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Epigenetics: spotlight on type 2 diabetes and obesity

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Abstract

Type 2 diabetes (T2D) and obesity are the major public health problems. Substantial efforts have been made to define loci and variants contributing to the individual risk of these disorders. However, the overall risk explained by genetic variation is very modest. Epigenetics is one of the fastest growing research areas in biomedicine as changes in the epigenome are involved in many biological processes, impact on the risk for several complex diseases including diabetes and may explain susceptibility. In this review, we focus on the role of DNA methylation in contributing to the risk of T2D and obesity.

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References

  1. Rappaport SM, Smith MT (2010) Epidemiology. Environment and disease risks. Science 330:460–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Holliday R (2006) Epigenetics: a historical overview. Epigenetics 1:76–80

    Article  PubMed  Google Scholar 

  3. Waddington CH (1942) The epigenotype. Endeavour 1:18–20

    Google Scholar 

  4. Dupont C, Armant DR, Brenner CA (2009) Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med 27:351–357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Davis TL, Yang GJ, McCarrey JR, Bartolomei MS (2000) The H19 methylation imprint is erased and re-established differentially on the parental alleles during male germ cell development. Hum Mol Genet 9:2885–2894

    Article  CAS  PubMed  Google Scholar 

  6. Bollati V, Baccarelli A (2010) Environmental epigenetics. Heredity 105(1):105–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tyson FL, Heindel J (2005) Environmental Influences on Epigenetic Regulation. Environ Health Perspect 113:A839

    Google Scholar 

  8. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254

    Article  CAS  PubMed  Google Scholar 

  9. Raciti GA, Nigro C, Longo M et al (2014) Personalized medicine and type 2 diabetes: lesson from epigenetics. Epigenomics 6:229–238

    Article  CAS  PubMed  Google Scholar 

  10. Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463

    Article  CAS  PubMed  Google Scholar 

  11. Sun C, Burgner DP, Ponsonby AL et al (2013) Effects of early-life environment and epigenetics on cardiovascular disease risk in children: highlighting the role of twin studies. Pediatr Res 73:523–530

    Article  CAS  PubMed  Google Scholar 

  12. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159

    Article  CAS  PubMed  Google Scholar 

  13. Coulondre C, Miller JH, Farabaugh PJ, Gilbert W (1978) Molecular basis of base substitution hotspots in Escherichia coli. Nature 274:775–780

    Article  CAS  PubMed  Google Scholar 

  14. Gonzalgo ML, Jones PA (1997) Mutagenic and epigenetic effects of DNA methylation. Mutat Res 386:107–118

    Article  CAS  PubMed  Google Scholar 

  15. Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 3:662–673

    Article  CAS  PubMed  Google Scholar 

  16. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293:1089–1093

    Article  CAS  PubMed  Google Scholar 

  17. Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97

    Article  CAS  PubMed  Google Scholar 

  18. Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14:204–220

    Article  CAS  PubMed  Google Scholar 

  19. Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25:1010–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mohn F, Weber M, Rebhan M et al (2008) Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol Cell 30:755–766

    Article  CAS  PubMed  Google Scholar 

  21. Payer B, Lee JT (2008) X chromosome dosage compensation: how mammals keep the balance. Annu Rev Genet 42:733–772

    Article  CAS  PubMed  Google Scholar 

  22. Luger K (2001). Nucleosomes: Structure and Function. Encyclopedia of Life Sciences 1–8

  23. Cooper GM (2000) The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates. Chromosomes and Chromatin. Available from: http://www.ncbi.nlm.nih.gov/books/NBK9863/

  24. Ma J (2005) Crossing the line between activation and repression. Trends Genet 21:54–59

    Article  CAS  PubMed  Google Scholar 

  25. Richards EJ, Elgin SC (2002) Epigenetic codes for heterochromatin formation and silencing: rounding up the usual suspects. Cell 108:489–500

    Article  CAS  PubMed  Google Scholar 

  26. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

    Article  CAS  PubMed  Google Scholar 

  27. Tamaru H (2010) Confining euchromatin/heterochromatin territory: jumonji crosses the line. Genes Dev 24:1465–1478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Seol JH, Kim HJ, Yang YJ et al (2006) Different roles of histone H3 lysine 4 methylation in chromatin maintenance. Biochem Biophys Res Commun 349:463–470

    Article  CAS  PubMed  Google Scholar 

  29. Costa FF (2008) Non-coding RNAs, epigenetics and complexity. Gene 410:9–17

    Article  CAS  PubMed  Google Scholar 

  30. Mattick JS, Makunin IV (2006) Non-coding RNA. Hum Mol Genet 15 Spec No 1:R17–29

  31. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  32. Londin E, Loher P, Telonis AG et al (2015) Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc Natl Acad Sci USA 112:E1106–E1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mattick JS, Makunin IV (2005) Small regulatory RNAs in mammals. Hum Mol Genet 14 Spec No 1:R121–132

  34. Guo X, Zhang Z, Gerstein MB, Zheng D (2009) Small RNAs originated from pseudogenes: cis- or trans-acting? PLoS Comput Biol 5:e1000449

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wienholds E, Plasterk RH (2005) MicroRNA function in animal development. FEBS Lett 579:5911–5922

    Article  CAS  PubMed  Google Scholar 

  36. Vrba L, Muñoz-Rodríguez JL, Stampfer MR, Futscher BW (2013) miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer. PLoS One 8:e54398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sato F, Tsuchiya S, Meltzer SJ, Shimizu K (2011) MicroRNAs and epigenetics. FEBS J 278:1598–1609

    Article  CAS  PubMed  Google Scholar 

  38. International Diabetes Federation. Diabetes Atlas 6th ed, 2013 Brussels, Belgium: International Diabetes Federation, 2014

  39. Ng M, Fleming T, Robinson M et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384:766–781

    Article  PubMed  PubMed Central  Google Scholar 

  40. InterAct Consortium et al (2013) The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study. Diabetologia 56:60–69

    Article  Google Scholar 

  41. Meigs JB, Cupples LA, Wilson PW (2000) Parental transmission of type 2 diabetes: the Framingham Offspring Study. Diabetes 49:2201–2207

    Article  CAS  PubMed  Google Scholar 

  42. Klein BE, Klein R, Moss SE, Cruickshanks KJ (1996) Parental history of diabetes in a population-based study. Diabetes Care 19:827–830

    Article  CAS  PubMed  Google Scholar 

  43. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE (1990) The body-mass index of twins who have been reared apart. N Engl J Med 322:1483–1487

    Article  CAS  PubMed  Google Scholar 

  44. Rice T, Pérusse L, Bouchard C, Rao DC (1999) Familial aggregation of body mass index and subcutaneous fat measures in the longitudinal Québec family study. Genet Epidemiol 16:316–334

    Article  CAS  PubMed  Google Scholar 

  45. Segal NL, Allison DB (2002) Twins and virtual twins: bases of relative body weight revisited. Int J Obes Relat Metab Disord 26:437–441

    Article  CAS  PubMed  Google Scholar 

  46. Grarup N, Sandholt CH, Hansen T, Pedersen O (2014) Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia 57:1528–1541

    Article  CAS  PubMed  Google Scholar 

  47. Al-Azzam SI, Khabour OF, Alzoubi KH, Alzayadeen RN (2014) The effect of leptin promoter and leptin receptor gene polymorphisms on lipid profile among the diabetic population: modulations by atorvastatin treatment and environmental factors. J Endocrinol Invest 37(9):835–842

    Article  CAS  PubMed  Google Scholar 

  48. Drong AW, Lindgren CM, McCarthy MI (2012) The genetic and epigenetic basis of type 2 diabetes and obesity. Clin Pharmacol Ther 92:707–715

    Article  CAS  PubMed  Google Scholar 

  49. Bloom JS, Ehrenreich IM, Loo WT, Lite TL, Kruglyak L (2013) Finding the sources of missing heritability in a yeast cross. Nature 494(7436):234–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253–262

    Article  CAS  PubMed  Google Scholar 

  51. Cropley JE, Suter CM, Beckman KB, Martin DI (2006) Germ-line epigenetic modification of the murine A vy allele by nutritional supplementation. Proc Natl Acad Sci U S A 103:17308–17312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Saad MI, Abdelkhalek TM, Haiba MM, Saleh MM, Hanafi MY, Tawfik SH, Kamel MA (2016) Maternal obesity and malnourishment exacerbate perinatal oxidative stress resulting in diabetogenic programming in F1 offspring. J Endocrinol Invest 39(6):643–655

    Article  CAS  PubMed  Google Scholar 

  53. Speakman JR, O’Rahilly S (2012) Fat: an evolving issue. Dis Model Mech 5:569–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Castillo-Fernandez JE, Spector TD, Bell JT (2014) Epigenetics of discordant monozygotic twins: implications for disease. Genome Med 6:60

    Article  PubMed  PubMed Central  Google Scholar 

  55. Poulsen P, Esteller M, Vaag A, Fraga MF (2007) The epigenetic basis of twin discordance in age-related diseases. Pediatr Res 61:38R–42R

    Article  PubMed  Google Scholar 

  56. Lyssenko V, Laakso M (2015) Genetic Screening for the Risk of Type 2 Diabetes: worthless or valuable? Diabetes Care 36:S120–S126

    Article  Google Scholar 

  57. Raciti GA, Longo M, Parrillo L et al (2015) Understanding type 2 diabetes: from genetics to epigenetics. Acta Diabetol 52(5):821–827

    Article  CAS  PubMed  Google Scholar 

  58. Ling C, Del Guerra S, Lupi R et al (2008) Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51:615–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Barrès R, Osler ME, Yan J et al (2009) Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab 10:189–198

    Article  PubMed  Google Scholar 

  60. Barres R, Kirchner H, Rasmussen M et al (2013) Weight loss after gastric bypass surgery in human obesity remodels promoter methylation. Cell Rep 3:1020–1027

    Article  CAS  PubMed  Google Scholar 

  61. Velho G, Robert JJ (2002) Maturity-onset diabetes of the young (MODY): genetic and clinical characteristics. Horm Res 57(Suppl 1):29–33

    CAS  PubMed  Google Scholar 

  62. Ahlgren U, Jonsson J, Jonsson L, Simu K, Edlund H (1998) beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev 12:1763–1768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang BT, Dayeh TA, Volkov PA et al (2012) Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. Mol Endocrinol 26:1203–1212

    Article  CAS  PubMed  Google Scholar 

  64. Toperoff G, Aran D, Kark JD et al (2012) Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Hum Mol Genet 21:371–383

    Article  CAS  PubMed  Google Scholar 

  65. Jung UJ, Choi MS (2014) Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci 15(4):6184–6223

    Article  PubMed  PubMed Central  Google Scholar 

  66. Shen W, Wang C, Xia L et al (2014) Epigenetic modification of the leptin promoter in diet-induced obese mice and the effects of N-3 polyunsaturated fatty acids. Sci Rep 4:5282

    CAS  PubMed  Google Scholar 

  67. Cifani C, Micioni Di Bonaventura MV et al (2015) Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction? Front Neurosci 9:187

    Article  PubMed  PubMed Central  Google Scholar 

  68. Dolinoy DC (2008) The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutr Rev 66(Suppl 1):S7–11

    Article  PubMed  PubMed Central  Google Scholar 

  69. Cooney CA, Dave AA, Wolff GL (2002) Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr 132:2393S–2400S

    CAS  PubMed  Google Scholar 

  70. Wolff GL, Kodell RL, Moore SR, Cooney CA (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12:949–957

    CAS  PubMed  Google Scholar 

  71. Ling C, Groop L (2009) Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58:2718–2725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kuehnen P, Mischke M, Wiegand S et al (2012) An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity. PLoS Genet 8:e1002543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Reddy MA, Natarajan R (2015) Recent developments in epigenetics of acute and chronic kidney diseases. Kidney Int 88:250–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Godfrey KM, Sheppard A, Gluckman PD et al (2011) Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 60(5):1528–1534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Campión J, Milagro FI, Martínez JA (2009) Individuality and epigenetics in obesity. Obes Rev 10:383–392

    Article  PubMed  Google Scholar 

  76. Seki Y, Williams L, Vuguin PM, Charron MJ (2012) Minireview: epigenetic programming of diabetes and obesity: animal models. Endocrinology 153:1031–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Parrillo L, Costa V, Raciti GA, et al (2016) Hoxa5 undergoes dynamic DNA methylation and transcriptional repression in the adipose tissue of mice exposed to high-fat diet. Int J obesity. (in press)

  78. Cowherd RM, Lyle RE, Miller CP, Mcgehee RE Jr (1997) Developmental profile of homeobox gene expression during 3T3-L1 adipogenesis. Biochem Biophys Res Commun 237:470–475

    Article  CAS  PubMed  Google Scholar 

  79. Charlier C, Segers K, Karim L et al (2001) The callipyge mutation enhances the expression of coregulated imprinted genes in cis without affecting their imprinting status. Nat Genet 27:367–369

    Article  CAS  PubMed  Google Scholar 

  80. Dong C, Li WD, Geller F et al (2005) Possible genomic imprinting of three human obesity-related genetic loci. Am J Hum Genet 76:427–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bera TK, Liu XF, Yamada M et al (2008) A model for obesity and gigantism due to disruption of the Ankrd26 gene. Proc Natl Acad Sci USA 105:270–275

    Article  CAS  PubMed  Google Scholar 

  82. Raciti GA, Bera TK, Gavrilova O, Pastan I (2011) Partial inactivation of Ankrd26 causes diabetes with enhanced insulin responsiveness of adipose tissue in mice. Diabetologia 54:2911–2922

    Article  CAS  PubMed  Google Scholar 

  83. Acs P, Bauer PO, Mayer B et al (2015) A novel form of ciliopathy underlies hyperphagia and obesity in Ankrd26 knockout mice. Brain Struct Funct 220:1511–1528

    Article  CAS  PubMed  Google Scholar 

  84. Fei Z, Bera TK, Liu X, Xiang L, Pastan I (2011) Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts. J Biol Chem 286:27761–27768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Liu XF, Bera TK, Kahue C et al (2012) ANKRD26 and its interacting partners TRIO, GPS2, HMMR and DIPA regulate adipogenesis in 3T3-L1 cells. PLoS ONE 7:e38130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rönn T, Volkov P, Gillberg L et al (2015) Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood. Hum Mol Genet 24:3792–3813

    PubMed  Google Scholar 

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Authors and Affiliations

  1. URT of the Institute of Experimental Endocrinology and Oncology “G. Salvatore”, National Council of Research, Naples, Italy

    A. Desiderio, R. Spinelli, M. Ciccarelli, C. Nigro, C. Miele, F. Beguinot & G. A. Raciti

  2. Department of Translational Medical Sciences, University of Naples “Federico II”, Via Pansini 5, 80131, Naples, Italy

    A. Desiderio, R. Spinelli, M. Ciccarelli, C. Nigro, C. Miele, F. Beguinot & G. A. Raciti

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  1. A. Desiderio
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  2. R. Spinelli
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Correspondence to F. Beguinot.

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Funding

This study was funded by the European Foundation for the Study of Diabetes (EFSD), by the Ministero dell’Università e della Ricerca Scientifica (grants PRIN and FIRB-MERIT, and PON 01_02460) and by the Società Italiana di Diabetologia (SID-FO.DI.RI). This work was further supported by the P.O.R. Campania FSE 2007-2013, Project CREMe.

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The authors declare that they have no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Desiderio, A., Spinelli, R., Ciccarelli, M. et al. Epigenetics: spotlight on type 2 diabetes and obesity. J Endocrinol Invest 39, 1095–1103 (2016). https://doi.org/10.1007/s40618-016-0473-1

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