PARylation, DNA (De)methylation, and Diabetes

  • Melita VidakovićEmail author
  • Anja Tolić
  • Nevena Grdović
  • Mirunalini Ravichandran
  • Tomasz P. Jurkowski
Reference work entry


Diabetes and diabetic complications, autoimmunity and inflammatory diseases, have recently become the focus of epigenetic therapy, since with epigenetic drugs it is possible to reverse aberrant gene expression profiles associated with the disease states. For diabetes, the therapy challenges depend on identifying the most appropriate molecular target and its influence on a relevant gene product. This chapter summarizes the current view on the interplay between ten-eleven translocation (TETs) and the poly(ADP-ribose) polymerase (PARPs) family of enzymes in regulating DNA methylation and how this interplay could be targeted to attenuate diabetes. This molecular interchange jigsaw puzzle is emerging as an important focus of research, and we can expect to see further advances in the elucidation of its role in diabetes as well as other pathologies. Moreover, the possibility for designating specific PARP-1 inhibitors as potential “EPI-drugs” for diabetes prevention/attenuation is also discussed. Understanding the epigenetic machinery and the differential roles of its components is essential for the development of targeted epigenetic therapies for diseases.


Diabetes DNA methylation DNA demethylation DNMT enzymes Epigenetic drug targets Chromatin architecture PARylation PARP-1 inhibitors TET enzymes 

List of Abbreviations














base excision repair






clustered regularly interspaced short palindromic repeats/associated protein-9 nuclease


DNA methyltransferases


nicotinamide adenine dinucleotide


poly(ADP-ribose) polymerase family of enzymes


poly(ADP-ribose) polymers




poly(ADP-ribose) glycohydrolases


reactive oxygen/nitrogen species


type 1 diabetes


type 2 diabetes


thymine-DNA glycosylase


ten-eleven translocation family of enzymes





This work was supported by the Alexander von Humboldt foundation, program for funding a Research Group Linkage (2014) and Ministry of Education, Science and Technological Development of the Republic of Serbia, Grant No. 173020. This article is based upon work from COST Action (CM1406), supported by COST (European Cooperation in Science and Technology), participants MV and TPJ.


  1. Agardh E, Lundstig A, Perfilyev A et al (2015) Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy. BMC Med 13:182CrossRefGoogle Scholar
  2. Arguelles AO, Meruvu S, Bowman JD et al (2016) Are epigenetic drugs for diabetes and obesity at our door step? Drug Discov Today 21:499–509CrossRefGoogle Scholar
  3. Ba X, Garg NJ (2011) Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol 178:946–955CrossRefGoogle Scholar
  4. Bai P (2015) Biology of poly(ADP-Ribose) polymerases: the factotums of cell maintenance. Mol Cell 58:947–958CrossRefGoogle Scholar
  5. Bouwens L, Rooman I (2005) Regulation of pancreatic beta-cell mass. Physiol Rev 85:1255–1270CrossRefGoogle Scholar
  6. Burkart V, Wang ZQ, Radons J et al (1999) Mice lacking the poly(ADP-ribose) polymerase gene are resistant to pancreatic beta-cell destruction and diabetes development induced by streptozocin. Nat Med 5:314–319CrossRefGoogle Scholar
  7. Caramori ML, Kim Y, Moore JH et al (2012) Gene expression differences in skin fibroblasts in identical twins discordant for type 1 diabetes. Diabetes 61:739–744CrossRefGoogle Scholar
  8. Carretero MV, Torres L, Latasa U et al (1998) Transformed but not normal hepatocytes express UCP2. FEBS Lett 439:55–58CrossRefGoogle Scholar
  9. Chen CC, Wang KY, Shen CK (2012) The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases. J Biol Chem 287:33116–33121CrossRefGoogle Scholar
  10. Christensen BC, Houseman EA, Marsit CJ et al (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5:e1000602CrossRefGoogle Scholar
  11. Ciccarone F, Klinger FG, Catizone A et al (2012) Poly(ADP-ribosyl)ation acts in the DNA demethylation of mouse primordial germ cells also with DNA damage-independent roles. PLoS One 7:e46927CrossRefGoogle Scholar
  12. Ciccarone F, Valentini E, Bacalini MG et al (2014) Poly(ADP-ribosyl)ation is involved in the epigenetic control of TET1 gene transcription. Oncotarget 5:10356–10367CrossRefGoogle Scholar
  13. Ciccarone F, Valentini E, Zampieri M et al (2015) 5mC-hydroxylase activity is influenced by the PARylation of TET1 enzyme. Oncotarget 6:24333–24347CrossRefGoogle Scholar
  14. Dayeh T, Volkov P, Salo S et al (2014) Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet 10:e1004160CrossRefGoogle Scholar
  15. Dhawan S, Georgia S, Tschen SI et al (2011) Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell 20:419–429CrossRefGoogle Scholar
  16. Dhliwayo N, Sarras MP Jr, Luczkowski E et al (2014) Parp inhibition prevents ten-eleven translocase enzyme activation and hyperglycemia-induced DNA demethylation. Diabetes 63:3069–3076CrossRefGoogle Scholar
  17. Dodge JE, Okano M, Dick F et al (2005) Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J Biol Chem 280:17986–17991CrossRefGoogle Scholar
  18. Doege CA, Inoue K, Yamashita T et al (2012) Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488:652–655CrossRefGoogle Scholar
  19. Fujiki K, Shinoda A, Kano F et al (2013) PPARgamma-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine. Nat Commun 4:2262CrossRefGoogle Scholar
  20. Gallou-Kabani C, Junien C (2005) Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic. Diabetes 54:1899–1906CrossRefGoogle Scholar
  21. Grdović N, Dinic S, Mihailovic M et al (2014) CXC chemokine ligand 12 protects pancreatic beta-cells from necrosis through Akt kinase-mediated modulation of poly(ADP-ribose) polymerase-1 activity. PLoS One 9:e101172CrossRefGoogle Scholar
  22. Guastafierro T, Cecchinelli B, Zampieri M et al (2008) CCCTC-binding factor activates PARP-1 affecting DNA methylation machinery. J Biol Chem 283:21873–21880CrossRefGoogle Scholar
  23. Guastafierro T, Catizone A, Calabrese R et al (2013) ADP-ribose polymer depletion leads to nuclear Ctcf re-localization and chromatin rearrangement(1). Biochem J 449:623–630CrossRefGoogle Scholar
  24. Guo JU, Su Y, Zhong C et al (2011) Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145:423–434CrossRefGoogle Scholar
  25. Ha HC, Snyder SH (1999) Poly(ADP-ribose) polymerase is a mediator of necrotic cell death by ATP depletion. Proc Natl Acad Sci U S A 96:13978–13982CrossRefGoogle Scholar
  26. Hermann A, Goyal R, Jeltsch A (2004) The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem 279:48350–48359CrossRefGoogle Scholar
  27. Hill PW, Amouroux R, Hajkova P (2014) DNA demethylation, Tet proteins and 5-hydroxymethylcytosine in epigenetic reprogramming: an emerging complex story. Genomics 104:324–333CrossRefGoogle Scholar
  28. Ito S, D'Alessio AC, Taranova OV et al (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466:1129–1133CrossRefGoogle Scholar
  29. Ito S, Shen L, Dai Q et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–1303CrossRefGoogle Scholar
  30. Jeltsch A, Jurkowska RZ (2014) New concepts in DNA methylation. Trends Biochem Sci 39:310–318CrossRefGoogle Scholar
  31. Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293:1068–1070CrossRefGoogle Scholar
  32. Kagiwada S, Kurimoto K, Hirota T et al (2013) Replication-coupled passive DNA demethylation for the erasure of genome imprints in mice. EMBO J 32:340–353CrossRefGoogle Scholar
  33. Khan JA, Forouhar F, Tao X et al (2007) Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery. Expert Opin Ther Targets 11:695–705CrossRefGoogle Scholar
  34. Kohli RM, Zhang Y (2013) TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502:472–479CrossRefGoogle Scholar
  35. 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 51:615–622CrossRefGoogle Scholar
  36. Masiello P, Novelli M, Fierabracci V et al (1990) Protection by 3-aminobenzamide and nicotinamide against streptozotocin-induced beta-cell toxicity in vivo and in vitro. Res Commun Chem Pathol Pharmacol 69:17–32PubMedGoogle Scholar
  37. Muller U, Bauer C, Siegl M et al (2014) TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation. Nucleic Acids Res 42:8592–8604CrossRefGoogle Scholar
  38. Pacher P, Szabo C (2007) Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc Drug Rev 25:235–260CrossRefGoogle Scholar
  39. Pandya KG, Patel MR, Lau-Cam CA (2010) Comparative study of the binding characteristics to and inhibitory potencies towards PARP and in vivo antidiabetogenic potencies of taurine, 3-aminobenzamide and nicotinamide. J Biomed Sci 17(Suppl 1):S16CrossRefGoogle Scholar
  40. Park JH, Stoffers DA, Nicholls RD et al (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 118:2316–2324CrossRefGoogle Scholar
  41. Paul DS, Teschendorff AE, Dang MA et al (2016) Increased DNA methylation variability in type 1 diabetes across three immune effector cell types. Nat Commun 7:13555CrossRefGoogle Scholar
  42. Pennarossa G, Maffei S, Campagnol M et al (2013) Brief demethylation step allows the conversion of adult human skin fibroblasts into insulin-secreting cells. Proc Natl Acad Sci U S A 110:8948–8953CrossRefGoogle Scholar
  43. Pirola CJ, Scian R, Gianotti TF et al (2015) Epigenetic modifications in the biology of nonalcoholic fatty liver disease: the role of DNA hydroxymethylation and TET proteins. Medicine (Baltimore) 94:e1480CrossRefGoogle Scholar
  44. Rakyan VK, Beyan H, Down TA et al (2011) Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet 7:e1002300CrossRefGoogle Scholar
  45. Reale A, Matteis GD, Galleazzi G et al (2005) Modulation of DNMT1 activity by ADP-ribose polymers. Oncogene 24:13–19CrossRefGoogle Scholar
  46. Schuhwerk H, Atteya R, Siniuk K et al (2016) PARPing for balance in the homeostasis of poly(ADP-ribosyl)ation. Semin Cell Dev Biol.
  47. Sookoian S, Rosselli MS, Gemma C et al (2010) Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter. Hepatology 52:1992–2000CrossRefGoogle Scholar
  48. Stead LM, Brosnan JT, Brosnan ME et al (2006) Is it time to reevaluate methyl balance in humans? Am J Clin Nutr 83:5–10CrossRefGoogle Scholar
  49. Stepper P, Kungulovski G, Jurkowska RZ et al (2016) Efficient targeted DNA methylation with chimeric dCas9-Dnmt3a-Dnmt3L methyltransferase. Nucleic Acids Res 45(4):1703–713Google Scholar
  50. Szabo C, Virag L, Cuzzocrea S et al (1998) Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthase. Proc Natl Acad Sci U S A 95:3867–3872CrossRefGoogle Scholar
  51. Szabo C, Biser A, Benko R et al (2006) Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Leprdb/db mice. Diabetes 55:3004–3012CrossRefGoogle Scholar
  52. 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 21:371–383CrossRefGoogle Scholar
  53. Virag L, Szabo C (2002) The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev 54:375–429CrossRefGoogle Scholar
  54. Volkmar M, Dedeurwaerder S, Cunha DA et al (2012) DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 31:1405–1426CrossRefGoogle Scholar
  55. Williams KT, Garrow TA, Schalinske KL (2008) Type I diabetes leads to tissue-specific DNA hypomethylation in male rats. J Nutr 138:2064–69CrossRefGoogle Scholar
  56. Wurzer G, Herceg Z, Wesierska-Gadek J (2000) Increased resistance to anticancer therapy of mouse cells lacking the poly(ADP-ribose) polymerase attributable to up-regulation of the multidrug resistance gene product P-glycoprotein. Cancer Res 60:4238–4244PubMedGoogle Scholar
  57. Yokochi T, Robertson KD (2002) Preferential methylation of unmethylated DNA by Mammalian de novo DNA methyltransferase Dnmt3a. J Biol Chem 277:11735–11745CrossRefGoogle Scholar
  58. Yokomori N, Tawata M, Onaya T (1999) DNA demethylation during the differentiation of 3T3-L1 cells affects the expression of the mouse GLUT4 gene. Diabetes 48:685–690CrossRefGoogle Scholar
  59. Yu W, Ginjala V, Pant V et al (2004) Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Nat Genet 36:1105–1110CrossRefGoogle Scholar
  60. Zampieri M, Passananti C, Calabrese R et al (2009) Parp1 localizes within the Dnmt1 promoter and protects its unmethylated state by its enzymatic activity. PLoS One 4:e4717CrossRefGoogle Scholar
  61. Zardo G, D'Erme M, Reale A et al (1997) Does poly(ADP-ribosyl)ation regulate the DNA methylation pattern? Biochemistry 36:7937–7943CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Melita Vidaković
    • 3
    Email author
  • Anja Tolić
    • 1
  • Nevena Grdović
    • 1
  • Mirunalini Ravichandran
    • 2
  • Tomasz P. Jurkowski
    • 2
  1. 1.Institute for Biological ResearchUniversity of BelgradeBelgradeSerbia
  2. 2.Institute of BiochemistryUniversity of StuttgartStuttgartGermany
  3. 3.Department of Molecular Biology, Institute for Biological Research Siniša StankovićUniversity of BelgradeBelgradeSerbia

Personalised recommendations