell M, Lofton-Day C et al (2014) Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut 63:317–325PubMedCrossRefGoogle Scholar
  166. 166.
    How Kit A, Nielsen HM, Tost J (2012) DNA methylation based biomarkers: practical considerations and applications. Biochimie 94:2314–2337PubMedCrossRefGoogle Scholar
  167. 167.
    Brocks D, Assenov Y, Minner S et al (2014) Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Rep 8:798–806PubMedCrossRefGoogle Scholar
  168. 168.
    Landau DA, Clement K, Ziller MJ et al (2014) Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia. Cancer Cell 26:813–825PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Sheffield NC, Pierron G, Klughammer J et al (2017) DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nat Med 23:386–395PubMedCrossRefGoogle Scholar
  170. 170.
    Moran S, Martinez-Cardus A, Sayols S et al (2016) Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol 17:1386–1395PubMedCrossRefGoogle Scholar
  171. 171.
    Guo S, Diep D, Plongthongkum N et al (2017) Identification of methylation haplotype blocks aids in deconvolution of heterogeneous tissue samples and tumor tissue-of-origin mapping from plasma DNA. Nat Genet 49:635–642PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Kang S, Li Q, Chen Q et al (2017) CancerLocator: non-invasive cancer diagnosis and tissue-of-origin prediction using methylation profiles of cell-free DNA. Genome Biol 18:53PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Sun K, Jiang P, Chan KC et al (2015) Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments. Proc Natl Acad Sci U S A 112:E5503–E5512PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003PubMedCrossRefGoogle Scholar
  175. 175.
    Weller M, Stupp R, Reifenberger G et al (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6:39–51PubMedCrossRefGoogle Scholar
  176. 176.
    Clozel T, Yang S, Elstrom RL et al (2013) Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma. Cancer Discov 3:1002–1019PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Ahuja N, Easwaran H, Baylin SB (2014) Harnessing the potential of epigenetic therapy to target solid tumors. J Clin Invest 124:56–63PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Treppendahl MB, Kristensen LS, Gronbaek K (2014) Predicting response to epigenetic therapy. J Clin Invest 124:47–55PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Gros C, Fahy J, Halby L et al (2012) DNA methylation inhibitors in cancer: recent and future approaches. Biochimie 94:2280–2296PubMedCrossRefGoogle Scholar
  180. 180.
    Gnyszka A, Jastrzebski Z, Flis S (2013) DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res 33:2989–2996PubMedGoogle Scholar
  181. 181.
    Yang X, Lay F, Han H et al (2010) Targeting DNA methylation for epigenetic therapy. Trends Pharmacol Sci 31:536–546PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Qin T, Jelinek J, Si J et al (2009) Mechanisms of resistance to 5-aza-2′-deoxycytidine in human cancer cell lines. Blood 113:659–667PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Stresemann C, Brueckner B, Musch T et al (2006) Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res 66:2794–2800PubMedCrossRefGoogle Scholar
  184. 184.
    Herranz M, Martin-Caballero J, Fraga MF et al (2006) The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma. Blood 107:1174–1177PubMedCrossRefGoogle Scholar
  185. 185.
    Fahy J, Jeltsch A, Arimondo PB (2012) DNA methyltransferase inhibitors in cancer: a chemical and therapeutic patent overview and selected clinical studies. Expert Opin Ther Pat 22:1427–1442PubMedCrossRefGoogle Scholar
  186. 186.
    Schecter J, Galili N, Raza A (2012) MDS: refining existing therapy through improved biologic insights. Blood Rev 26:73–80PubMedCrossRefGoogle Scholar
  187. 187.
    Lee YG, Kim I, Yoon SS et al (2013) Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes. Br J Haematol 161:339–347PubMedCrossRefGoogle Scholar
  188. 188.
    Linnekamp JF, Butter R, Spijker R et al (2017) Clinical and biological effects of demethylating agents on solid tumours—a systematic review. Cancer Treat Rev 54:10–23PubMedCrossRefGoogle Scholar
  189. 189.
    Cowan LA, Talwar S, Yang AS (2010) Will DNA methylation inhibitors work in solid tumors? A review of the clinical experience with azacitidine and decitabine in solid tumors. Epigenomics 2:71–86PubMedCrossRefGoogle Scholar
  190. 190.
    Appleton K, Mackay HJ, Judson I et al (2007) Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol 25:4603–4609PubMedCrossRefGoogle Scholar
  191. 191.
    Fang F, Munck J, Tang J et al (2014) The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin Cancer Res 20:6504–6516PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Li H, Chiappinelli KB, Guzzetta AA et al (2014) Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 5:587–598PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Laird PW (2010) Principles and challenges of genomewide DNA methylation analysis. Nat Rev Genet 11:191–203PubMedCrossRefGoogle Scholar
  194. 194.
    Tost J (2016) Current and emerging technologies for the analysis of the genome-wide and locus-specific DNA methylation patterns. Adv Exp Med Biol 945:343–430PubMedCrossRefGoogle Scholar
  195. 195.
    Rakyan VK, Down TA, Balding DJ et al (2011) Epigenome-wide association studies for common human diseases. Nat Rev Genet 12:529–541PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Kaminsky ZA, Tang T, Wang SC et al (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41:240–245PubMedCrossRefGoogle Scholar
  197. 197.
    Terry MB, Delgado-Cruzata L, Vin-Raviv N et al (2011) DNA methylation in white blood cells: association with risk factors in epidemiologic studies. Epigenetics 6:828–837PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Breitling LP, Yang R, Korn B et al (2011) Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. Am J Hum Genet 88:450–457PubMedPubMedCentralCrossRefGoogle Scholar
  199. 199.
    Shenker NS, Polidoro S, van Veldhoven K et al (2013) Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking. Hum Mol Genet 22:843–851PubMedCrossRefGoogle Scholar
  200. 200.
    Monick MM, Beach SR, Plume J et al (2012) Coordinated changes in AHRR methylation in lymphoblasts and pulmonary macrophages from smokers. Am J Med Genet B Neuropsychiatr Genet 159B:141–151PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Heiss JA, Brenner H (2017) Impact of confounding by leukocyte composition on associations of leukocyte DNA methylation with common risk factors. Epigenomics 9:659–668PubMedCrossRefGoogle Scholar
  202. 202.
    Joubert BR, Felix JF, Yousefi P et al (2016) DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis. Am J Hum Genet 98:680–696PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Zhang Y, Florath I, Saum KU et al (2016) Self-reported smoking, serum cotinine, and blood DNA methylation. Environ Res 146:395–403PubMedCrossRefGoogle Scholar
  204. 204.
    Lee DH, Hwang SH, Lim MK et al (2017) Performance of urine cotinine and hypomethylation of AHRR and F2RL3 as biomarkers for smoking exposure in a population-based cohort. PLoS One 12:e0176783PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Liang L, Willis-Owen SA, Laprise C et al (2015) An epigenome-wide association study of total serum immunoglobulin E concentration. Nature 520:670–674PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Ai S, Shen L, Guo J et al (2012) DNA methylation as a biomarker for neuropsychiatric diseases. Int J Neurosci 122:165–176PubMedCrossRefGoogle Scholar
  207. 207.
    Hannon E, Dempster E, Viana J et al (2016) An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol 17:176PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Graff J, Mansuy IM (2009) Epigenetic dysregulation in cognitive disorders. Eur J Neurosci 30:1–8PubMedCrossRefGoogle Scholar
  209. 209.
    Adwan L, Zawia NH (2013) Epigenetics: a novel therapeutic approach for the treatment of Alzheimer’s disease. Pharmacol Ther 139:41–50PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Day JJ, Sweatt JD (2011) Epigenetic mechanisms in cognition. Neuron 70:813–829PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Nielsen HM, Tost J (2013) Epigenetic changes in inflammatory and autoimmune diseases. Subcell Biochem 61:455–478PubMedCrossRefGoogle Scholar
  212. 212.
    Miceli-Richard C, Wang-Renault SF, Boudaoud S et al (2016) Overlap between differentially methylated DNA regions in blood B lymphocytes and genetic at-risk loci in primary Sjogren’s syndrome. Ann Rheum Dis 75:933–940PubMedCrossRefGoogle Scholar
  213. 213.
    Fogel O, Richard-Miceli C, Tost J (2017) Epigenetic changes in chronic inflammatory diseases. Adv Protein Chem Struct Biol 106:139–189PubMedCrossRefGoogle Scholar
  214. 214.
    Potaczek DP, Harb H, Michel S et al (2017) Epigenetics and allergy: from basic mechanisms to clinical applications. Epigenomics 9:539–571PubMedCrossRefGoogle Scholar
  215. 215.
    Valencia-Morales Mdel P, Zaina S, Heyn H et al (2015) The DNA methylation drift of the atherosclerotic aorta increases with lesion progression. BMC Med Genet 8:7Google Scholar
  216. 216.
    Ronn T, Ling C (2015) DNA methylation as a diagnostic and therapeutic target in the battle against Type 2 diabetes. Epigenomics 7:451–460PubMedCrossRefGoogle Scholar
  217. 217.
    Martinez D, Pentinat T, Ribo S et al (2014) In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered Lxra DNA methylation. Cell Metab 19:941–951PubMedCrossRefGoogle Scholar
  218. 218.
    Jimenez-Chillaron JC, Ramon-Krauel M, Ribo S et al (2016) Transgenerational epigenetic inheritance of diabetes risk as a consequence of early nutritional imbalances. Proc Nutr Soc 75:78–89PubMedCrossRefGoogle Scholar
  219. 219.
    Liu Y, Aryee MJ, Padyukov L et al (2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol 31:142–147PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Low D, Mizoguchi A, Mizoguchi E (2013) DNA methylation in inflammatory bowel disease and beyond. World J Gastroenterol 19:5238–5249PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Hong X, Hao K, Ladd-Acosta C et al (2015) Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nat Commun 6:6304PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Tufarelli C, Stanley JA, Garrick D et al (2003) Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet 34:157–165PubMedCrossRefGoogle Scholar
  223. 223.
    Jacquemont S, Curie A, des Portes V et al (2011) Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 3:64ra61CrossRefGoogle Scholar
  224. 224.
    Tost J (2016) Follow the trace of death: methylation analysis of cell-free DNA for clinical applications in non-cancerous diseases. Epigenomics 8:1169–1172PubMedCrossRefGoogle Scholar
  225. 225.
    Lehmann-Werman R, Neiman D, Zemmour H et al (2016) Identification of tissue-specific cell death using methylation patterns of circulating DNA. Proc Natl Acad Sci U S A 113:E1826–E1834PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Akirav EM, Lebastchi J, Galvan EM et al (2011) Detection of beta cell death in diabetes using differentially methylated circulating DNA. Proc Natl Acad Sci U S A 108:19018–19023PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Zhang K, Lin G, Han Y et al (2017) Circulating unmethylated insulin DNA as a potential non-invasive biomarker of beta cell death in type 1 Diabetes: a review and future prospect. Clin Epigenetics 9:44PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Hardy T, Zeybel M, Day CP et al (2017) Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 66(7):1321–1328PubMedCrossRefGoogle Scholar
  229. 229.
    Wong AI, Lo YM (2015) Noninvasive fetal genomic, methylomic, and transcriptomic analyses using maternal plasma and clinical implications. Trends Mol Med 21:98–108PubMedCrossRefGoogle Scholar
  230. 230.
    Wong FC, Lo YM (2016) Prenatal diagnosis innovation: genome sequencing of maternal plasma. Annu Rev Med 67:419–432PubMedCrossRefGoogle Scholar
  231. 231.
    Al-Mahdawi S, Virmouni SA, Pook MA (2014) The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases. Front Neurosci 8:397PubMedPubMedCentralCrossRefGoogle Scholar
  232. 232.
    Sherwani SI, Khan HA (2015) Role of 5-hydroxymethylcytosine in neurodegeneration. Gene 570:17–24PubMedCrossRefGoogle Scholar
  233. 233.
    McEwen BS, Bowles NP, Gray JD et al (2015) Mechanisms of stress in the brain. Nat Neurosci 18:1353–1363PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Coppieters N, Dieriks BV, Lill C et al (2014) Global changes in DNA methylation and hydroxymethylation in Alzheimer’s disease human brain. Neurobiol Aging 35:1334–1344PubMedCrossRefGoogle Scholar
  235. 235.
    Condliffe D, Wong A, Troakes C et al (2014) Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer’s disease brain. Neurobiol Aging 35:1850–1854PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  1. 1.Department of BiomedicineAarhus UniversityAarhusDenmark
  2. 2.Laboratory for Epigenetics & Environment, Centre National de Recherche en Génomique HumaineCEA—Institut de Biologie Francois JacobEvryFrance

Personalised recommendations