Parent-of-Origin Effects Implicate Epigenetic Regulation of Experimental Autoimmune Encephalomyelitis and Identify Imprinted as a Novel Risk Gene

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Even with recent progress in determining the genetic basis of complex diseases, the issue of ‘missing heritability’ remains and its potential sources are frequently speculated about but rarely explained. Parent-of-origin effects might contribute to the ‘missing heritability’ and involve genetic and epigenetic mechanisms of inheritance. Our study is the first that establishes (i) the magnitude and (ii) the type of parent-of-origin effects in the pathogenesis of a multiple sclerosis-like disease, experimental autoimmune encephalomyelitis (EAE) in rat, using a strategy designed to identify genes that confer risk only when inherited from either mother or father. A striking 37-54% of all risk loci depended on parental origin. Accounting for parent-of-origin enabled more powerful and precise identification of novel risk factors for EAE, such as the imprinted Dlk1gene. Disease-predisposing alleles conferred lower Dlk1 expression in rats and transgenic Dlk1 mice demonstrated that lower Dlk1 drives more severe EAE and modulates adaptive immune responses. Because parental-origin effects are epigenetically regulated, our data implicate a contributory role for epigenetic mechanisms in complex diseases. Considering parent-of-origin effects in complex disease has enabled more powerful and precise identification of novel risk factors.

Vyšlo v časopise: Parent-of-Origin Effects Implicate Epigenetic Regulation of Experimental Autoimmune Encephalomyelitis and Identify Imprinted as a Novel Risk Gene. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004265
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004265

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1. HandelAE, EbersGC, RamagopalanSV (2009) Epigenetics: molecular mechanisms and implications for disease. Trends Mol Med 16: 7–16.

2. WaterlandRA, JirtleRL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23: 5293–5300.

3. StricklandFM, HewagamaA, WuA, SawalhaAH, DelaneyC, et al. (2013) Diet influences expression of autoimmune-associated genes and disease severity by epigenetic mechanisms in a transgenic mouse model of lupus. Arthritis and rheumatism 65: 1872–1881.

4. FragaMF, BallestarE, PazMF, RoperoS, SetienF, et al. (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102: 10604–10609.

5. KaminskyZA, TangT, WangSC, PtakC, OhGH, et al. (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41: 240–245.

6. JavierreBM, FernandezAF, RichterJ, Al-ShahrourF, Martin-SuberoJI, et al. (2009) Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 20: 170–179.

7. PembreyME, BygrenLO, KaatiG, EdvinssonS, NorthstoneK, et al. (2006) Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14: 159–166.

8. TobiEW, LumeyLH, TalensRP, KremerD, PutterH, et al. (2009) DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Human molecular genetics 18: 4046–4053.

9. MorganHD, SutherlandHG, MartinDI, WhitelawE (1999) Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23: 314–318.

10. AnwayMD, CuppAS, UzumcuM, SkinnerMK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466–1469.

11. CaroneBR, FauquierL, HabibN, SheaJM, HartCE, et al. (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143: 1084–1096.

12. EbersGC, SadovnickAD, DymentDA, YeeIM, WillerCJ, et al. (2004) Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet 363: 1773–1774.

13. RamagopalanSV, HerreraBM, BellJT, DymentDA, DelucaGC, et al. (2008) Parental transmission of HLA-DRB1*15 in multiple sclerosis. Hum Genet 122: 661–663.

14. ChaoMJ, RamagopalanSV, HerreraBM, LincolnMR, DymentDA, et al. (2009) Epigenetics in multiple sclerosis susceptibility: difference in transgenerational risk localizes to the major histocompatibility complex. Hum Mol Genet 18: 261–266.

15. WrightKL, TingJP (2006) Epigenetic regulation of MHC-II and CIITA genes. Trends Immunol 27: 405–412.

16. OrtonSM, HerreraBM, YeeIM, ValdarW, RamagopalanSV, et al. (2006) Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol 5: 932–936.

17. SadovnickAD, YeeIM, EbersGC (2000) Factors influencing sib risks for multiple sclerosis. Clin Genet 58: 431–435.

18. WeissertR, WallstromE, StorchMK, StefferlA, LorentzenJ, et al. (1998) MHC haplotype-dependent regulation of MOG-induced EAE in rats. J Clin Invest 102: 1265–1273.

19. StorchMK, StefferlA, BrehmU, WeissertR, WallstromE, et al. (1998) Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol 8: 681–694.

20. TeuscherC, NoubadeR, SpachK, McElvanyB, BunnJY, et al. (2006) Evidence that the Y chromosome influences autoimmune disease in male and female mice. Proc Natl Acad Sci U S A 103: 8024–8029.

21. SpachKM, BlakeM, BunnJY, McElvanyB, NoubadeR, et al. (2009) Cutting edge: the Y chromosome controls the age-dependent experimental allergic encephalomyelitis sexual dimorphism in SJL/J mice. J Immunol 182: 1789–1793.

22. BecanovicK, WallstromE, KornekB, GlaserA, BromanKW, et al. (2003) New loci regulating rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. J Immunol 170: 1062–1069.

23. CuiY, CheverudJM, WuR (2007) A statistical model for dissecting genomic imprinting through genetic mapping. Genetica 130: 227–239.

24. DeChiaraTM, RobertsonEJ, EfstratiadisA (1991) Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64: 849–859.

25. BromanKW, WuH, SenS, ChurchillGA (2003) R/qtl: QTL mapping in experimental crosses. Bioinformatics 19: 889–890.

26. Schuster-GosslerK, BilinskiP, SadoT, Ferguson-SmithA, GosslerA (1998) The mouse Gtl2 gene is differentially expressed during embryonic development, encodes multiple alternatively spliced transcripts, and may act as an RNA. Developmental dynamics : an official publication of the American Association of Anatomists 212: 214–228.

27. KobayashiS, WagatsumaH, OnoR, IchikawaH, YamazakiM, et al. (2000) Mouse Peg9/Dlk1 and human PEG9/DLK1 are paternally expressed imprinted genes closely located to the maternally expressed imprinted genes: mouse Meg3/Gtl2 and human MEG3. Genes to cells : devoted to molecular & cellular mechanisms 5: 1029–1037.

28. TakadaS, TevendaleM, BakerJ, GeorgiadesP, CampbellE, et al. (2000) Delta-like and gtl2 are reciprocally expressed, differentially methylated linked imprinted genes on mouse chromosome 12. Current biology : CB 10: 1135–1138.

29. LinSP, YoungsonN, TakadaS, SeitzH, ReikW, et al. (2003) Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Nat Genet 35: 97–102.

30. HaganJP, O'NeillBL, StewartCL, KozlovSV, CroceCM (2009) At least ten genes define the imprinted Dlk1-Dio3 cluster on mouse chromosome 12qF1. PLoS One 4: e4352.

31. RaghunandanR, Ruiz-HidalgoM, JiaY, EttingerR, RudikoffE, et al. (2008) Dlk1 influences differentiation and function of B lymphocytes. Stem Cells Dev 17: 495–507.

32. AbdallahBM, BoissyP, TanQ, DahlgaardJ, TraustadottirGA, et al. (2007) dlk1/FA1 regulates the function of human bone marrow mesenchymal stem cells by modulating gene expression of pro-inflammatory cytokines and immune response-related factors. J Biol Chem 282: 7339–7351.

33. ChaconMR, MirandaM, JensenCH, Fernandez-RealJM, VilarrasaN, et al. (2008) Human serum levels of fetal antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro. Int J Obes (Lond) 32: 1122–1129.

34. da RochaST, CharalambousM, LinSP, GutteridgeI, ItoY, et al. (2009) Gene dosage effects of the imprinted delta-like homologue 1 (dlk1/pref1) in development: implications for the evolution of imprinting. PLoS genetics 5: e1000392.

35. BaronJL, MadriJA, RuddleNH, HashimG, JanewayCAJr (1993) Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med 177: 57–68.

36. KroenkeMA, CarlsonTJ, AndjelkovicAV, SegalBM (2008) IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 205: 1535–1541.

37. StromnesIM, CerrettiLM, LiggittD, HarrisRA, GovermanJM (2008) Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med 14: 337–342.

38. EncinasJA, LeesMB, SobelRA, SymonowiczC, WeinerHL, et al. (2001) Identification of genetic loci associated with paralysis, inflammation and weight loss in mouse experimental autoimmune encephalomyelitis. Int Immunol 13: 257–264.

39. BergsteinsdottirK, YangHT, PetterssonU, HolmdahlR (2000) Evidence for common autoimmune disease genes controlling onset, severity, and chronicity based on experimental models for multiple sclerosis and rheumatoid arthritis. J Immunol 164: 1564–1568.

40. DahlmanI, JacobssonL, GlaserA, LorentzenJC, AnderssonM, et al. (1999) Genome-wide linkage analysis of chronic relapsing experimental autoimmune encephalomyelitis in the rat identifies a major susceptibility locus on chromosome 9. J Immunol 162: 2581–2588.

41. DahlmanI, WallstromE, WeissertR, StorchM, KornekB, et al. (1999) Linkage analysis of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the rat identifies a locus controlling demyelination on chromosome 18. Hum Mol Genet 8: 2183–2190.

42. RothMP, ViratelleC, DolboisL, DelverdierM, BorotN, et al. (1999) A genome-wide search identifies two susceptibility loci for experimental autoimmune encephalomyelitis on rat chromosomes 4 and 10. J Immunol 162: 1917–1922.

43. DahlmanI, LorentzenJC, de GraafKL, StefferlA, LiningtonC, et al. (1998) Quantitative trait loci disposing for both experimental arthritis and encephalomyelitis in the DA rat; impact on severity of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis and antibody isotype pattern. Eur J Immunol 28: 2188–2196.

44. HaywardBE, MoranV, StrainL, BonthronDT (1998) Bidirectional imprinting of a single gene: GNAS1 encodes maternally, paternally, and biallelically derived proteins. Proc Natl Acad Sci U S A 95: 15475–15480.

45. BarlowDP, StogerR, HerrmannBG, SaitoK, SchweiferN (1991) The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 349: 84–87.

46. IkushimaH, MunakataY, IshiiT, IwataS, TerashimaM, et al. (2000) Internalization of CD26 by mannose 6-phosphate/insulin-like growth factor II receptor contributes to T cell activation. Proc Natl Acad Sci U S A 97: 8439–8444.

47. LuediPP, HarteminkAJ, JirtleRL (2005) Genome-wide prediction of imprinted murine genes. Genome Res 15: 875–884.

48. MoroyT, KhandanpourC (2011) Growth factor independence 1 (Gfi1) as a regulator of lymphocyte development and activation. Semin Immunol 23: 368–378.

49. Ruiz-HidalgoMJ, GubinaE, TullL, BaladronV, LabordaJ (2002) dlk modulates mitogen-activated protein kinase signaling to allow or prevent differentiation. Exp Cell Res 274: 178–188.

50. WangY, ZhaoL, SmasC, SulHS (2010) Pref-1 interacts with fibronectin to inhibit adipocyte differentiation. Mol Cell Biol 30: 3480–3492.

51. MiyaokaY, TanakaM, ImamuraT, TakadaS, MiyajimaA (2010) A novel regulatory mechanism for Fgf18 signaling involving cysteine-rich FGF receptor (Cfr) and delta-like protein (Dlk). Development 137: 159–167.

52. BraySJ, TakadaS, HarrisonE, ShenSC, Ferguson-SmithAC (2008) The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila. BMC developmental biology 8: 11.

53. BaladronV, Ruiz-HidalgoMJ, NuedaML, Diaz-GuerraMJ, Garcia-RamirezJJ, et al. (2005) dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats. Experimental cell research 303: 343–359.

54. NuedaML, BaladronV, Sanchez-SolanaB, BallesterosMA, LabordaJ (2007) The EGF-like protein dlk1 inhibits notch signaling and potentiates adipogenesis of mesenchymal cells. Journal of molecular biology 367: 1281–1293.

55. JurynczykM, SelmajK (2010) Notch: a new player in MS mechanisms. Journal of neuroimmunology 218: 3–11.

56. MinterLM, TurleyDM, DasP, ShinHM, JoshiI, et al. (2005) Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nature immunology 6: 680–688.

57. JurynczykM, JurewiczA, BieleckiB, RaineCS, SelmajK (2005) Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis. Journal of neuroimmunology 170: 3–10.

58. FerronSR, CharalambousM, RadfordE, McEwenK, WildnerH, et al. (2011) Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis. Nature 475: 381–385.

59. GovermanJ (2009) Autoimmune T cell responses in the central nervous system. Nature reviews Immunology 9: 393–407.

60. AdlerSH, ChiffoleauE, XuL, DaltonNM, BurgJM, et al. (2003) Notch signaling augments T cell responsiveness by enhancing CD25 expression. Journal of immunology 171: 2896–2903.

61. SadeH, KrishnaS, SarinA (2004) The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. The Journal of biological chemistry 279: 2937–2944.

62. ThomasM, CalamitoM, SrivastavaB, MaillardI, PearWS, et al. (2007) Notch activity synergizes with B-cell-receptor and CD40 signaling to enhance B-cell activation. Blood 109: 3342–3350.

63. SantosMA, SarmentoLM, RebeloM, DoceAA, MaillardI, et al. (2007) Notch1 engagement by Delta-like-1 promotes differentiation of B lymphocytes to antibody-secreting cells. Proc Natl Acad Sci U S A 104: 15454–15459.

64. LanderES (2011) Initial impact of the sequencing of the human genome. Nature 470: 187–197.

65. Lango AllenH, EstradaK, LettreG, BerndtSI, WeedonMN, et al. (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467: 832–838.

66. FrankeA, McGovernDP, BarrettJC, WangK, Radford-SmithGL, et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42: 1118–1125.

67. SawcerS, HellenthalG, PirinenM, SpencerCC, PatsopoulosNA, et al. (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476: 214–219.

68. KongA, SteinthorsdottirV, MassonG, ThorleifssonG, SulemP, et al. (2009) Parental origin of sequence variants associated with complex diseases. Nature 462: 868–874.

69. WallaceC, SmythDJ, Maisuria-ArmerM, WalkerNM, ToddJA, et al. (2010) The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet 42: 68–71.

70. DarvasiA, SollerM (1995) Advanced intercross lines, an experimental population for fine genetic mapping. Genetics 141: 1199–1207.

71. SimmonsSB, PiersonER, LeeSY, GovermanJM (2013) Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol 34: 410–422.

72. AmorS, GroomeN, LiningtonC, MorrisMM, DornmairK, et al. (1994) Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J Immunol 153: 4349–4356.

73. HaleyCS, KnottSA (1992) A simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity 69: 315–324.

74. ChurchillGA, DoergeRW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138: 963–971.

75. JagodicM, OlssonT (2006) Combined-cross analysis of genome-wide linkage scans for experimental autoimmune encephalomyelitis in rat. Genomics 88: 737–744.