Skip to main content

Advertisement

SpringerLink
Log in

The Epigenome and Its Role in Diabetes

  • Genetics (T Frayling, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Both genetic and environmental factors play critical roles in the development of diabetes. Epidemiological evidence and data from clinical studies suggest the persistence of a “metabolic memory” of past exposures to environmental factors or glycemic control. Epigenetic mechanisms are regarded as one of the likeliest candidates underlying these phenomena. On the other hand, owing to the recent elucidation of mechanisms that erase epigenetic marks, it has gradually become recognized that epigenetic regulation is a more dynamic process than previously thought. A technological breakthrough in epigenome research in the past decade was the development of high-throughput sequencing. This new technology lets us investigate the epigenome in a global and comprehensive manner, and provides previously unrecognized findings and insights. This review presents an overview of the recent progress in our understanding of epigenetic regulation in type 1 and type 2 diabetes research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Holliday R. Epigenetics: a historical overview. Epigenetics. 2006;1:76–80.

    Article  PubMed  Google Scholar 

  2. Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007;8:253–62.

    Article  PubMed  CAS  Google Scholar 

  3. Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128:635–8.

    Article  PubMed  CAS  Google Scholar 

  4. Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem. 2005;74:481–514.

    Article  PubMed  CAS  Google Scholar 

  5. Meissner A. Epigenetic modifications in pluripotent and differentiated cells. Nat Biotechnol. 2010;28:1079–88.

    Article  PubMed  CAS  Google Scholar 

  6. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28:1057–68.

    Article  PubMed  CAS  Google Scholar 

  7. Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A. 2002;99:3740–5.

    Article  PubMed  CAS  Google Scholar 

  8. Straussman R, Nejman D, Roberts D, Steinfeld I, Blum B, Benvenisty N, et al. Developmental programming of CpG island methylation profiles in the human genome. Nat Struct Mol Biol. 2009;16:564–71.

    Article  PubMed  CAS  Google Scholar 

  9. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69:915–26.

    Article  PubMed  CAS  Google Scholar 

  10. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–57.

    Article  PubMed  CAS  Google Scholar 

  11. Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov. 2012;11:384–400.

    Article  PubMed  CAS  Google Scholar 

  12. Hanover JA, Krause MW, Love DC. Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol. 2012;13:312–21.

    Article  PubMed  CAS  Google Scholar 

  13. Kirmizis A, Santos-Rosa H, Penkett CJ, Singer MA, Vermeulen M, Mann M, et al. Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation. Nature. 2007;449:928–32.

    Article  PubMed  CAS  Google Scholar 

  14. Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–81.

    Article  PubMed  CAS  Google Scholar 

  15. Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T, et al. New nomenclature for chromatin-modifying enzymes. Cell. 2007;131:633–6.

    Article  PubMed  CAS  Google Scholar 

  16. Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science. 2010;330:612–6.

    Article  PubMed  CAS  Google Scholar 

  17. Zhou VW, Goren A, Bernstein BE. Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet. 2011;12:7–18.

    Article  PubMed  CAS  Google Scholar 

  18. Bruniquel D, Schwartz RH. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol. 2003;4:235–40.

    Article  PubMed  CAS  Google Scholar 

  19. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science. 2003;302:890–3.

    Article  PubMed  CAS  Google Scholar 

  20. •• Barrès R, Yan J, Egan B, Treebak JT, Rasmussen M, Fritz T, et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 2012;15:405–11. This paper reports alteration of DNA methylation status in skeletal muscle biopsy samples from human subjects after acute exercise.

    Article  PubMed  CAS  Google Scholar 

  21. Wu SC, Zhang Y. Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol. 2010;11:607–20.

    Article  PubMed  CAS  Google Scholar 

  22. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119:941–53.

    Article  PubMed  CAS  Google Scholar 

  23. Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J, et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell. 2006;125:483–95.

    Article  PubMed  CAS  Google Scholar 

  24. Agger K, Cloos PAC, Christensen J, Pasini D, Rose S, Rappsilber J, et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007;449:731–4.

    Article  PubMed  CAS  Google Scholar 

  25. Hong S, Cho Y, Yu L, Yu H, Veenstra TD, Ge K. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci U S A. 2007;104:18439–44.

    Article  PubMed  CAS  Google Scholar 

  26. De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. 2007;130:1083–94.

    Article  PubMed  CAS  Google Scholar 

  27. Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007;449:689–94.

    Article  PubMed  CAS  Google Scholar 

  28. Lee MG, Villa R, Trojer P, Norman J, Yan K-P, Reinberg D, et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science. 2007;318:447–50.

    Article  PubMed  CAS  Google Scholar 

  29. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  PubMed  CAS  Google Scholar 

  30. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature. 2007;448:318–24.

    Article  PubMed  CAS  Google Scholar 

  31. Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2007;1:55–70.

    Article  PubMed  CAS  Google Scholar 

  32. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007;448:313–7.

    Article  PubMed  CAS  Google Scholar 

  33. Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, et al. Dissecting direct reprogramming through integrative genomic analysis. Nature. 2008;454:49–55.

    Article  PubMed  CAS  Google Scholar 

  34. Doi A, Park I-H, Wen B, Murakami P, Aryee MJ, Irizarry R, et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet. 2009;41:1350–3.

    Article  PubMed  CAS  Google Scholar 

  35. Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467:285–90.

    Article  PubMed  CAS  Google Scholar 

  36. Bock C, Kiskinis E, Verstappen G, Gu H, Boulting G, Smith ZD, et al. Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell. 2011;144:439–52.

    Article  PubMed  CAS  Google Scholar 

  37. Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011;471:68–73.

    Article  PubMed  CAS  Google Scholar 

  38. Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus–present and future perspectives. Nat Rev Endocrinol. 2012;8:228–36.

    Article  CAS  Google Scholar 

  39. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005;102:10604–9.

    Article  PubMed  CAS  Google Scholar 

  40. Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012;13:97–109.

    PubMed  CAS  Google Scholar 

  41. Martin GM. Epigenetic drift in aging identical twins. Proc Natl Acad Sci U S A. 2005;102:10413–4.

    Article  PubMed  CAS  Google Scholar 

  42. Prospective UK, Study D. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–53.

    Article  Google Scholar 

  43. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.

    Article  PubMed  CAS  Google Scholar 

  44. Group TWT for the DC and CT of DI and CR. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287:2563–9.

    Article  Google Scholar 

  45. Pop-Busui R, Herman WH, Feldman EL, Low PA, Martin CL, Cleary PA, et al. DCCT and EDIC studies in type 1 diabetes: lessons for diabetic neuropathy regarding metabolic memory and natural history. Curr Diabetes Rep. 2010;10:276–82.

    Article  Google Scholar 

  46. Polak JF, Backlund JC, Cleary PA, Harrington AP, O’Leary DH, Lachin JM, et al. Progression of carotid artery intima-media thickness during 12 years in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Diabetes. 2011;60:607–13.

    Article  PubMed  CAS  Google Scholar 

  47. de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, Steffes MW, et al. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med. 2011;365:2366–76.

    Article  PubMed  CAS  Google Scholar 

  48. Symonds ME, Sebert SP, Hyatt MA, Budge H. Nutritional programming of the metabolic syndrome. Nat Rev Endocrinol. 2009;5:604–10.

    Article  PubMed  CAS  Google Scholar 

  49. Gluckman PD. Epigenetics and metabolism in 2011: epigenetics, the life-course and metabolic disease. Nat Rev Endocrinol. 2012;8:74–6.

    Article  CAS  Google Scholar 

  50. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A. 2008;105:17046–9.

    Article  PubMed  CAS  Google Scholar 

  51. • Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, McLean C, et al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes. 2011;60:1528–34. This paper suggested that the epigenetic state at birth can predict childhood adiposity.

    Article  PubMed  CAS  Google Scholar 

  52. Toperoff G, Aran D, Kark JD, Rosenberg M, Dubnikov T, Nissan B, et al. Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Hum Mol Genet. 2012;21:371–83.

    Article  PubMed  CAS  Google Scholar 

  53. Morgan HD, Sutherland HG, Martin DI, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nat Genet. 1999;23:314–8.

    Article  PubMed  CAS  Google Scholar 

  54. Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23:5293–300.

    Article  PubMed  CAS  Google Scholar 

  55. Park JH, Stoffers DA, Nicholls RD, Simmons RA. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest. 2008;118:2316–24.

    Article  PubMed  CAS  Google Scholar 

  56. Sandovici I, Smith NH, Nitert MD, Ackers-Johnson M, Uribe-Lewis S, Ito Y, et al. Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A. 2011;108:5449–54.

    Article  PubMed  CAS  Google Scholar 

  57. Daxinger L, Whitelaw E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet. 2012;13:153–62.

    Article  PubMed  CAS  Google Scholar 

  58. Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature. 2011;479:365–71.

    Article  PubMed  CAS  Google Scholar 

  59. Seong K-H, Li D, Shimizu H, Nakamura R, Ishii S. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell. 2011;145:1049–61.

    Article  PubMed  CAS  Google Scholar 

  60. Jimenez-Chillaron JC, Isganaitis E, Charalambous M, Gesta S, Pentinat-Pelegrin T, Faucette RR, et al. Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes. 2009;58:460–8.

    Article  PubMed  CAS  Google Scholar 

  61. Dunn GA, Bale L. Maternal high-fat diet effects on third-generation female body size via the paternal lineage. Endocrinology. 2011;152:2228–36.

    Article  PubMed  CAS  Google Scholar 

  62. •• Ng S-F, Lin RCY, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature. 2010;467:963–6. This and the next papers suggested not only maternal nutrition but also paternal nutrition have an impact on the health outcomes of adult offspring.

    Article  PubMed  CAS  Google Scholar 

  63. •• Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R, et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010;143:1084–96. This and the previous papers suggested not only maternal nutrition but also paternal nutrition have an impact on the health outcomes of adult offspring.

    Article  PubMed  CAS  Google Scholar 

  64. Lu C, Thompson CB. Metabolic regulation of epigenetics. Cell Metab. 2012;16:9–17.

    Article  PubMed  CAS  Google Scholar 

  65. Katada S, Imhof A, Sassone-Corsi P. Connecting Threads: epigenetics and metabolism. Cell. 2012;148:24–8.

    Article  PubMed  CAS  Google Scholar 

  66. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009;324:1076–80.

    Article  PubMed  CAS  Google Scholar 

  67. Cai L, Sutter BM, Li B, Tu BP. Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol Cell. 2011;42:426–37.

    Article  PubMed  CAS  Google Scholar 

  68. Collins F. Has the revolution arrived? Nature. 2010;464:674–5.

    Article  PubMed  CAS  Google Scholar 

  69. Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, et al. Identification and analysis of functional elements in 1 % of the human genome by the ENCODE pilot project. Nature. 2007;447:799–816.

    Article  PubMed  CAS  Google Scholar 

  70. Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol. 2010;28:1045–8.

    Article  PubMed  CAS  Google Scholar 

  71. Task E, Board SA. Moving AHEAD with an international human epigenome project. Nature. 2008;454:711–5.

    Article  CAS  Google Scholar 

  72. •• Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74. In this paper and related papers in the same issue of Nature and other journals, The ENCODE consortium provided 1,640 genome-wide epigenome data sets prepared from 147 cell types, which illuminate the roles of the functional elements of the human and murine genome.

    Article  PubMed  CAS  Google Scholar 

  73. Waki H, Tontonoz P. Endocrine functions of adipose tissue. Annu Rev Pathol. 2007;2:31–56.

    Article  PubMed  CAS  Google Scholar 

  74. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 2008;77:289–312.

    Article  PubMed  CAS  Google Scholar 

  75. Lefterova MI, Zhang Y, Steger DJ, Schupp M, Schug J, Cristancho A, et al. PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev. 2008;22:2941–52.

    Article  PubMed  CAS  Google Scholar 

  76. Nielsen R, Pedersen TA, Hagenbeek D, Moulos P, Siersbaek R, Megens E, et al. Genome-wide profiling of PPARgamma: RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes Dev. 2008;22:2953–67.

    Article  PubMed  CAS  Google Scholar 

  77. Steger DJ, Grant GR, Schupp M, Tomaru T, Lefterova MI, Schug J, et al. Propagation of adipogenic signals through an epigenomic transition state. Genes Dev. 2010;24:1035–44.

    Article  PubMed  CAS  Google Scholar 

  78. • Siersbæk R, Nielsen R, John S, Sung M-H, Baek S, Loft A, et al. Extensive chromatin remodelling and establishment of transcription factor “hotspots” during early adipogenesis. EMBO J. 2011;30:1459–72. This paper revealed a dramatic and dynamic modulation of the chromatin landscape during the first hours of adipocyte differentiation.

    Article  PubMed  CAS  Google Scholar 

  79. • Lefterova MI, Steger DJ, Zhuo D, Qatanani M, Mullican SE, Tuteja G, et al. Cell-specific determinants of peroxisome proliferator-activated receptor gamma function in adipocytes and macrophages. Mol Cell Biol. 2010;30:2078–89. This paper demonstrated that PPARγ occupancy in the genome is cell-type-specific and determined by cell-type-specific co-localizing factors.

    Article  PubMed  CAS  Google Scholar 

  80. Eguchi J, Yan Q, Schones DE, Kamal M, Hsu C, Zhang MQ, et al. Interferon regulatory factors are transcriptional regulators of adipogenesis. Cell Metab. 2008;7:86–94.

    Article  PubMed  CAS  Google Scholar 

  81. • Mikkelsen TS, Xu Z, Zhang X, Wang L, Gimble JM, Lander ES, et al. Comparative epigenomic analysis of murine and human adipogenesis. Cell. 2010;143:156–69. This paper examined comparative analysis on murine and human adipogenesis and discovered unexpectedly high evolutional turnover of adipocyte-specific cis-regulatory elements in the genome.

    Article  PubMed  CAS  Google Scholar 

  82. • Waki H, Nakamura M, Yamauchi T, Wakabayashi K, Yu J, Hirose-Yotsuya L, et al. Global mapping of cell type-specific open chromatin by FAIRE-seq reveals the regulatory role of the NFI family in adipocyte differentiation. PLoS Genet. 2011;7:e1002311. This paper shows the utility of FAIRE-seq in providing a global view of cell type–specific regulatory elements in the genome and in identifying transcriptional regulators of adipocyte differentiation.

    Article  PubMed  CAS  Google Scholar 

  83. Okamura M, Kudo H, Wakabayashi K, Tanaka T, Nonaka A, Uchida A, et al. COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis. Proc Natl Acad Sci U S A. 2009;106:5819–24.

    Article  PubMed  CAS  Google Scholar 

  84. Wakabayashi K, Okamura M, Tsutsumi S, Nishikawa NS, Tanaka T, Sakakibara I, et al. The peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha heterodimer targets the histone modification enzyme PR-Set7/Setd8 gene and regulates adipogenesis through a positive feedback loop. Mol Cell Biol. 2009;29:3544–55.

    Article  PubMed  CAS  Google Scholar 

  85. Li M, Wu H, Luo Z, Xia Y, Guan J, Wang T, et al. An atlas of DNA methylomes in porcine adipose and muscle tissues. Nat Commun. 2012;3:850.

    Article  PubMed  CAS  Google Scholar 

  86. Blow MJ, McCulley DJ, Li Z, Zhang T, Akiyama JA, Holt A, et al. ChIP-Seq identification of weakly conserved heart enhancers. Nat Genet. 2010;42:806–10.

    Article  PubMed  CAS  Google Scholar 

  87. He A, Kong SW, Ma Q, Pu WT. Co-occupancy by multiple cardiac transcription factors identifies transcriptional enhancers active in heart. Proc Natl Acad Sci U S A. 2011;108:5632–7.

    Article  PubMed  CAS  Google Scholar 

  88. Asp P, Blum R, Vethantham V, Parisi F, Micsinai M, Cheng J, et al. Genome-wide remodeling of the epigenetic landscape during myogenic differentiation. Proc Natl Acad Sci U S A. 2011;108:E149–58.

    Article  PubMed  Google Scholar 

  89. Kuo T, Lew MJ, Mayba O, Harris CA, Speed TP, Wang J-C. Genome-wide analysis of glucocorticoid receptor-binding sites in myotubes identifies gene networks modulating insulin signaling. Proc Natl Acad Sci U S A. 2012;109:11160–5.

    Article  PubMed  CAS  Google Scholar 

  90. Li S, Liu C, Li N, Hao T, Han T, Hill DE, et al. Genome-wide coactivation analysis of PGC-1alpha identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metab. 2008;8:105–17.

    Article  PubMed  CAS  Google Scholar 

  91. Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science. 2011;331:1315–9.

    Article  PubMed  CAS  Google Scholar 

  92. Sun Z, Miller RA, Patel RT, Chen J, Dhir R, Wang H, et al. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat Med. 2012;18:934–42.

    Google Scholar 

  93. • Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi PG, Fogarty MP, et al. A map of open chromatin in human pancreatic islets. Nat Genet. 2010;42:255–9. This and the next papers reported generation of a map of open chromatin in human pancreatic islets and demonstrated its utility in identifying the putative causative SNPs discovered in genome-wide association studies of type 2 diabetes.

    Article  PubMed  CAS  Google Scholar 

  94. • Stitzel ML, Sethupathy P, Pearson DS, Chines PS, Song L, Erdos MR, et al. Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab. 2010;12:443–55. This and the previous papers reported generation of a map of open chromatin in human pancreatic islets and demonstrated its utility in identifying the putative causative SNPs discovered in genome-wide association studies of type 2 diabetes.

    Article  PubMed  CAS  Google Scholar 

  95. Bhandare R, Schug J, Le Lay J, Fox A, Smirnova O, Liu C, et al. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res. 2010;20:428–33.

    Article  PubMed  CAS  Google Scholar 

  96. Hoffman BG, Robertson G, Zavaglia B, Beach M, Cullum R, Lee S, et al. Locus co-occupancy, nucleosome positioning, and H3K4me1 regulate the functionality of FOXA2-, HNF4A-, and PDX1-bound loci in islets and liver. Genome Res. 2010;20:1037–51.

    Article  PubMed  CAS  Google Scholar 

  97. Pirola L, Balcerczyk A, Tothill RW, Haviv I, Kaspi A, Lunke S, et al. Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Res. 2011;21:1601–15.

    Article  PubMed  CAS  Google Scholar 

  98. Miao F, Wu X, Zhang L, Yuan Y-C, Riggs AD, Natarajan R. Genome-wide analysis of histone lysine methylation variations caused by diabetic conditions in human monocytes. J Biol Chem. 2007;282:13854–63.

    Article  PubMed  CAS  Google Scholar 

  99. Miao F, Smith DD, Zhang L, Min A, Feng W, Natarajan R. Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation: an epigenetic study in diabetes. Diabetes. 2008;57:3189–98.

    Article  PubMed  CAS  Google Scholar 

  100. Yamauchi T, Oike Y, Kamon J, Waki H, Komeda K, Tsuchida A, et al. Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. Nat Genet. 2002;30:221–6.

    Article  PubMed  CAS  Google Scholar 

  101. •• Inagaki T, Tachibana M, Magoori K, Kudo H, Tanaka T, Okamura M, et al. Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice. Genes Cells. 2009;14:991–1001. This and the next papers demonstrated that loss of a single histone-modifying enzyme have impact on adiposity.

    Article  PubMed  CAS  Google Scholar 

  102. •• Tateishi K, Okada Y, Kallin EM, Zhang Y. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature. 2009;458:757–61. This and the previous papers demonstrated that loss of a single histone-modifying enzyme have impact on adiposity.

    Article  PubMed  CAS  Google Scholar 

  103. Hino S, Sakamoto A, Nagaoka K, Anan K, Wang Y, Mimasu S, et al. FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat Commun. 2012;3:758.

    Article  PubMed  CAS  Google Scholar 

  104. Musri MM, Carmona MC, Hanzu FA, Kaliman P, Gomis R, Párrizas M. Histone demethylase LSD1 regulates adipogenesis. J Biol Chem. 2010;285:30034–41.

    Article  PubMed  CAS  Google Scholar 

  105. Wang L, Jin Q, Lee J-E, Su I, Ge K. Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc Natl Acad Sci U S A. 2010;107:7317–22.

    Article  PubMed  CAS  Google Scholar 

  106. Kamei Y, Suganami T, Ehara T, Kanai S, Hayashi K, Yamamoto Y, et al. Increased expression of DNA methyltransferase 3a in obese adipose tissue: studies with transgenic mice. Obesity. 2010;18:314–21.

    Article  PubMed  CAS  Google Scholar 

  107. Cho Y, Hong S, Jin Q, Wang L, Lee J-E, Gavrilova O, et al. Histone methylation regulator PTIP is required for PPARgamma and C/EBPalpha expression and adipogenesis. Cell Metab. 2009;10:27–39.

    Article  PubMed  CAS  Google Scholar 

  108. Leonardsson G, Steel JH, Christian M, Pocock V, Milligan S, Bell J, et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci U S A. 2004;101:8437–42.

    Article  PubMed  CAS  Google Scholar 

  109. Picard F, Géhin M, Annicotte J-S, Rocchi S, Champy M-F, O’Malley BW, et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell. 2002;111:931–41.

    Article  PubMed  CAS  Google Scholar 

  110. Wang Z, Qi C, Krones A, Woodring P, Zhu X, Reddy JK, et al. Critical roles of the p160 transcriptional coactivators p/CIP and SRC-1 in energy balance. Cell Metab. 2006;3:111–22.

    Article  PubMed  CAS  Google Scholar 

  111. Li P, Fan W, Xu J, Lu M, Yamamoto H, Auwerx J, et al. Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity. Cell. 2011;147:815–26.

    Article  PubMed  CAS  Google Scholar 

  112. Reilly SM, Bhargava P, Liu S, Gangl MR, Gorgun C, Nofsinger RR, et al. Nuclear receptor corepressor SMRT regulates mitochondrial oxidative metabolism and mediates aging-related metabolic deterioration. Cell Metab. 2010;12:643–53.

    Article  PubMed  CAS  Google Scholar 

  113. Nofsinger RR, Li P, Hong S, Jonker JW, Barish GD, Ying H, et al. SMRT repression of nuclear receptors controls the adipogenic set point and metabolic homeostasis. Proc Natl Acad Sci U S A. 2008;105:20021–6.

    Google Scholar 

  114. Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008;454:463–9.

    Article  PubMed  CAS  Google Scholar 

  115. Xu C-R, Cole PA, Meyers DJ, Kormish J, Dent S, Zaret KS. Chromatin “prepattern” and histone modifiers in a fate choice for liver and pancreas. Science. 2011;332:963–6.

    Article  PubMed  CAS  Google Scholar 

  116. • Chen H, Gu X, Su I, Bottino R, Contreras JL, Tarakhovsky A, et al. Polycomb protein Ezh2 regulates pancreatic beta-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev. 2009;23:975–85. This and the next papers showed that regulation of histone-modifying enzymes play a critical role in pancreatic beta-cell proliferation.

    Article  PubMed  CAS  Google Scholar 

  117. • Dhawan S, Tschen S-I, Bhushan A. BMI-1 regulates the Ink4a/Arf locus to control pancreatic beta-cell proliferation. Genes Dev. 2009;23:906–11. This and the previous papers showed that regulation of histone-modifying enzymes play a critical role in pancreatic beta-cell proliferation.

    Article  PubMed  CAS  Google Scholar 

  118. Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, et al. PDGF signalling controls age-dependent proliferation in pancreatic β-cells. Nature. 2011;478:349–55.

    Article  PubMed  CAS  Google Scholar 

  119. Papizan JB, Singer RA, Tschen S-I, Dhawan S, Friel JM, Hipkens SB, et al. Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming. Genes Dev. 2011;25:2291–305.

    Article  PubMed  CAS  Google Scholar 

  120. Barrès R, Osler ME, Yan J, Rune A, Fritz T, Caidahl K, et al. Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab. 2009;10:189–98.

    Article  PubMed  CAS  Google Scholar 

  121. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455:406–10.

    Article  PubMed  CAS  Google Scholar 

  122. Duteil D, Chambon C, Ali F, Malivindi R, Zoll J, Kato S, et al. The transcriptional coregulators TIF2 and SRC-1 regulate energy homeostasis by modulating mitochondrial respiration in skeletal muscles. Cell Metab. 2010;12:496–508.

    Article  PubMed  CAS  Google Scholar 

  123. Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010;140:280–93.

    Article  PubMed  CAS  Google Scholar 

  124. Pan D, Mao C, Zou T, Yao AY, Cooper MP, Boyartchuk V, et al. The histone demethylase jhdm1a regulates hepatic gluconeogenesis. PLoS Genet. 2012;8:e1002761.

    Article  PubMed  CAS  Google Scholar 

  125. Winkler R, Benz V, Clemenz M, Bloch M, Foryst-Ludwig A, Wardat S, et al. Histone deacetylase 6 (HDAC6) is an essential modifier of glucocorticoid-induced hepatic gluconeogenesis. Diabetes. 2012;61:513–23.

    Article  PubMed  CAS  Google Scholar 

  126. Ehara T, Kamei Y, Takahashi M, Yuan X, Kanai S, Tamura E, et al. Role of DNA methylation in the regulation of lipogenic glycerol-3-phosphate acyltransferase 1 gene expression in the mouse neonatal liver. Diabetes 2012;61:2442–50.

    Article  Google Scholar 

  127. El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205:2409–17.

    Article  PubMed  CAS  Google Scholar 

  128. Villeneuve LM, Reddy MA, Lanting LL, Wang M, Meng L, Natarajan R. Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes. Proc Natl Acad Sci U S A. 2008;105:9047–52.

    Article  PubMed  CAS  Google Scholar 

  129. De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J. 2009;28:3341–52.

    Article  PubMed  CAS  Google Scholar 

  130. Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol. 2010;11:936–44.

    Article  PubMed  CAS  Google Scholar 

  131. Reddy M, Natarajan R. Epigenetic mechanisms in diabetic vascular complications. Cardiovasc Res. 2011;90:421–9.

    Article  PubMed  CAS  Google Scholar 

  132. Kruidenier L, Chung C, Cheng Z, Liddle J, Che K, Joberty G, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 2012;488:404–8.

    Google Scholar 

  133. Yamauchi T, Hara K, Maeda S, Yasuda K, Takahashi A, Horikoshi M, et al. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat Genet. 2010;42:864–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Conflicts of interest: H. Waki: has received grants the following grants: a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS) (#20890055, #21790864, #23791021); a Grant-in-Aid for Scientific Research on Innovative Areas from Ministry of Education, Culture, Sports, Science and Technology (MEXT) (#23126506, #23126101), the Kanae Foundation for the Promotion of Medical Science; Takeda Science Foundation; Japan Foundation for Applied Enzymology; Sankyo Foundation of Life Science; Banyu Life Science Foundation International and Novartis Pharma K.K.; T. Yamauchi: Funding Program for Next Generation World-Leading Researchers (NEXT Program) from Cabinet Office, Government of Japan and Novartis Pharma K.K.; T. Kadowaki: has received grants the following grants: A grant from Ministry of Health, Labour and Welfare (#11103444) ; Grant-in-aid for Scientific Research (S) Japan Society for the Promotion of Science (#08090448); Translational Systems Biology and Medicine Initiative, the Ministry of Education, Culture, Sports, Science and Technology of Japan (#11105302); Global center of education and research for chemical biology of the diseases, the Ministry of Education, Culture, Sports, Science and Technology of Japan (#08080172); Grants from Ministry of Health, Labor, and Welfare (#11103444, #24080101); and a grant from the Leading Project of Ministry of Education, Culture, Sports, Science, and Technology Japan (#09151060)

Author information

Authors and Affiliations

  1. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo, Tokyo, 113-8655, Japan

    Hironori Waki, Toshimasa Yamauchi & Takashi Kadowaki

  2. Functional Regulation of Adipocytes, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo, Tokyo, 113-8655, Japan

    Hironori Waki

Authors
  1. Hironori Waki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshimasa Yamauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Kadowaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takashi Kadowaki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Waki, H., Yamauchi, T. & Kadowaki, T. The Epigenome and Its Role in Diabetes. Curr Diab Rep 12, 673–685 (2012). https://doi.org/10.1007/s11892-012-0328-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-012-0328-x

Keywords

Search

Navigation