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Cellular and Molecular Life Sciences

, Volume 70, Issue 9, pp 1609–1621 | Cite as

Bridging epigenomics and complex disease: the basics

  • Raffaele Teperino
  • Adelheid Lempradl
  • J. Andrew Pospisilik
Multi-author review

Abstract

The DNA sequence largely defines gene expression and phenotype. However, it is becoming increasingly clear that an additional chromatin-based regulatory network imparts both stability and plasticity to genome output, modifying phenotype independently of the genetic blueprint. Indeed, alterations in this “epigenetic” control layer underlie, at least in part, the reason for monozygotic twins being discordant for disease. Functionally, this regulatory layer comprises post-translational modifications of DNA and histones, as well as small and large noncoding RNAs. Together these regulate gene expression by changing chromatin organization and DNA accessibility. Successive technological advances over the past decade have enabled researchers to map the chromatin state with increasing accuracy and comprehensiveness, catapulting genetic research into a genome-wide era. Here, aiming particularly at the genomics/epigenomics newcomer, we review the epigenetic basis that has helped drive the technological shift and how this progress is shaping our understanding of complex disease.

Keywords

Complex diseases Chromatin Epigenomics 

References

  1. 1.
    Mattick JS (2007) A new paradigm for developmental biology. J Exp Biol 210(Pt 9):1526–1547. doi: 10.1242/jeb.005017 PubMedCrossRefGoogle Scholar
  2. 2.
    Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447(7143):433–440. doi: 10.1038/nature05919 PubMedCrossRefGoogle Scholar
  3. 3.
    Hewagama A, Richardson B (2009) The genetics and epigenetics of autoimmune diseases. J Autoimmun 33(1):3–11. doi: 10.1016/j.jaut.2009.03.007 PubMedCrossRefGoogle Scholar
  4. 4.
    Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P, Besenbacher S et al (2009) Parental origin of sequence variants associated with complex diseases. Nature 462(7275):868–874. doi: 10.1038/nature08625 PubMedCrossRefGoogle Scholar
  5. 5.
    Ling C, Groop L (2009) Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58(12):2718–2725. doi: 10.2337/db09-1003 PubMedCrossRefGoogle Scholar
  6. 6.
    Schanen NC (2006) Epigenetics of autism spectrum disorders. Hum Mol Genet 15 (Spec No 2):R138–R150. doi: 10.1093/hmg/ddl213 PubMedCrossRefGoogle Scholar
  7. 7.
    Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271):315–322. doi: 10.1038/nature08514 PubMedCrossRefGoogle Scholar
  8. 8.
    Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R (2000) Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci USA 97(10):5237–5242PubMedCrossRefGoogle Scholar
  9. 9.
    Ziller MJ, Müller F, Liao J, Zhang Y, Gu H, Bock C et al (2011) Genomic distribution and inter-sample variation of non-CpG methylation across human cell types. PLoS Genet 7(12):e1002389. doi: 10.1371/journal.pgen.1002389 PubMedCrossRefGoogle Scholar
  10. 10.
    Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM (2010) Reprogramming towards pluripotency requires aid-dependent DNA demethylation. Nature 463(7284):1042–1047. doi: 10.1038/nature08752 PubMedCrossRefGoogle Scholar
  11. 11.
    Cortázar D, Kunz C, Selfridge J, Lettieri T, Saito Y, MacDougall E et al (2011) Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature 470(7334):419–423. doi: 10.1038/nature09672 PubMedCrossRefGoogle Scholar
  12. 12.
    Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466(7310):1129–1133. doi: 10.1038/nature09303 PubMedCrossRefGoogle Scholar
  13. 13.
    Li E, Beard C, Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366(6453):362–365. doi: 10.1038/366362a0 PubMedCrossRefGoogle Scholar
  14. 14.
    Cedar H, Bergman Y (2012) Programming of DNA methylation patterns. Annu Rev Biochem 81:97–117. doi: 10.1146/annurev-biochem-052610-091920 PubMedCrossRefGoogle Scholar
  15. 15.
    Razin A, Szyf M (1984) DNA methylation patterns. Formation and function. Biochim Biophys Acta 782(4):331–342PubMedCrossRefGoogle Scholar
  16. 16.
    Bird AP (1984) DNA methylation versus gene expression. J Embryol Exp Morphol 83 Suppl:31–40PubMedGoogle Scholar
  17. 17.
    Wolf SF, Jolly DJ, Lunnen KD, Friedmann T, Migeon BR (1984) Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: implications for X-chromosome inactivation. Proc Natl Acad Sci USA 81(9):2806–2810PubMedCrossRefGoogle Scholar
  18. 18.
    Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A et al (2012) Landscape of transcription in human cells. Nature 489(7414):101–108. doi: 10.1038/nature11233 PubMedCrossRefGoogle Scholar
  19. 19.
    Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H et al (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22(9):1775–1789. doi: 10.1101/gr.132159.111 PubMedCrossRefGoogle Scholar
  20. 20.
    van Bakel H, Nislow C, Blencowe BJ, Hughes TR (2010) Most “dark matter” transcripts are associated with known genes. PLoS Biol 8(5):e1000371. doi: 10.1371/journal.pbio.1000371 PubMedCrossRefGoogle Scholar
  21. 21.
    Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM et al (2006) A pattern-based method for the identification of microRNA binding sites and their corresponding heteroduplexes. Cell 126(6):1203–1217. doi: 10.1016/j.cell.2006.07.031 PubMedCrossRefGoogle Scholar
  22. 22.
    Mendell JT (2005) MicroRNAs: critical regulators of development, cellular physiology and malignancy. Cell Cycle 4(9):1179–1184PubMedCrossRefGoogle Scholar
  23. 23.
    Aravin AA, Hannon GJ, Brennecke J (2007) The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science 318(5851):761–764. doi: 10.1126/science.1146484 PubMedCrossRefGoogle Scholar
  24. 24.
    Brennecke J, Malone CD, Aravin AA, Sachidanandam R, Stark A, Hannon GJ (2008) An epigenetic role for maternally inherited piRNAs in transposon silencing. Science 322(5906):1387–1392. doi: 10.1126/science.1165171 PubMedCrossRefGoogle Scholar
  25. 25.
    King FJ, Szakmary A, Cox DN, Lin H (2001) Yb modulates the divisions of both germline and somatic stem cells through piwi- and hh-mediated mechanisms in the Drosophila ovary. Mol Cell 7(3):497–508PubMedCrossRefGoogle Scholar
  26. 26.
    Sharma AK, Nelson MC, Brandt JE, Wessman M, Mahmud N, Weller KP, Hoffman R (2001) Human CD34(+) stem cells express the hiwi gene, a human homologue of the Drosophila gene piwi. Blood 97(2):426–434PubMedCrossRefGoogle Scholar
  27. 27.
    Rajasethupathy P, Antonov I, Sheridan R, Frey S, Sander C, Tuschl T, Kandel ER (2012) A role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity. Cell 149(3):693–707. doi: 10.1016/j.cell.2012.02.057 PubMedCrossRefGoogle Scholar
  28. 28.
    Nielsen H, Orum H, Engberg J (1992) A novel class of nucleolar RNAs from tetrahymena. FEBS Lett 307(3):337–342PubMedCrossRefGoogle Scholar
  29. 29.
    Kiss-László Z, Henry Y, Bachellerie JP, Caizergues-Ferrer M, Kiss T (1996) Site-specific ribose methylation of preribosomal RNA: a novel function for small nucleolar RNAs. Cell 85(7):1077–1088PubMedCrossRefGoogle Scholar
  30. 30.
    Ni J, Tien AL, Fournier MJ (1997) Small nucleolar RNAs direct site-specific synthesis of pseudouridine in ribosomal RNA. Cell 89(4):565–573PubMedCrossRefGoogle Scholar
  31. 31.
    Tycowski KT, You ZH, Graham PJ, Steitz JA (1998) Modification of U6 spliceosomal RNA is guided by other small RNAs. Mol Cell 2(5):629–638PubMedCrossRefGoogle Scholar
  32. 32.
    King TH, Liu B, McCully RR, Fournier MJ (2003) Ribosome structure and activity are altered in cells lacking snoRNPs that form pseudouridines in the peptidyl transferase center. Mol Cell 11(2):425–435PubMedCrossRefGoogle Scholar
  33. 33.
    Li SG, Zhou H, Luo YP, Zhang P, Qu LH (2005) Identification and functional analysis of 20 box H/ACA small nucleolar RNAs (snoRNAs) from Schizosaccharomyces pombe. J Biol Chem 280(16):16446–16455. doi: 10.1074/jbc.M500326200 PubMedCrossRefGoogle Scholar
  34. 34.
    Yang JH, Zhang XC, Huang ZP, Zhou H, Huang MB, Zhang S et al (2006) Snoseeker: an advanced computational package for screening of guide and orphan snoRNA genes in the human genome. Nucleic Acids Res 34(18):5112–5123. doi: 10.1093/nar/gkl672 PubMedCrossRefGoogle Scholar
  35. 35.
    Kishore S, Stamm S (2006) The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311(5758):230–232. doi: 10.1126/science.1118265 PubMedCrossRefGoogle Scholar
  36. 36.
    Nagano T, Fraser P (2011) No-nonsense functions for long noncoding RNAs. Cell 145(2):178–181. doi: 10.1016/j.cell.2011.03.014 PubMedCrossRefGoogle Scholar
  37. 37.
    Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43(6):904–914. doi: 10.1016/j.molcel.2011.08.018 PubMedCrossRefGoogle Scholar
  38. 38.
    Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G et al (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477(7364):295–300. doi: 10.1038/nature10398 PubMedCrossRefGoogle Scholar
  39. 39.
    Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E et al (2011) Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146(6):1016–1028. doi: 10.1016/j.cell.2011.08.008 PubMedCrossRefGoogle Scholar
  40. 40.
    Sandoval J, Esteller M (2012) Cancer epigenomics: beyond genomics. Curr Opin Genet Dev 22(1):50–55. doi: 10.1016/j.gde.2012.02.008 PubMedCrossRefGoogle Scholar
  41. 41.
    Feige JN, Auwerx J (2007) Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol 17(6):292–301. doi: 10.1016/j.tcb.2007.04.001 PubMedCrossRefGoogle Scholar
  42. 42.
    Haberland M, Montgomery RL, Olson EN (2009) The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10(1):32–42. doi: 10.1038/nrg2485 PubMedCrossRefGoogle Scholar
  43. 43.
    Rosenfeld MG, Lunyak VV, Glass CK (2006) Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev 20(11):1405–1428. doi: 10.1101/gad.1424806 PubMedCrossRefGoogle Scholar
  44. 44.
    Smith CL, O’Malley BW (2004) Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 25(1):45–71PubMedCrossRefGoogle Scholar
  45. 45.
    Spiegelman BM, Heinrich R (2004) Biological control through regulated transcriptional coactivators. Cell 119(2):157–167. doi: 10.1016/j.cell.2004.09.037 PubMedCrossRefGoogle Scholar
  46. 46.
    Vaquero A, Reinberg D (2009) Calorie restriction and the exercise of chromatin. Genes Dev 23(16):1849–1869. doi: 10.1101/gad.1807009 PubMedCrossRefGoogle Scholar
  47. 47.
    Chan HM, Krstic-Demonacos M, Smith L, Demonacos C, La Thangue NB (2001) Acetylation control of the retinoblastoma tumour-suppressor protein. Nat Cell Biol 3(7):667–674. doi: 10.1038/35083062 PubMedCrossRefGoogle Scholar
  48. 48.
    Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90(4):595–606PubMedCrossRefGoogle Scholar
  49. 49.
    Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434(7029):113–118. doi: 10.1038/nature03354 PubMedCrossRefGoogle Scholar
  50. 50.
    Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T et al (2010) Regulation of cellular metabolism by protein lysine acetylation. Science 327(5968):1000–1004. doi: 10.1126/science.1179689 PubMedCrossRefGoogle Scholar
  51. 51.
    Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC et al (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325(5942):834–840. doi: 10.1126/science.1175371 PubMedCrossRefGoogle Scholar
  52. 52.
    Kim SC, Sprung R, Chen Y, Xu Y, Ball H, Pei J et al (2006) Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 23(4):607–618. doi: 10.1016/j.molcel.2006.06.026 PubMedCrossRefGoogle Scholar
  53. 53.
    Gilmour DS, Lis JT (1984) Detecting protein-DNA interactions in vivo: distribution of RNA polymerase on specific bacterial genes. Proc Natl Acad Sci USA 81(14):4275–4279PubMedCrossRefGoogle Scholar
  54. 54.
    Solomon MJ, Larsen PL, Varshavsky A (1988) Mapping protein-DNA interactions in vivo with formaldehyde: evidence that histone H4 is retained on a highly transcribed gene. Cell 53(6):937–947PubMedCrossRefGoogle Scholar
  55. 55.
    Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW et al (1992) A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA 89(5):1827–1831PubMedCrossRefGoogle Scholar
  56. 56.
    Sanger F, Coulson AR (1975) A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase. J Mol Biol 94(3):441–448PubMedCrossRefGoogle Scholar
  57. 57.
    Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74(12):5463–5467PubMedCrossRefGoogle Scholar
  58. 58.
    Munroe DJ, Harris TJ (2010) Third-generation sequencing fireworks at Marco Island. Nat Biotech 28(5):426–428. doi: 10.1038/nbt0510-426 CrossRefGoogle Scholar
  59. 59.
    Metzker ML (2010) Sequencing technologies – the next generation. Nat Rev Genet 11(1):31–46. doi: 10.1038/nrg2626 PubMedCrossRefGoogle Scholar
  60. 60.
    Schadt EE, Turner S, Kasarskis A (2010) A window into third-generation sequencing. Hum Mol Genet 19(R2):R227–R240. doi: 10.1093/hmg/ddq416 PubMedCrossRefGoogle Scholar
  61. 61.
    Sexton T, Schober H, Fraser P, Gasser SM (2007) Gene regulation through nuclear organization. Nat Struct Mol Biol 14(11):1049–1055. doi: 10.1038/nsmb1324 PubMedCrossRefGoogle Scholar
  62. 62.
    Dekker J, Rippe K, Dekker M, Kleckner N (2002) Capturing chromosome conformation. Science 295(5558):1306–1311. doi: 10.1126/science.1067799 PubMedCrossRefGoogle Scholar
  63. 63.
    Zhao Z, Tavoosidana G, Sjölinder M, Göndör A, Mariano P, Wang S et al (2006) Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nat Genet 38(11):1341–1347. doi: 10.1038/ng1891 PubMedCrossRefGoogle Scholar
  64. 64.
    Dostie J, Richmond TA, Arnaout RA, Selzer RR, Lee WL, Honan TA et al (2006) Chromosome conformation capture carbon copy (5C): a massively parallel solution for mapping interactions between genomic elements. Genome Res 16(10):1299–1309. doi: 10.1101/gr.5571506 PubMedCrossRefGoogle Scholar
  65. 65.
    Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326(5950):289–293. doi: 10.1126/science.1181369 PubMedCrossRefGoogle Scholar
  66. 66.
    Fullwood MJ, Ruan Y (2009) Chip-based methods for the identification of long-range chromatin interactions. J Cell Biochem 107(1):30–39. doi: 10.1002/jcb.22116 PubMedCrossRefGoogle Scholar
  67. 67.
    Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93(18):9821–9826PubMedCrossRefGoogle Scholar
  68. 68.
    Down TA, Rakyan VK, Turner DJ, Flicek P, Li H, Kulesha E et al (2008) A bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat Biotechnol 26(7):779–785. doi: 10.1038/nbt1414 PubMedCrossRefGoogle Scholar
  69. 69.
    Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M, Lam WL, Schübeler D (2005) Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 37(8):853–862. doi: 10.1038/ng1598 PubMedCrossRefGoogle Scholar
  70. 70.
    Serre D, Lee BH, Ting AH (2010) MBD-isolated Genome Sequencing provides a high-throughput and comprehensive survey of DNA methylation in the human genome. Nucleic Acids Res 38(2):391–399. doi: 10.1093/nar/gkp992 PubMedCrossRefGoogle Scholar
  71. 71.
    Harris RA, Wang T, Coarfa C, Nagarajan RP, Hong C, Downey SL et al (2010) Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. Nat Biotechnol 28(10):1097–1105. doi: 10.1038/nbt.1682 PubMedCrossRefGoogle Scholar
  72. 72.
    Meissner A, Gnirke A, Bell GW, Ramsahoye B, Lander ES, Jaenisch R (2005) Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res 33(18):5868–5877. doi: 10.1093/nar/gki901 PubMedCrossRefGoogle Scholar
  73. 73.
    Sutherland E, Coe L, Raleigh EA (1992) McrBC: a multisubunit GTP-dependent restriction endonuclease. J Mol Biol 225(2):327–348PubMedCrossRefGoogle Scholar
  74. 74.
    Ren B, Robert F, Wyrick JJ, Aparicio O, Jennings EG, Simon I et al (2000) Genome-wide location and function of DNA binding proteins. Science 290(5500):2306–2309. doi: 10.1126/science.290.5500.2306 PubMedCrossRefGoogle Scholar
  75. 75.
    Robertson G, Hirst M, Bainbridge M, Bilenky M, Zhao Y, Zeng T et al (2007) Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods 4(8):651–657. doi: 10.1038/nmeth1068 PubMedCrossRefGoogle Scholar
  76. 76.
    Shen Y, Yue F, McCleary DF, Ye Z, Edsall L, Kuan S et al (2012) A map of the cis-regulatory sequences in the mouse genome. Nature 488(7409):116–120. doi: 10.1038/nature11243 PubMedCrossRefGoogle Scholar
  77. 77.
    Ernst J, Kellis M (2010) Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol 28(8):817–825. doi: 10.1038/nbt.1662 PubMedCrossRefGoogle Scholar
  78. 78.
    Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB et al (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473(7345):43–49. doi: 10.1038/nature09906 PubMedCrossRefGoogle Scholar
  79. 79.
    Crawford GE, Holt IE, Whittle J, Webb BD, Tai D, Davis S et al (2006) Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS). Genome Res 16(1):123–131. doi: 10.1101/gr.4074106 PubMedCrossRefGoogle Scholar
  80. 80.
    Weiner A, Hughes A, Yassour M, Rando OJ, Friedman N (2010) High-resolution nucleosome mapping reveals transcription-dependent promoter packaging. Genome Res 20(1):90–100. doi: 10.1101/gr.098509.109 PubMedCrossRefGoogle Scholar
  81. 81.
    Giresi PG, Kim J, McDaniell RM, Iyer VR, Lieb JD (2007) FAIRE (formaldehyde-assisted isolation of regulatory elements) isolates active regulatory elements from human chromatin. Genome Res 17(6):877–885. doi: 10.1101/gr.5533506 PubMedCrossRefGoogle Scholar
  82. 82.
    Djebali S, Lagarde J, Kapranov P, Lacroix V, Borel C, Mudge JM et al (2012) Evidence for transcript networks composed of chimeric RNAs in human cells. PLoS One 7(1):e28213. doi: 10.1371/journal.pone.0028213 PubMedCrossRefGoogle Scholar
  83. 83.
    Niranjanakumari S, Lasda E, Brazas R, Garcia-Blanco MA (2002) Reversible cross-linking combined with immunoprecipitation to study RNA-protein interactions in vivo. Methods 26(2):182–190. doi: 10.1016/S1046-2023(02)00021-X PubMedCrossRefGoogle Scholar
  84. 84.
    Ule J, Jensen KB, Ruggiu M, Mele A, Ule A, Darnell RB (2003) CLIP identifies nova-regulated RNA networks in the brain. Science 302(5648):1212–1215. doi: 10.1126/science.1090095 PubMedCrossRefGoogle Scholar
  85. 85.
    Darnell RB (2010) HITS-CLIP: panoramic views of protein-RNA regulation in living cells. Wiley Interdiscip Rev RNA 1(2):266–286. doi: 10.1002/wrna.31 PubMedCrossRefGoogle Scholar
  86. 86.
    Yeo GW, Coufal NG, Liang TY, Peng GE, Fu XD, Gage FH (2009) An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells. Nat Struct Mol Biol 16(2):130–137. doi: 10.1038/nsmb.1545 PubMedCrossRefGoogle Scholar
  87. 87.
    Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P et al (2010) Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141(1):129–141. doi: 10.1016/j.cell.2010.03.009 PubMedCrossRefGoogle Scholar
  88. 88.
    König J, Zarnack K, Rot G, Curk T, Kayikci M, Zupan B et al (2010) iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution. Nat Struct Mol Biol 17(7):909–915. doi: 10.1038/nsmb.1838 PubMedCrossRefGoogle Scholar
  89. 89.
    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 USA 107(Suppl 1):1757–1764. doi: 10.1073/pnas.0906183107 PubMedCrossRefGoogle Scholar
  90. 90.
    Kulis M, Esteller M (2010) DNA methylation and cancer. Adv Genet 70:27–56. doi: 10.1016/B978-0-12-380866-0.60002-2 PubMedCrossRefGoogle Scholar
  91. 91.
    Petronis A (2010) Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature 465(7299):721–727. doi: 10.1038/nature09230 PubMedCrossRefGoogle Scholar
  92. 92.
    Morgan HD, Sutherland HG, Martin DI, Whitelaw E (1999) Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23(3):314–318. doi: 10.1038/15490 PubMedCrossRefGoogle Scholar
  93. 93.
    Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR et al (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7(8):847–854. doi: 10.1038/nn1276 PubMedCrossRefGoogle Scholar
  94. 94.
    Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8(4):253–262. doi: 10.1038/nrg2045 PubMedCrossRefGoogle Scholar
  95. 95.
    Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD et al (2009) DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 18(21):4046–4053. doi: 10.1093/hmg/ddp353 PubMedCrossRefGoogle Scholar
  96. 96.
    Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ (2010) Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467(7318):963–966. doi: 10.1038/nature09491 PubMedCrossRefGoogle Scholar
  97. 97.
    Chong S, Vickaryous N, Ashe A, Zamudio N, Youngson N, Hemley S et al (2007) Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nat Genet 39(5):614–622. doi: 10.1038/ng2031 PubMedCrossRefGoogle Scholar
  98. 98.
    Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R et al (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143(7):1084–1096. doi: 10.1016/j.cell.2010.12.008 PubMedCrossRefGoogle Scholar
  99. 99.
    Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102(30):10604–10609. doi: 10.1073/pnas.0500398102 PubMedCrossRefGoogle Scholar
  100. 100.
    Brasacchio D, Okabe J, Tikellis C, Balcerczyk A, George P, Baker EK et al (2009) Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes 58(5):1229–1236. doi: 10.2337/db08-1666 PubMedCrossRefGoogle Scholar
  101. 101.
    El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG et al (2008) Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 205(10):2409–2417. doi: 10.1084/jem.20081188 PubMedCrossRefGoogle Scholar
  102. 102.
    Tateishi K, Okada Y, Kallin EM, Zhang Y (2009) Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458(7239):757–761. doi: 10.1038/nature07777 PubMedCrossRefGoogle Scholar
  103. 103.
    Mikkelsen TS, Xu Z, Zhang X, Wang L, Gimble JM, Lander ES, Rosen ED (2010) Comparative epigenomic analysis of murine and human adipogenesis. Cell 143(1):156–169. doi: 10.1016/j.cell.2010.09.006 PubMedCrossRefGoogle Scholar
  104. 104.
    Norton L, Fourcaudot M, Abdul-Ghani MA, Winnier D, Mehta FF, Jenkinson CP, Defronzo RA (2011) Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism. Diabetologia 54(12):3132–3142. doi: 10.1007/s00125-011-2289-z PubMedCrossRefGoogle Scholar
  105. 105.
    Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ et al (1999) Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am J Hum Genet 64(4):1127–1140PubMedCrossRefGoogle Scholar
  106. 106.
    Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J et al (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38(3):320–323. doi: 10.1038/ng1732 PubMedCrossRefGoogle Scholar
  107. 107.
    Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T et al (2011) A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331(6022):1315–1319. doi: 10.1126/science.1198125 PubMedCrossRefGoogle Scholar
  108. 108.
    Lechner M, Boshoff C, Beck S (2010) Cancer epigenome. Adv Genet 70:247–276. doi: 10.1016/B978-0-12-380866-0.60009-5 PubMedCrossRefGoogle Scholar
  109. 109.
    Bach JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347(12):911–920. doi: 10.1056/NEJMra020100 PubMedCrossRefGoogle Scholar
  110. 110.
    Rakyan VK, Down TA, Balding DJ, Beck S (2011) Epigenome-wide association studies for common human diseases. Nat Rev Genet 12(8):529–541. doi: 10.1038/nrg3000 PubMedCrossRefGoogle Scholar
  111. 111.
    Mack GS (2010) To selectivity and beyond. Nat Biotechnol 28(12):1259–1266. doi: 10.1038/nbt.1724 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Raffaele Teperino
    • 1
  • Adelheid Lempradl
    • 1
  • J. Andrew Pospisilik
    • 1
  1. 1.Max-Planck Institute of Immunobiology and EpigeneticsFreiburgGermany

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