An Alu Element–Associated Hypermethylation Variant of the Gene Is Associated with Childhood Obesity

English version České info

The individual risk for common diseases not only depends on genetic but also on epigenetic polymorphisms. To assess the role of epigenetic variations in the individual risk for obesity, we have determined the methylation status of two CpG islands at the POMC locus in obese and normal-weight children. We found a hypermethylation variant targeting individual CpGs at the intron2–exon3 boundary of the POMC gene by bisulphite sequencing that was significantly associated with obesity. POMC exon3 hypermethylation interferes with binding of the transcription enhancer P300 and reduces expression of the POMC transcript. Since intron2 contains Alu elements that are known to influence methylation in their genomic vicinity, the exon3 methylation variant seems to result from an Alu element–triggered default state of methylation boundary definition. Exon3 hypermethylation in the POMC locus represents the first identified DNA methylation variant that is associated with the individual risk for obesity.

Vyšlo v časopise: An Alu Element–Associated Hypermethylation Variant of the Gene Is Associated with Childhood Obesity. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002543
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002543

Souhrn

Zdroje

1. BjornssonHTFallinMDFeinbergAP 2004 An integrated epigenetic and genetic approach to common human disease. Trends Genet 20 350 358

2. BoksMPDerksEMWeisenbergerDJStrengmanEJansonE 2009 The relationship of DNA methylation with age, gender and genotype in twins and healthy controls. PLoS ONE 4 e6767 doi:10.1371/journal.pone.0006767

3. FragaMFBallestarEPazMFRoperoSSetienF 2005 Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102 10604 10609

4. JirtleRLSkinnerMK 2007 Environmental epigenomics and disease susceptibility. Nat Rev Genet 8 253 262

5. BjornssonHTSigurdssonMIFallinMDIrizarryRAAspelundT 2008 Intra-individual change over time in DNA methylation with familial clustering. JAMA 299 2877 2883

6. BollatiVSchwartzJWrightRLitonjuaATarantiniL 2009 Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev 130 234 239

7. GronnigerEWeberBHeilOPetersNStabF 2010 Aging and chronic sun exposure cause distinct epigenetic changes in human skin. PLoS Genet 6 e1000971 doi:10.1371/journal.pgen.1000971

8. BorgelJGuibertSLiYChibaHSchubelerD 2010 Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet 42 1093 1100

9. ReikWDeanWWalterJ 2001 Epigenetic reprogramming in mammalian development. Science 293 1089 1093

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

11. FeinbergAPIrizarryRAFradinDAryeeMJMurakamiP 2010 Personalized epigenomic signatures that are stable over time and covary with body mass index. Sci Transl Med 2 49ra67

12. MartinowichKHattoriDWuHFouseSHeF 2003 DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302 890 893

13. KrudeHBiebermannHLuckWHornRBrabantG 1998 Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19 155 157

14. SpeliotesEKWillerCJBerndtSIMondaKLThorleifssonG 2010 Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet

15. FarooqiISDropSClementsAKeoghJMBiernackaJ 2006 Heterozygosity for a POMC-null mutation and increased obesity risk in humans. Diabetes 55 2549 2553

16. TakahashiHHakamataYWatanabeYKikunoRMiyataT 1983 Complete nucleotide sequence of the human corticotropin-beta-lipotropin precursor gene. Nucleic Acids Res 11 6847 6858

17. Lacaze-MasmonteilTde KeyzerYLutonJPKahnABertagnaX 1987 Characterization of proopiomelanocortin transcripts in human nonpituitary tissues. Proc Natl Acad Sci U S A 84 7261 7265

18. Gardiner-GardenMFrommerM 1994 Transcripts and CpG islands associated with the pro-opiomelanocortin gene and other neurally expressed genes. J Mol Endocrinol 12 365 382

19. EhrlichSWeissDBurghardtRInfante-DuarteCBrockhausS 2010 Promoter specific DNA methylation and gene expression of POMC in acutely underweight and recovered patients with anorexia nervosa. J Psychiatr Res 44 827 833

20. AndersenGNHagglundMNagaevaOFrangsmyrLPetrovskaR 2005 Quantitative measurement of the levels of melanocortin receptor subtype 1, 2, 3 and 5 and pro-opio-melanocortin peptide gene expression in subsets of human peripheral blood leucocytes. Scand J Immunol 61 279 284

21. BuzzettiRMcLoughlinLLavenderPMClarkAJReesLH 1989 Expression of pro-opiomelanocortin gene and quantification of adrenocorticotropic hormone-like immunoreactivity in human normal peripheral mononuclear cells and lymphoid and myeloid malignancies. J Clin Invest 83 733 737

22. BiebermannHCastanedaTRvan LandeghemFvon DeimlingAEscherF 2006 A role for beta-melanocyte-stimulating hormone in human body-weight regulation. Cell Metab 3 141 146

23. Rolland-CacheraMFColeTJSempeMTichetJRossignolC 1991 Body Mass Index variations: centiles from birth to 87 years. Eur J Clin Nutr 45 13 21

24. BergmannRLBergmannKELau-SchadensdorfSLuckWDannemannA 1994 Atopic diseases in infancy. The German multicenter atopy study (MAS-90). Pediatr Allergy Immunol 5 19 25

25. JeannotteLBurbachJPDrouinJ 1987 Unusual proopiomelanocortin ribonucleic acids in extrapituitary tissues: intronless transcripts in testes and long poly(A) tails in hypothalamus. Mol Endocrinol 1 749 757

26. SlominskiAWortsmanJLugerTPausRSolomonS 2000 Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol Rev 80 979 1020

27. ClarkAJLavenderPMCoatesPJohnsonMRReesLH 1990 In vitro and in vivo analysis of the processing and fate of the peptide products of the short proopiomelanocortin mRNA. Mol Endocrinol 4 1737 1743

28. MillingtonWRRosenthalDWUnalCBNyquist-BattieC 1999 Localization of pro-opiomelanocortin mRNA transcripts and peptide immunoreactivity in rat heart. Cardiovasc Res 43 107 116

29. TaherzadehSSharmaSChhajlaniVGantzIRajoraN 1999 alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages. Am J Physiol 276 R1289 1294

30. JohanssonOVirtanenMHilligesMHanssonLO 1991 Gamma-melanocyte-stimulating hormone-like immunoreactivity in blood cells of human eosinophilic patients. Acta Haematol 86 206 208

31. KlugMRehliM 2006 Functional analysis of promoter CpG methylation using a CpG-free luciferase reporter vector. Epigenetics 1 127 130

32. LiuXWangLZhaoKThompsonPRHwangY 2008 The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451 846 850

33. HeintzmanNDStuartRKHonGFuYChingCW 2007 Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet 39 311 318

34. ChakrabartiSKFrancisJZiesmannSMGarmeyJCMirmiraRG 2003 Covalent histone modifications underlie the developmental regulation of insulin gene transcription in pancreatic beta cells. J Biol Chem 278 23617 23623

35. TsukadaTWatanabeYNakaiYImuraHNakanishiS 1982 Repetitive DNA sequences in the human corticotropin-beta-lipotrophin precursor gene region: Alu family members. Nucleic Acids Res 10 1471 1479

36. LiuWMSchmidCW 1993 Proposed roles for DNA methylation in Alu transcriptional repression and mutational inactivation. Nucleic Acids Res 21 1351 1359

37. KochanekSRenzDDoerflerW 1993 DNA methylation in the Alu sequences of diploid and haploid primary human cells. EMBO J 12 1141 1151

38. XingJWitherspoonDJRayDABatzerMAJordeLB 2007 Mobile DNA elements in primate and human evolution. Am J Phys Anthropol Suppl 45 2 19

39. LoosRJLindgrenCMLiSWheelerEZhaoJH 2008 Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40 768 775

40. LiSZhaoJHLuanJLubenRNRodwellSA 2010 Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies. Am J Clin Nutr 91 184 190

41. Newell-PriceJKingPClarkAJ 2001 The CpG island promoter of the human proopiomelanocortin gene is methylated in nonexpressing normal tissue and tumors and represses expression. Mol Endocrinol 15 338 348

42. YeLLiXKongXWangWBiY 2005 Hypomethylation in the promoter region of POMC gene correlates with ectopic overexpression in thymic carcinoids. J Endocrinol 185 337 343

43. StevensABegumGCookAConnorKRumballC 2010 Epigenetic changes in the hypothalamic proopiomelanocortin and glucocorticoid receptor genes in the ovine fetus after periconceptional undernutrition. Endocrinology 151 3652 3664

44. StevensABegumGWhiteA 2011 Epigenetic changes in the hypothalamic pro-opiomelanocortin gene: a mechanism linking maternal undernutrition to obesity in the offspring? Eur J Pharmacol 660 194 201

45. PlagemannAHarderTBrunnMHarderARoepkeK 2009 Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 587 4963 4976

46. ListerRPelizzolaMDowenRHHawkinsRDHonG 2009 Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462 315 322

47. LiYZhuJTianGLiNLiQ 2010 The DNA methylome of human peripheral blood mononuclear cells. PLoS Biol 8 e1000533 doi:10.1371/journal.pbio.1000533

48. MullerHJAltenburgE 1930 The Frequency of Translocations Produced by X-Rays in Drosophila. Genetics 15 283 311

49. MakinoSKajiRAndoSTomizawaMYasunoK 2007 Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am J Hum Genet 80 393 406

50. MartinATroadecCBoualemARajabMFernandezR 2009 A transposon-induced epigenetic change leads to sex determination in melon. Nature 461 1135 1138

51. MorganHDSutherlandHGMartinDIWhitelawE 1999 Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23 314 318

52. HajkovaPel-MaarriOEngemannSOswaldJOlekA 2002 DNA-methylation analysis by the bisulfite-assisted genomic sequencing method. Methods Mol Biol 200 143 154

53. KerjeanAVieillefondAThiounnNSibonyMJeanpierreM 2001 Bisulfite genomic sequencing of microdissected cells. Nucleic Acids Res 29 E106 106