Molecular Medicine

, Volume 21, Issue 1, pp 400–409 | Cite as

Genetic Determinants of Epigenetic Patterns: Providing Insight into Disease

  • Emma Cazaly
  • Jac Charlesworth
  • Joanne L. Dickinson
  • Adele F. Holloway
Review Article


The field of epigenetics and our understanding of the mechanisms that regulate the establishment, maintenance and heritability of epigenetic patterns continue to grow at a remarkable rate. This information is providing increased understanding of the role of epigenetic changes in disease, insight into the underlying causes of these epigenetic changes and revealing new avenues for therapeutic intervention. Epigenetic modifiers are increasingly being pursued as therapeutic targets in a range of diseases, with a number of agents targeting epigenetic modifications already proving effective in diseases such as cancer. Although it is well established that DNA mutations and aberrant expression of epigenetic modifiers play a key role in disease, attention is now turning to the interplay between genetic and epigenetic factors in complex disease etiology. The role of genetic variability in determining epigenetic profiles, which can then be modified by environmental and stochastic factors, is becoming more apparent. Understanding the interplay between genetic and epigenetic factors is likely to aid in identifying individuals most likely to benefit from epigenetic therapies. This goal is coming closer to realization because of continual advances in laboratory and statistical tools enabling improvements in the integration of genomic, epigenomic and phenotypic data.



The authors were supported by grants from the David Collins Leukaemia Foundation and The Cancer Council Tasmania. JL Dickinson is an Australian Research Council Future Fellow. E Cazaly was supported by a scholarship from the Royal Hobart Hospital Cancer Auxiliary.

The authors acknowledge the many researchers whose work has contributed to this field, but they are not specifically cited here because of space and referencing constraints.


  1. 1.
    Botstein D, Risch N. (2003) Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat. Genet. 33:228–37.CrossRefGoogle Scholar
  2. 2.
    Eichler EE, et al. (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet. 11:446–50.CrossRefGoogle Scholar
  3. 3.
    Hindorff LA, et al. (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. U. S. A. 106:9362–7.CrossRefGoogle Scholar
  4. 4.
    Furey TS, Sethupathy P. (2013) Genetics: genetics driving epigenetics. Science. 342:705–6CrossRefGoogle Scholar
  5. 5.
    Steves CJ, et al. (2012) Ageing, genes, environment and epigenetics: what twin studies tell us now, and in the future. Age Ageing. 41:581–6.CrossRefGoogle Scholar
  6. 6.
    Laird PW (2010) Principles and challenges of genome-wide DNA methylation analysis. Nat. Rev. Genet. 11:191–203.CrossRefGoogle Scholar
  7. 7.
    Montavon C, et al. (2012) Prognostic and diagnostic significance of DNA methylation patterns in high grade serous ovarian cancer. Gynecol. Oncol. 124:582–8.CrossRefGoogle Scholar
  8. 8.
    Waddington CH. (2012) The epigenotype. Int. J. Epidemiol. 41:10–3.CrossRefGoogle Scholar
  9. 9.
    Berger SL, et al. (2009) An operational definition of epigenetics. Genes Dev. 23:781–3.CrossRefGoogle Scholar
  10. 10.
    Skinner MK. (2011) Environmental epigenetic transgenerational inheritance and somatic epigenetic mitotic stability. Epigenetics. 6:838–42.CrossRefGoogle Scholar
  11. 11.
    Pembrey M, et al. (2014) Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J. Med. Genet. 51:563–72.CrossRefGoogle Scholar
  12. 12.
    Dawson MA, Kouzarides T. (2012) Cancer epigenetics: from mechanism to therapy. Cell. 150:12–27.CrossRefGoogle Scholar
  13. 13.
    Cedar H, Bergman Y. (2012) Programming of DNA methylation patterns. Annu. Rev. Biochem. 81:97–117.CrossRefGoogle Scholar
  14. 14.
    ENCODE Project Consortium. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature. 489:57–74.CrossRefGoogle Scholar
  15. 15.
    Seisenberger S, et al. (2012) The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell. 48:849–62.CrossRefGoogle Scholar
  16. 16.
    Sasaki H, Matsui Y. (2008) Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat. Rev. Genet. 9:129–40.CrossRefGoogle Scholar
  17. 17.
    Kriaucionis S, Heintz N. (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 324:929–30.CrossRefGoogle Scholar
  18. 18.
    Ito S, et al. (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 466:1129–33.CrossRefGoogle Scholar
  19. 19.
    Cimmino L, et al. (2011) TET family proteins and their role in stem cell differentiation and transformation. Stem Cell. 9:193–204.Google Scholar
  20. 20.
    Hackett JA, et al. (2013) Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science. 339:448–52.CrossRefGoogle Scholar
  21. 21.
    Barski A, et al. (2007) High-resolution profiling of histone methylations in the human genome. Cell. 129:823–37.CrossRefGoogle Scholar
  22. 22.
    Wang Y, et al. (2004) Beyond the double helix: reading and writing the histone code. Novartis Found. Symp. 259:3–17.PubMedGoogle Scholar
  23. 23.
    McVicker G, et al. (2013) Identification of genetic variants that affect histone modifications in human cells. Science. 342:747–9.CrossRefGoogle Scholar
  24. 24.
    Kilpinen H, et al. (2013) Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science. 342:744–7.CrossRefGoogle Scholar
  25. 25.
    Kasowski M, et al. (2013) Extensive variation in chromatin states across humans. Science. 342:750–2.CrossRefGoogle Scholar
  26. 26.
    Daxinger L, Whitelaw E. (2012) Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat. Rev. Genet. 13:153–62.CrossRefGoogle Scholar
  27. 27.
    Liebers R, et al. (2014) Epigenetic regulation by heritable RNA. PLoS. Genet. 10:e1004296.CrossRefGoogle Scholar
  28. 28.
    Kasinski AL, Slack FJ. (2011) Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat. Rev. Cancer. 11:849–64.CrossRefGoogle Scholar
  29. 29.
    Bell JT, Spector TD. (2011) A twin approach to unraveling epigenetics. Trends Genet. 27:116–25.CrossRefGoogle Scholar
  30. 30.
    Vickers MA, et al. (2001) Assessment of mechanism of acquired skewed X inactivation by analysis of twins. Blood. 97:1274–81.CrossRefGoogle Scholar
  31. 31.
    Kaminsky ZA, et al. (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat. Genet. 41:240–5.CrossRefGoogle Scholar
  32. 32.
    Race JP, et al. (2006) Chorion type, birthweight discordance and tooth-size variability in Australian monozygotic twins. Twin Res. Hum. Genet. 9:285–91.CrossRefGoogle Scholar
  33. 33.
    Morgan HD, et al. (1999) Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 23:314–8.CrossRefGoogle Scholar
  34. 34.
    Kerkel K, et al. (2008) Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat. Genet. 40:904–8.CrossRefGoogle Scholar
  35. 35.
    Gertz J, et al. (2011) Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation. PLoS. Genet. 7:e1002228.CrossRefGoogle Scholar
  36. 36.
    Shoemaker R, et al. (2010) Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Res. 20:883–9.CrossRefGoogle Scholar
  37. 37.
    Zhang D, et al. (2010) Genetic control of individual differences in gene-specific methylation in human brain. Am. J. Human Genet. 86:411–9.CrossRefGoogle Scholar
  38. 38.
    Bell JT, et al. (2011) DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol. 12:R10.CrossRefGoogle Scholar
  39. 39.
    Zhi D, et al. (2013) SNPs located at CpG sites modulate genome-epigenome interaction. Epigenetics. 8:802–6.CrossRefGoogle Scholar
  40. 40.
    Hesson LB, et al. (2010) Epimutations and cancer predisposition: importance and mechanisms. Curr. Opin. Genet. Dev. 20:290–8.CrossRefGoogle Scholar
  41. 41.
    Fu Y-H, et al. (1991) Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 67:1047–58.CrossRefGoogle Scholar
  42. 42.
    Meyer N, Penn LZ. (2008) Reflecting on 25 years with MYC. Nat. Rev. Cancer. 8:976–90.CrossRefGoogle Scholar
  43. 43.
    Haiman CA, et al. (2007) Multiple regions within 8q24 independently affect risk for prostate cancer. Nat. Rev. Cancer. 39:638–44.Google Scholar
  44. 44.
    Sotelo J, et al. (2010) Long-range enhancers on 8q24 regulate c-Myc. Proc. Natl. Acad. Sci. U. S. A. 107:3001–5.CrossRefGoogle Scholar
  45. 45.
    Ferguson-Smith AC. (2011) Genomic imprinting: the emergence of an epigenetic paradigm. Nat. Rev. Genet. 12:565.CrossRefGoogle Scholar
  46. 46.
    Banno K, et al. (2012) Epimutation and cancer: a new carcinogenic mechanism of Lynch syndrome (Review). Int. J. Oncol. 41:793–7.CrossRefGoogle Scholar
  47. 47.
    Buiting K, et al. (2003) Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am. J. Hum. Genet. 72:571–7.CrossRefGoogle Scholar
  48. 48.
    Heijmans BT, et al. (2007) Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Hum. Mol. Genet. 16:547–54.CrossRefGoogle Scholar
  49. 49.
    Ludgate JL, et al. (2013) Global demethylation in loss of imprinting subtype of Wilms tumor. Genes Chromosomes Cancer. 52:174–84.CrossRefGoogle Scholar
  50. 50.
    Fuke T, et al. (2013) Molecular and clinical studies in 138 Japanese patients with Silver-Russell syndrome. PLoS One. 8:e60105.CrossRefGoogle Scholar
  51. 51.
    Murrell A, et al. (2004) An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. Hum. Mol. Genet. 13:247–55.CrossRefGoogle Scholar
  52. 52.
    Weksberg R, et al. (2002) Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum. Mol. Genet. 11:1317–25.CrossRefGoogle Scholar
  53. 53.
    Cui H, et al. (2003) Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science. 299:1753–5.CrossRefGoogle Scholar
  54. 54.
    Murata A, et al. (2014) IGF2 DMR0 methylation, loss of imprinting, and patient prognosis in esophageal squamous cell carcinoma. Ann. Surg. Oncol. 21:1166–74.CrossRefGoogle Scholar
  55. 55.
    Yi JM, et al. (2011) Genomic and epigenomic integration identifies a prognostic signature in colon cancer. Clin. Cancer Res. 17:1535–45.CrossRefGoogle Scholar
  56. 56.
    Ward RL, et al. (2013) Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry. Genet. Med. 15:25–35.CrossRefGoogle Scholar
  57. 57.
    Hitchins MP, Lynch HT. (2014) Dawning of the epigenetic era in hereditary cancer. Clin. Genet. 85:413–6.CrossRefGoogle Scholar
  58. 58.
    Hitchins MP, et al. (2011) Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5′UTR. Cancer Cell. 20:200–13.CrossRefGoogle Scholar
  59. 59.
    Bennett KL, et al. (2010) Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. JAMA. 304:2724–31.CrossRefGoogle Scholar
  60. 60.
    Moore LE, et al. (2011) Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors. PLoS Genet. 7:e1002312.CrossRefGoogle Scholar
  61. 61.
    Ogino S, et al. (2007) MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. Carcinogenesis. 28:1985–90.CrossRefGoogle Scholar
  62. 62.
    You JS, Jones PA. (2012) Cancer genetics and epigenetics: two sides of the same coin? Cancer Cell. 22:9–20.CrossRefGoogle Scholar
  63. 63.
    Bjornsson H. (2004) An integrated epigenetic and genetic approach to common human disease. Trends Genet. 20:350–8.CrossRefGoogle Scholar
  64. 64.
    Ng SB, et al. (2010) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 42:790–3.CrossRefGoogle Scholar
  65. 65.
    Tsurusaki Y, et al. (2012) Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet. 44:376–8.CrossRefGoogle Scholar
  66. 66.
    Berdasco M, Esteller M. (2013) Genetic syndromes caused by mutations in epigenetic genes. Hum. Genet. 132:359–83.CrossRefGoogle Scholar
  67. 67.
    Hansen RS, et al. (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl. Acad. Sci. U.S.A. 96:14412–7.CrossRefGoogle Scholar
  68. 68.
    Liyanage VRB, Rastegar M. (2014) Rett syndrome and MeCP2. Neuromol. Med. 16:231–64.CrossRefGoogle Scholar
  69. 69.
    Chen WG, et al. (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 302:885–9.CrossRefGoogle Scholar
  70. 70.
    Feil R, Fraga MF. (2012) Epigenetics and the environment: emerging patterns and implications. Nat. Rev. Genet. DOI: 10.1038/nrg3142.CrossRefGoogle Scholar
  71. 71.
    Veenendaal MVE, et al. (2013) Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine. BJOG. 120:548–53.CrossRefGoogle Scholar
  72. 72.
    Guerrero-Bosagna C, Skinner MK. (2011) Environmentally induced epigenetic transgenerational inheritance of phenotype and disease. Mol. Cell. Endocrinol. 354:1–6.Google Scholar
  73. 73.
    Petronis A. (2010) Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature. 465:721–7.CrossRefGoogle Scholar
  74. 74.
    Gimelbrant A, et al. (2007) Widespread monoallelic expression on human autosomes. Science. 318:1136–40.CrossRefGoogle Scholar
  75. 75.
    Richards EJ. (2006) Inherited epigenetic variation: revisiting soft inheritance. Nat. Rev. Genet. 7:395–401.CrossRefGoogle Scholar
  76. 76.
    Feinberg AP, Irizarry RA. (2010) Evolution in health and medicine Sackler colloquium: stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proc. Natl. Acad. Sci. U. S. A. 107:1757–64.CrossRefGoogle Scholar
  77. 77.
    Hansen KD, et al. (2011) Increased methylation variation in epigenetic domains across cancer types. Nat. Genet. 43:768–75.CrossRefGoogle Scholar
  78. 78.
    Bojang P Jr, Ramos KS. (2014) The promise and failures of epigenetic therapies for cancer treatment. Cancer Treat. Rev. 40:153–69.CrossRefGoogle Scholar
  79. 79.
    Kaminskas E, et al. (2005) FDA drug approval summary: azacitidine (5-azacytidine, Vidaza™) for injectable suspension. Oncologist. 10:176–82.CrossRefGoogle Scholar
  80. 80.
    Kuo HK, et al. (2007) 5-Azacytidine-induced methyltransferase-DNA adducts block DNA replication in vivo. Cancer Res. 67:8248–54.CrossRefGoogle Scholar
  81. 81.
    Karpf AR, et al. (2001) Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2′-deoxycytidine. Mol. Pharmacol. 59:751–7.CrossRefGoogle Scholar
  82. 82.
    Garcia-Manero G, et al. (2006) Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood. 108:3271–9.CrossRefGoogle Scholar
  83. 83.
    Teschendorff AE, Widschwendter M. (2012) Differential variability improves the identification of cancer risk markers in DNA methylation studies profiling precursor cancer lesions. Bioinformatics. 28:1487–94.CrossRefGoogle Scholar
  84. 84.
    Teschendorff AE, et al. (2012) Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. Genome Med. 4:24.CrossRefGoogle Scholar
  85. 85.
    Feinberg AP. (2014) Epigenetic stochasticity, nuclear structure and cancer: the implications for medicine. J. Intern. Med. 276:5–11.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2015

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  • Emma Cazaly
    • 1
  • Jac Charlesworth
    • 1
  • Joanne L. Dickinson
    • 1
  • Adele F. Holloway
    • 2
  1. 1.Menzies Institute for Medical ResearchUniversity of TasmaniaHobartAustralia
  2. 2.School of MedicineUniversity of TasmaniaHobartAustralia

Personalised recommendations