Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation

English version České info

The methylation of cytosines in CpG dinucleotides is essential for cellular differentiation and the progression of many cancers, and it plays an important role in gametic imprinting. To assess variation and inheritance of genome-wide patterns of DNA methylation simultaneously in humans, we applied reduced representation bisulfite sequencing (RRBS) to somatic DNA from six members of a three-generation family. We observed that 8.1% of heterozygous SNPs are associated with differential methylation in cis, which provides a robust signature for Mendelian transmission and relatedness. The vast majority of differential methylation between homologous chromosomes (>92%) occurs on a particular haplotype as opposed to being associated with the gender of the parent of origin, indicating that genotype affects DNA methylation of far more loci than does gametic imprinting. We found that 75% of genotype-dependent differential methylation events in the family are also seen in unrelated individuals and that overall genotype can explain 80% of the variation in DNA methylation. These events are under-represented in CpG islands, enriched in intergenic regions, and located in regions of low evolutionary conservation. Even though they are generally not in functionally constrained regions, 22% (twice as many as expected by chance) of genes harboring genotype-dependent DNA methylation exhibited allele-specific gene expression as measured by RNA-seq of a lymphoblastoid cell line, indicating that some of these events are associated with gene expression differences. Overall, our results demonstrate that the influence of genotype on patterns of DNA methylation is widespread in the genome and greatly exceeds the influence of imprinting on genome-wide methylation patterns.

Vyšlo v časopise: Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation. PLoS Genet 7(8): e32767. doi:10.1371/journal.pgen.1002228
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002228

Souhrn

Zdroje

1. OkanoMBellDWHaberDALiE 1999 DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99 247 257

2. FeinbergAPTyckoB 2004 The history of cancer epigenetics. Nat Rev Cancer 4 143 153

3. JonesPA 2002 DNA methylation and cancer. Oncogene 21 5358 5360

4. MillJTangTKaminskyZKhareTYazdanpanahS 2008 Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 82 696 711

5. RichardsonB 2003 DNA methylation and autoimmune disease. Clin Immunol 109 72 79

6. LingCGroopL 2009 Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58 2718 2725

7. ReikWWalterJ 2001 Genomic imprinting: parental influence on the genome. Nat Rev Genet 2 21 32

8. WilkinsJF 2005 Genomic imprinting and methylation: epigenetic canalization and conflict. Trends Genet 21 356 365

9. HashimshonyTZhangJKeshetIBustinMCedarH 2003 The role of DNA methylation in setting up chromatin structure during development. Nat Genet 34 187 192

10. NorrisDPBrockdorffNRastanS 1991 Methylation status of CpG-rich islands on active and inactive mouse X chromosomes. Mamm Genome 1 78 83

11. ChandlerLAGhaziHJonesPABoukampPFusenigNE 1987 Allele-specific methylation of the human c-Ha-ras-1 gene. Cell 50 711 717

12. SilvaAJWhiteR 1988 Inheritance of allelic blueprints for methylation patterns. Cell 54 145 152

13. KerkelKSpadolaAYuanEKosekJJiangL 2008 Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet 40 904 908

14. ShoemakerRDengJWangWZhangK 2010 Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Res

15. ZhangYRohdeCReinhardtRVoelcker-RehageCJeltschA 2009 Non-imprinted allele-specific DNA methylation on human autosomes. Genome Biol 10 R138

16. BaranziniSEMudgeJvan VelkinburghJCKhankhanianPKhrebtukovaI 2010 Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464 1351 1356

17. KaminskyZATangTWangSCPtakCOhGH 2009 DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41 240 245

18. LairdPW 2003 The power and the promise of DNA methylation markers. Nat Rev Cancer 3 253 266

19. MeissnerAMikkelsenTSGuHWernigMHannaJ 2008 Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454 766 770

20. HuangYPastorWAShenYTahilianiMLiuDR 2010 The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing. PLoS ONE 5 e8888 doi:10.1371/journal.pone.0008888

21. ThomsonJAItskovitz-EldorJShapiroSSWaknitzMASwiergielJJ 1998 Embryonic stem cell lines derived from human blastocysts. Science 282 1145 1147

22. CarrelLWillardHF 2005 X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434 400 404

23. TalensRPBoomsmaDITobiEWKremerDJukemaJW 2010 Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J 24 3135 3144

24. HuWHPendergastJSMoXMBrambillaRBracchi-RicardV 2005 NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation. J Biol Chem 280 29233 29241

25. KentJWJrPetersonCPDyerTDAlmasyLBlangeroJ 2009 Genome-wide discovery of maternal effect variants. BMC Proc 3 Suppl 7 S19

26. LuediPPDietrichFSWeidmanJRBoskoJMJirtleRL 2007 Computational and experimental identification of novel human imprinted genes. Genome Res 17 1723 1730

27. RabenNPlotzPByrneBJ 2002 Acid alpha-glucosidase deficiency (glycogenosis type II, Pompe disease). Curr Mol Med 2 145 166

28. FeinbergAPIrizarryRA 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 Suppl 1 1757 1764

29. BirdA 2002 DNA methylation patterns and epigenetic memory. Genes Dev 16 6 21

30. FiczGBrancoMRSeisenbergerSSantosFKruegerF 2011 Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473 398 402

31. PastorWAPapeUJHuangYHendersonHRListerR 2011 Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473 394 397

32. WilliamsKChristensenJPedersenMTJohansenJVCloosPA 2011 TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473 343 348

33. RosenbloomKRDreszerTRPheasantMBarberGPMeyerLR 2010 ENCODE whole-genome data in the UCSC Genome Browser. Nucleic Acids Res 38 D620 625

34. McDaniellRLeeBKSongLLiuZBoyleAP 2010 Heritable individual-specific and allele-specific chromatin signatures in humans. Science 328 235 239

35. Myers Lab RRBS Protocol. Available: http://myers.hudsonalpha.org/documents/Myers%20Lab%20RRBS%20Protocol%2003-24-10.pdf. Accessed 2011 July 1

36. LangmeadBTrapnellCPopMSalzbergSL 2009 Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10 R25

37. StoreyJDTibshiraniR 2003 Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100 9440 9445

38. VarleyKEMutchDGEdmonstonTBGoodfellowPJMitraRD 2009 Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing. Nucleic Acids Res 37 4603 4612

39. Gardiner-GardenMFrommerM 1987 CpG islands in vertebrate genomes. J Mol Biol 196 261 282

40. PollardKSHubiszMJRosenbloomKRSiepelA 2010 Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res 20 110 121

41. PruittKDTatusovaTMaglottDR 2007 NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins. Nucleic Acids Res 35 D61 65

42. RheadBKarolchikDKuhnRMHinrichsASZweigAS 2010 The UCSC Genome Browser database: update 2010. Nucleic Acids Res 38 D613 619

43. de HoonMJImotoSNolanJMiyanoS 2004 Open source clustering software. Bioinformatics 20 1453 1454

44. EisenMBSpellmanPTBrownPOBotsteinD 1998 Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 95 14863 14868

45. MortazaviAWilliamsBAMcCueKSchaefferLWoldB 2008 Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 5 621 628

46. DurbinRMAbecasisGRAltshulerDLAutonABrooksLD 2010 A map of human genome variation from population-scale sequencing. Nature 467 1061 1073

47. BenjaminiYDraiDElmerGKafkafiNGolaniI 2001 Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125 279 284