The inflammatory effect of epigenetic factors and modifications in type 2 diabetes

  • Mohamad Akbari
  • Vahideh Hassan-ZadehEmail author


Inflammation has a central role in the etiology of type 2 diabetes (T2D) and its complications. Both genetic and epigenetic factors have been implicated in the development of T2D-associated inflammation. Epigenetic mechanisms regulate the function of several components of the immune system. Diabetic conditions trigger aberrant epigenetic alterations that contribute to the progression of insulin resistance and β-cell dysfunction by induction of inflammatory responses. Thus, targeting epigenetic factors and modifications, as one of the underlying causes of inflammation, could lead to the development of novel immune-based strategies for the treatment of T2D. The aim of this review is to provide an overview of the epigenetic mechanisms involved in the propagation and perpetuation of chronic inflammation in T2D. We also discuss the possible anti-inflammatory approaches that target epigenetic factors for the treatment of T2D.


Type 2 diabetes Inflammation Epigenetics Immunometabolism Epigenetic therapy 



This work was supported by the Iran National Science Foundation with the award number 94000647.

Compliance with ethical standards

Conflict of interest

There are no commercial affiliations to declare.

Supplementary material

10787_2019_663_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 20 kb)


  1. Akbari M, Hassan-Zadeh V (2018) Hyperglycemia affects the expression of inflammatory genes in peripheral blood mononuclear cells of patients with type 2 diabetes. Immunol Invest 47:654–665PubMedCrossRefGoogle Scholar
  2. Arab Sadeghabadi Z, Nourbakhsh M, Pasalar P, Emamgholipour S, Golestani A, Larijani B, Razzaghy-Azar M (2018) Reduced gene expression of sirtuins and active AMPK levels in children and adolescents with obesity and insulin resistance. Obes Res Clin Pract 12:167–173PubMedCrossRefPubMedCentralGoogle Scholar
  3. Babu M, Devi TD, Mäkinen P, Kaikkonen M, Lesch HP, Junttila S, Laiho A, Ghimire B, Gyenesei A, Ylä-Herttuala S (2015) Differential promoter methylation of macrophage genes is associated with impaired vascular growth in ischemic muscles of hyperlipidemic and type 2 diabetic micenovelty and significance: genome-wide promoter methylation study. Circ Res 117:289–299PubMedCrossRefGoogle Scholar
  4. Bae EJ (2017) Sirtuin 6, a possible therapeutic target for type 2 diabetes. Arch Pharm Res 40:1380–1389PubMedCrossRefGoogle Scholar
  5. Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U, Kundu TK (2004) Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem 279:51163–51171PubMedCrossRefGoogle Scholar
  6. Balasubramanyam M, Aravind S, Gokulakrishnan K, Prabu P, Sathishkumar C, Ranjani H, Mohan V (2011) Impaired miR-146a expression links subclinical inflammation and insulin resistance in Type 2 diabetes. Mol Cell Biochem 351:197–205PubMedCrossRefGoogle Scholar
  7. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395PubMedPubMedCentralCrossRefGoogle Scholar
  8. Batista PJ, Chang HY (2013) Long noncoding RNAs: cellular address codes in development and disease. Cell 152:1298–1307PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bhatt D, Ghosh S (2014) Regulation of the NF-κB-mediated transcription of inflammatory genes. Front Immunol 5:71PubMedPubMedCentralCrossRefGoogle Scholar
  10. Biswas S, Thomas AA, Chen S, Aref-Eshghi E, Feng B, Gonder J, Sadikovic B, Chakrabarti S (2018) MALAT1: an epigenetic regulator of inflammation in diabetic retinopathy. Sci Rep 8:6526PubMedPubMedCentralCrossRefGoogle Scholar
  11. Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, Garcia-Flores Y, Luong M, Devrekanli A, Xu J, Sun G, Tay J, Linsley PS, Baltimore D (2011) miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med 208:1189–1201PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bowers EM, Yan G, Mukherjee C, Orry A, Wang L, Holbert MA, Crump NT, Hazzalin CA, Liszczak G, Yuan H, Larocca C, Saldanha SA, Abagyan R, Sun Y, Meyers DJ, Marmorstein R, Mahadevan LC, Alani RM, Cole PA (2010) Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem Biol 17:471–482PubMedPubMedCentralCrossRefGoogle Scholar
  13. Brasacchio D, Okabe J, Tikellis C, Balcerczyk A, George P, Baker EK, Calkin AC, Brownlee M, Cooper ME, El-Osta A (2009) Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes 58:1229–1236PubMedPubMedCentralCrossRefGoogle Scholar
  14. Buerki C, Rothgiesser KM, Valovka T, Owen HR, Rehrauer H, Fey M, Lane WS, Hottiger MO (2008) Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65. Nucleic Acids Res 36:1665–1680PubMedPubMedCentralCrossRefGoogle Scholar
  15. Calao M, Burny A, Quivy V, Dekoninck A, Van Lint C (2008) A pervasive role of histone acetyltransferases and deacetylases in an NF-kappaB-signaling code. Trends Biochem Sci 33:339–349PubMedCrossRefPubMedCentralGoogle Scholar
  16. Cao F, Zwinderman MRH, Dekker FJ (2018) The process and strategy for developing selective histone deacetylase 3 inhibitors. Molecules 23:551PubMedCentralCrossRefGoogle Scholar
  17. Chen L, Fischle W, Verdin E, Greene WC (2001) Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293:1653–1657CrossRefGoogle Scholar
  18. Chen LF, Mu Y, Greene WC (2002) Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. EMBO J 21:6539–6548PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chen X, Barozzi I, Termanini A, Prosperini E, Recchiuti A, Dalli J, Mietton F, Matteoli G, Hiebert S, Natoli G (2012) Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc Natl Acad Sci USA 109:E2865–E2874PubMedCrossRefPubMedCentralGoogle Scholar
  20. Chou DH-C, Holson EB, Wagner FF, Tang AJ, Maglathlin RL, Lewis TA, Schreiber SL, Wagner BK (2012) Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem Biol 19:669–673PubMedPubMedCentralCrossRefGoogle Scholar
  21. Crujeiras AB, Parra D, Goyenechea E, Martinez JA (2008) Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur J Clin Investig 38:672–678CrossRefGoogle Scholar
  22. Dai H, Sinclair DA, Ellis JL, Steegborn C (2018) Sirtuin activators and inhibitors: promises, achievements, and challenges. Pharmacol Ther 188:140–154PubMedPubMedCentralCrossRefGoogle Scholar
  23. Dayeh T, Tuomi T, Almgren P, Perfilyev A, Jansson P-A, de Mello VD, Pihlajamäki J, Vaag A, Groop L, Nilsson E (2016) DNA methylation of loci within ABCG1 and PHOSPHO1 in blood DNA is associated with future type 2 diabetes risk. Epigenetics 11:482–488PubMedPubMedCentralCrossRefGoogle Scholar
  24. De Kreutzenberg SV, Ceolotto G, Papparella I, Bortoluzzi A, Semplicini A, Dalla Man C, Cobelli C, Fadini GP, Avogaro A (2010) Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes 59:1006–1015PubMedPubMedCentralCrossRefGoogle Scholar
  25. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, Hu FB, Kahn CR, Raz I, Shulman GI (2015) Type 2 diabetes mellitus. Nat Rev Dis Primers 1:15019PubMedCrossRefGoogle Scholar
  26. Di Lorenzo A, Bedford MT (2011) Histone arginine methylation. FEBS Lett 585:2024–2031PubMedCrossRefGoogle Scholar
  27. Dinarello CA, Donath MY, Mandrup-Poulsen T (2010) Role of IL-1β in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes 17:314–321PubMedGoogle Scholar
  28. Dirice E, Ng RWS, Martinez R, Hu J, Wagner FF, Holson EB, Wagner BK, Kulkarni RN (2017) Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes. J Biol Chem 292:17598–17608PubMedPubMedCentralCrossRefGoogle Scholar
  29. Donath MY (2014) Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov 13:465–476PubMedCrossRefGoogle Scholar
  30. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107PubMedCrossRefGoogle Scholar
  31. Ea CK, Baltimore D (2009) Regulation of NF-kappaB activity through lysine monomethylation of p65. Proc Natl Acad Sci USA 106:18972–18977PubMedCrossRefPubMedCentralGoogle Scholar
  32. Ehses JA, Ellingsgaard H, Böni-Schnetzler M, Donath MY (2009) Pancreatic islet inflammation in type 2 diabetes: from α and β cell compensation to dysfunction. Arch Physiol Biochem 115:240–247PubMedCrossRefGoogle Scholar
  33. El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, Cooper ME, Brownlee M (2008) Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 205:2409–2417PubMedPubMedCentralCrossRefGoogle Scholar
  34. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N (2014) Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 105:141–150PubMedCrossRefGoogle Scholar
  35. Esteller M (2007) Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet 16:R50–R59PubMedPubMedCentralCrossRefGoogle Scholar
  36. Fang F, Li G, Jing M, Xu L, Li Z, Li M, Yang C, Liu Y, Qian G, Hu X, Li G, Xie Y, Feng C, Li X, Pan J, Li Y, Feng X, Li Y (2019) C646 modulates inflammatory response and antibacterial activity of macrophage. Int Immunopharmacol 74:105736PubMedCrossRefPubMedCentralGoogle Scholar
  37. Ghosh S, Banerjee S, Sil PC (2015) The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: a recent update. Food Chem Toxicol 83:111–124PubMedCrossRefGoogle Scholar
  38. Gillespie J, Savic S, Wong C, Hempshall A, Inman M, Emery P, Grigg R, McDermott MF (2012) Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum 64:418–422PubMedCrossRefGoogle Scholar
  39. Goldfine AB, Shoelson SE (2017) Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest 127:83–93PubMedPubMedCentralCrossRefGoogle Scholar
  40. Gonzales AM, Orlando RA (2008) Curcumin and resveratrol inhibit nuclear factor-kappaB-mediated cytokine expression in adipocytes. Nutr Metab (Lond) 5:17CrossRefGoogle Scholar
  41. Greer EL, Shi Y (2012) Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 13:343–357PubMedPubMedCentralCrossRefGoogle Scholar
  42. Gu ML, Wang YM, Zhou XX, Yao HP, Zheng S, Xiang Z, Ji F (2016) An inhibitor of the acetyltransferases CBP/p300 exerts antineoplastic effects on gastrointestinal stromal tumor cells. Oncol Rep 36:2763–2770PubMedCrossRefGoogle Scholar
  43. Gupta SC, Tyagi AK, Deshmukh-Taskar P, Hinojosa M, Prasad S, Aggarwal BB (2014) Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch Biochem Biophys 559:91–99PubMedCrossRefGoogle Scholar
  44. Guzik TJ, Cosentino F (2018) Epigenetics and immunometabolism in diabetes and aging. Antioxid Redox Signal 29:257–274PubMedPubMedCentralCrossRefGoogle Scholar
  45. Hassan FU, Rehman MS, Khan MS, Ali MA, Javed A, Nawaz A, Yang C (2019) Curcumin as an alternative epigenetic modulator: mechanism of action and potential effects. Front Genet 10:514PubMedPubMedCentralCrossRefGoogle Scholar
  46. Hausenblas HA, Schoulda JA, Smoliga JM (2015) Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus—systematic review and meta-analysis. Mol Nutr Food Res 59:147–159PubMedCrossRefGoogle Scholar
  47. Holoch D, Moazed D (2015) RNA-mediated epigenetic regulation of gene expression. Nat Rev Genet 16:71–84PubMedPubMedCentralCrossRefGoogle Scholar
  48. Huang B, Yang XD, Zhou MM, Ozato K, Chen LF (2009) Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA. Mol Cell Biol 29:1375–1387PubMedCrossRefGoogle Scholar
  49. Huang B, Yang XD, Lamb A, Chen LF (2010) Posttranslational modifications of NF-kappaB: another layer of regulation for NF-kappaB signaling pathway. Cell Signal 22:1282–1290PubMedPubMedCentralCrossRefGoogle Scholar
  50. Hui X, Zhang M, Gu P, Li K, Gao Y, Wu D, Wang Y, Xu A (2017) Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue. EMBO Rep 18:645–657PubMedPubMedCentralCrossRefGoogle Scholar
  51. Hyun K, Jeon J, Park K, Kim J (2017) Writing, erasing and reading histone lysine methylations. Exp Mol Med 49:e324PubMedPubMedCentralCrossRefGoogle Scholar
  52. Iachettini S, Trisciuoglio D, Rotili D, Lucidi A, Salvati E, Zizza P, Di Leo L, Del Bufalo D, Ciriolo MR, Leonetti C, Steegborn C, Mai A, Rizzo A, Biroccio A (2018) Pharmacological activation of SIRT6 triggers lethal autophagy in human cancer cells. Cell Death Dis 9:996PubMedPubMedCentralCrossRefGoogle Scholar
  53. Inagaki Y, Shiraki K, Sugimoto K, Yada T, Tameda M, Ogura S, Yamamoto N, Takei Y, Ito M (2016) Epigenetic regulation of proliferation and invasion in hepatocellular carcinoma cells by CBP/p300 histone acetyltransferase activity. Int J Oncol 48:533–540PubMedCrossRefGoogle Scholar
  54. Jain SK, Rains J, Croad J, Larson B, Jones K (2009) Curcumin supplementation lowers TNF-alpha, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-alpha, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats. Antioxid Redox Signal 11:241–249PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kaikkonen MU, Lam MT, Glass CK (2011) Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc Res 90:430–440PubMedPubMedCentralCrossRefGoogle Scholar
  56. Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, Chua KF (2009) SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB- dependent gene expression and organismal life span. Cell 136:62–74PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kiernan R, Bres V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, Jin DY, Emiliani S, Benkirane M (2003) Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J Biol Chem 278:2758–2766PubMedCrossRefGoogle Scholar
  58. Kim HJ, Kim SH, Yun J-M (2012) Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evid Based Complement Alternat Med 2012:639469PubMedPubMedCentralGoogle Scholar
  59. Kitada M, Ogura Y, Monno I, Koya D (2019) Sirtuins and type 2 diabetes: role in inflammation, oxidative stress, and mitochondrial function. Front Endocrinol (Lausanne) 10:187CrossRefGoogle Scholar
  60. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705PubMedCrossRefGoogle Scholar
  61. Kuang J, Zhang Y, Liu Q, Shen J, Pu S, Cheng S, Chen L, Li H, Wu T, Li R, Li Y, Zou M, Zhang Z, Jiang W, Xu G, Qu A, Xie W, He J (2017) Fat-specific SIRT6 ablation sensitizes mice to high-fat diet-induced obesity and insulin resistance by inhibiting lipolysis. Diabetes 66:1159–1171PubMedCrossRefGoogle Scholar
  62. Kuboyama T, Wahane S, Huang Y, Zhou X, Wong JK, Koemeter-Cox A, Martini M, Friedel RH, Zou H (2017) HDAC3 inhibition ameliorates spinal cord injury by immunomodulation. Sci Rep 7(1):8641. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Lappas M (2012) Anti-inflammatory properties of sirtuin 6 in human umbilical vein endothelial cells. Med Inflamm 2012:597514CrossRefGoogle Scholar
  64. Lasko LM, Jakob CG, Edalji RP, Qiu W, Montgomery D, Digiammarino EL, Hansen TM, Risi RM, Frey R, Manaves V, Shaw B, Algire M, Hessler P, Lam LT, Uziel T, Faivre E, Ferguson D, Buchanan FG, Martin RL, Torrent M, Chiang GG, Karukurichi K, Langston JW, Weinert BT, Choudhary C, de Vries P, Van Drie JH, McElligott D, Kesicki E, Marmorstein R, Sun C, Cole PA, Rosenberg SH, Michaelides MR, Lai A, Bromberg KD (2017) Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours. Nature 550:128–132PubMedPubMedCentralCrossRefGoogle Scholar
  65. Lee JH, Song MY, Song EK, Kim EK, Moon WS, Han MK, Park JW, Kwon KB, Park BH (2009) Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway. Diabetes 58:344–351PubMedPubMedCentralCrossRefGoogle Scholar
  66. Lee Y, Ka SO, Cha HN, Chae YN, Kim MK, Park SY, Bae EJ, Park BH (2017) Myeloid Sirtuin 6 deficiency causes insulin resistance in high-fat diet-fed mice by eliciting macrophage polarization toward an M1 phenotype. Diabetes 66:2659–2668PubMedCrossRefGoogle Scholar
  67. Leibowitz G, Ktorza A, Cerasi E (2014) The role of txnip in the pathophysiology of diabetes and its vascular complications: a concise review. Medicographia 36:391–397Google Scholar
  68. Leus NG, van der Wouden PE, van den Bosch T, Hooghiemstra WTR, Ourailidou ME, Kistemaker LE, Bischoff R, Gosens R, Haisma HJ, Dekker FJ (2016a) HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity. Biochem Pharmacol 108:58–74PubMedPubMedCentralCrossRefGoogle Scholar
  69. Leus NG, Zwinderman MR, Dekker FJ (2016b) Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-κB-mediated inflammation. Curr Opin Chem Biol 33:160–168PubMedPubMedCentralCrossRefGoogle Scholar
  70. Li M-F, Zhang R, Li T-T, Chen M-Y, Li L-X, Lu J-X, Jia W-P (2016) High glucose increases the expression of inflammatory cytokine genes in macrophages through H3K9 methyltransferase mechanism. J Interferon Cytokine Res 36:48–61PubMedCrossRefGoogle Scholar
  71. Liang F, Kume S, Koya D (2009) SIRT1 and insulin resistance. Nat Rev Endocrinol 5:367–373PubMedCrossRefPubMedCentralGoogle Scholar
  72. Ling C, Groop L (2009) Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58:2718–2725PubMedPubMedCentralCrossRefGoogle Scholar
  73. Liu Z, Chen L, Deng X, Song H, Liao Y, Zeng T, Zheng J, Li H (2012) Methylation status of CpG sites in the MCP-1 promoter is correlated to serum MCP-1 in Type 2 diabetes. J Endocrinol Invest 35:585–589PubMedPubMedCentralGoogle Scholar
  74. Lo Sasso G, Menzies KJ, Mottis A, Piersigilli A, Perino A, Yamamoto H, Schoonjans K, Auwerx J (2014) SIRT2 deficiency modulates macrophage polarization and susceptibility to experimental colitis. PLoS One 9:e103573PubMedPubMedCentralCrossRefGoogle Scholar
  75. Lo W-S, Trievel RC, Rojas JR, Duggan L, Hsu J-Y, Allis CD, Marmorstein R, Berger SL (2000) Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol Cell 5:917–926PubMedCrossRefPubMedCentralGoogle Scholar
  76. Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389:251–260PubMedCrossRefGoogle Scholar
  77. Lundh M, Christensen D, Nielsen MD, Richardson S, Dahllöf M, Skovgaard T, Berthelsen J, Dinarello C, Stevenazzi A, Mascagni P (2012) Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children. Diabetologia 55:2421–2431PubMedCrossRefGoogle Scholar
  78. Lundh M, Galbo T, Poulsen SS, Mandrup-Poulsen T (2015) Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes Obes Metab 17:703–707PubMedCrossRefGoogle Scholar
  79. Mandrup-Poulsen T (2013) Type 2 diabetes mellitus: a metabolic autoinflammatory disease. Dermatol Clin 31:495–506PubMedCrossRefGoogle Scholar
  80. Manzo F, Tambaro FP, Mai A, Altucci L (2009) Histone acetyltransferase inhibitors and preclinical studies. Expert Opin Ther Pat 19:761–774PubMedCrossRefGoogle Scholar
  81. Margueron R, Trojer P, Reinberg D (2005) The key to development: interpreting the histone code? Curr Opin Genet Dev 15:163–176PubMedCrossRefGoogle Scholar
  82. Matsui M, Corey DR (2017) Non-coding RNAs as drug targets. Nat Rev Drug Discov 16:167–179PubMedCrossRefGoogle Scholar
  83. Mattick JS, Makunin IV (2006) Non-coding RNA. Hum Mol Genet 15:R17–R29PubMedCrossRefGoogle Scholar
  84. Meier BC, Wagner BK (2014) Inhibition of HDAC3 as a strategy for developing novel diabetes therapeutics. Epigenomics 6:209–214PubMedCrossRefGoogle Scholar
  85. Mendes KL, Lelis DF, Santos SHS (2017) Nuclear sirtuins and inflammatory signaling pathways. Cytokine Growth Factor Rev 38:98–105PubMedCrossRefGoogle Scholar
  86. Miao F, Gonzalo IG, Lanting L, Natarajan R (2004) In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. J Biol Chem 279:18091–18097PubMedCrossRefGoogle Scholar
  87. Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, Cheung P, Kusumoto R, Kawahara TL, Barrett JC, Chang HY, Bohr VA, Ried T, Gozani O, Chua KF (2008) SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452:492–496PubMedPubMedCentralCrossRefGoogle Scholar
  88. Miranda TB, Jones PA (2007) DNA methylation: the nuts and bolts of repression. J Cell Physiol 213:384–390PubMedCrossRefGoogle Scholar
  89. Mullican SE, Gaddis CA, Alenghat T, Nair MG, Giacomin PR, Everett LJ, Feng D, Steger DJ, Schug J, Artis D, Lazar MA (2011) Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev 25:2480–2488PubMedPubMedCentralCrossRefGoogle Scholar
  90. Naidoo V, Naidoo M, Ghai M (2018) Cell- and tissue-specific epigenetic changes associated with chronic inflammation in insulin resistance and type 2 diabetes mellitus. Scand J Immunol 88:e12723PubMedCrossRefGoogle Scholar
  91. Nicoglou A, Merlin F (2017) Epigenetics: a way to bridge the gap between biological fields. Stud Hist Philos Biol Biomed Sci 66:73–82PubMedCrossRefGoogle Scholar
  92. Nilsson E, Jansson PA, Perfilyev A, Volkov P, Pedersen M, Svensson MK, Poulsen P, Ribel-Madsen R, Pedersen NL, Almgren P (2014) Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. Diabetes 63:2962–2976PubMedCrossRefGoogle Scholar
  93. Okabe J, Orlowski C, Balcerczyk A, Tikellis C, Thomas MC, Cooper ME, El-Osta A (2012) Distinguishing hyperglycemic changes by set7 in vascular endothelial cells. Circ Res 110:1067–1076PubMedCrossRefGoogle Scholar
  94. Pais TF, Szego EM, Marques O, Miller-Fleming L, Antas P, Guerreiro P, de Oliveira RM, Kasapoglu B, Outeiro TF (2013) The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation. EMBO J 32:2603–2616PubMedPubMedCentralCrossRefGoogle Scholar
  95. Paneni F, Costantino S, Battista R, Castello L, Capretti G, Chiandotto S, Scavone G, Villano A, Pitocco D, Lanza G (2014) Adverse epigenetic signatures by histone methyltransferase set7 contribute to vascular dysfunction in patients with type 2 diabetes. Circ Cardiovasc Genet 8:150–158PubMedCrossRefGoogle Scholar
  96. Parikh H, Carlsson E, Chutkow WA, Johansson LE, Storgaard H, Poulsen P, Saxena R, Ladd C, Schulze PC, Mazzini MJ (2007) TXNIP regulates peripheral glucose metabolism in humans. PLoS Med 4:e158PubMedPubMedCentralCrossRefGoogle Scholar
  97. Phillips D (1963) The presence of acetyl groups in histones. Biochem J 87:258–263PubMedPubMedCentralGoogle Scholar
  98. Pirola L, Balcerczyk A, Tothill RW, Haviv I, Kaspi A, Lunke S, Ziemann M, Karagiannis T, Tonna S, Kowalczyk A (2011) Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Res 21:1601–1615PubMedPubMedCentralCrossRefGoogle Scholar
  99. Pivari F, Mingione A, Brasacchio C, Soldati L (2019) Curcumin and type 2 diabetes mellitus: prevention and treatment. Nutrients 11:1837PubMedCentralCrossRefGoogle Scholar
  100. Ponting CP, Oliver PL, Reik W (2009) Evolution and functions of long noncoding RNAs. Cell 136:629–641PubMedCrossRefPubMedCentralGoogle Scholar
  101. Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057–1068PubMedPubMedCentralCrossRefGoogle Scholar
  102. Puthanveetil P, Chen S, Feng B, Gautam A, Chakrabarti S (2015) Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells. J Cell Mol Med 19:1418–1425PubMedPubMedCentralCrossRefGoogle Scholar
  103. Raghuraman S, Donkin I, Versteyhe S, Barres R, Simar D (2016) The emerging role of epigenetics in inflammation and immunometabolism. Trends Endocrinol Metab 27:782–795PubMedCrossRefGoogle Scholar
  104. Reddy MA, Jin W, Villeneuve L, Wang M, Lanting L, Todorov I, Kato M, Natarajan R (2012) Proinflammatory role of microrna-200 in vascular smooth muscle cells from diabetic mice. Arterioscler Thromb Vasc Biol 32:721–729PubMedPubMedCentralCrossRefGoogle Scholar
  105. Reddy MA, Chen Z, Park JT, Wang M, Lanting L, Zhang Q, Bhatt K, Leung A, Wu X, Putta S (2014) Regulation of inflammatory phenotype in macrophages by a diabetes-induced long non-coding RNA. Diabetes 63:4249–4261PubMedPubMedCentralCrossRefGoogle Scholar
  106. Reddy MA, Das S, Zhuo C, Jin W, Wang M, Lanting L, Natarajan R (2016) Regulation of vascular smooth muscle cell dysfunction under diabetic conditions by miR-504. Arterioscler Thromb Vasc Biol 36:864–873PubMedPubMedCentralCrossRefGoogle Scholar
  107. Roshanzamir N, Hassan-Zadeh V (2019) Methylation of specific CpG sites in IL-1β and IL1R1 genes is affected by hyperglycaemia in type 2 diabetic patients. Immunol Invest 3:1–12CrossRefGoogle Scholar
  108. Rothgiesser KM, Erener S, Waibel S, Lüscher B, Hottiger MO (2010) SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci 123:4251–4258PubMedCrossRefGoogle Scholar
  109. Santer FR, Höschele PP, Oh SJ, Erb HH, Bouchal J, Cavarretta IT, Parson W, Meyers DJ, Cole PA, Culig Z (2011) Inhibition of the acetyltransferases p300 and CBP reveals a targetable function for p300 in the survival and invasion pathways of prostate cancer cell lines. Mol Cancer Ther 10:1644–1655PubMedCrossRefGoogle Scholar
  110. Sathishkumar C, Prabu P, Mohan V, Balasubramanyam M (2018) Linking a role of lncRNAs (long non-coding RNAs) with insulin resistance, accelerated senescence, and inflammation in patients with type 2 diabetes. Hum Genom 12:41CrossRefGoogle Scholar
  111. Schug TT, Xu Q, Gao H, Peres-da-Silva A, Draper DW, Fessler MB, Purushotham A, Li X (2010) Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol 30:4712–4721PubMedPubMedCentralCrossRefGoogle Scholar
  112. Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O’Leary JJ, Ruan Q, Johnson DS, Chen Y, O’Neill LA (2010) Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol 11:141–147PubMedCrossRefPubMedCentralGoogle Scholar
  113. Singh AK, Bishayee A, Pandey AK (2018) Targeting histone deacetylases with natural and synthetic agents: an emerging anticancer strategy. Nutrients 10:731PubMedCentralCrossRefGoogle Scholar
  114. Smith KM et al (2012) miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. J Immunol 189:1567–1576PubMedPubMedCentralCrossRefGoogle Scholar
  115. Sterner DE, Berger SL (2000) Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 64:435–459PubMedPubMedCentralCrossRefGoogle Scholar
  116. Suraweera A, O’Byrne KJ, Richard DJ (2018) Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi. Front Oncol 8:92PubMedPubMedCentralCrossRefGoogle Scholar
  117. Szabo M, Mate B, Csep K, Benedek T (2018) Epigenetic modifications linked to T2D, the heritability gap, and potential therapeutic targets. Biochem Genet 56:553–574PubMedCrossRefGoogle Scholar
  118. Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103:12481–12486PubMedCrossRefPubMedCentralGoogle Scholar
  119. Tahrani AA, Barnett AH, Bailey CJ (2016) Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol 12:566–592PubMedCrossRefPubMedCentralGoogle Scholar
  120. Takeda-Watanabe A, Kitada M, Kanasaki K, Koya D (2012) SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells. Biochem Biophys Res Commun 427:191–196PubMedCrossRefPubMedCentralGoogle Scholar
  121. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S (2011) Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 14:612–622PubMedCrossRefGoogle Scholar
  122. Turner BM (1993) Decoding the nucleosome. Cell 75:5–8PubMedCrossRefGoogle Scholar
  123. van den Bosch T, Boichenko A, Leus NGJ, Ourailidou ME, Wapenaar H, Rotili D, Mai A, Imhof A, Bischoff R, Haisma HJ, Dekker FJ (2016) The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases. Biochem Pharmacol 102:130–140PubMedCrossRefGoogle Scholar
  124. Villeneuve LM, Reddy MA, Lanting LL, Wang M, Meng L, Natarajan R (2008) Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes. Proc Natl Acad Sci USA 105:9047–9052PubMedCrossRefGoogle Scholar
  125. Villeneuve LM, Kato M, Reddy MA, Wang M, Lanting L, Natarajan R (2010) Enhanced levels of microRNA-125b in vascular smooth muscle cells of diabetic db/db mice lead to increased inflammatory gene expression by targeting the histone methyltransferase Suv39h1. Diabetes 59:2904–2915PubMedPubMedCentralCrossRefGoogle Scholar
  126. Wagner FF, Lundh M, Kaya T, McCarren P, Zhang YL, Chattopadhyay S, Gale JP, Galbo T, Fisher SL, Meier BC, Vetere A, Richardson S, Morgan NG, Christensen DP, Gilbert TJ, Hooker JM, Leroy M, Walpita D, Mandrup-Poulsen T, Wagner BK, Holson EB (2016) An isochemogenic set of inhibitors to define the therapeutic potential of histone deacetylases in β-Cell protection. ACS Chem Biol 11:363–374PubMedCrossRefGoogle Scholar
  127. Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS, Zhang Y (2004) Role of histone H2A ubiquitination in Polycomb silencing. Nature 431:873–878PubMedCrossRefGoogle Scholar
  128. Wang R, He Y, Robinson V, Yang Z, Hessler P, Lasko LM, Lu X, Bhathena A, Lai A, Uziel T, Lam LT (2018) Targeting lineage-specific MITF pathway in human melanoma cell lines by A-485, the selective small-molecule inhibitor of p300/CBP. Mol Cancer Ther 17:2543–2550PubMedCrossRefGoogle Scholar
  129. Xiao C, Wang RH, Lahusen TJ, Park O, Bertola A, Maruyama T, Reynolds D, Chen Q, Xu X, Young HA, Chen WJ, Gao B, Deng CX (2012) Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in SIRT6 mutant mice. J Biol Chem 287:41903–41913PubMedPubMedCentralCrossRefGoogle Scholar
  130. Xu Z, Tong Q, Zhang Z, Wang S, Zheng Y, Liu Q, Qian LB, Chen SY, Sun J, Cai L (2017) Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway. Clin Sci (Lond) 131:1841–1857CrossRefGoogle Scholar
  131. Yan G, Eller MS, Elm C, Larocca CA, Ryu B, Panova IP, Dancy BM, Bowers EM, Meyers D, Lareau L, Cole PA, Taverna SD, Alani RM (2013) Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells. J Invest Dermatol 133:2444–2452PubMedPubMedCentralCrossRefGoogle Scholar
  132. Yang XD, Huang B, Li M, Lamb A, Kelleher NL, Chen LF (2009) Negative regulation of NF-kappaB action by Set9-mediated lysine methylation of the RelA subunit. EMBO J 28:1055–1066PubMedPubMedCentralCrossRefGoogle Scholar
  133. Ye EA, Liu L, Jiang Y, Jan J, Gaddipati S, Suvas S, Steinle JJ (2016) miR-15a/16 reduces retinal leukostasis through decreased proinflammatory signaling. J Neuroinflamm 13:305CrossRefGoogle Scholar
  134. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380PubMedPubMedCentralCrossRefGoogle Scholar
  135. Yoshizaki T, Milne JC, Imamura T, Schenk S, Sonoda N, Babendure JL, Lu J-C, Smith JJ, Jirousek MR, Olefsky JM (2009) SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol 29:1363–1374PubMedCrossRefGoogle Scholar
  136. Yoshizaki T, Schenk S, Imamura T, Babendure JL, Sonoda N, Bae EJ, Oh DY, Lu M, Milne JC, Westphal C (2010) SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab 298:E419–E428PubMedCrossRefGoogle Scholar
  137. Yu X-Y, Geng Y-J, Liang J-L, Zhang S, Lei H-P, Zhong S-L, Lin Q-X, Shan Z-X, Lin S-G, Li Y (2012) High levels of glucose induce “metabolic memory” in cardiomyocyte via epigenetic histone H3 lysine 9 methylation. Mol Biol Rep 39:8891–8898PubMedCrossRefGoogle Scholar
  138. Yun J-M, Jialal I, Devaraj S (2011) Epigenetic regulation of high glucose-induced proinflammatory cytokine production in monocytes by curcumin. J Nutr Biochem 22:450–458PubMedCrossRefGoogle Scholar
  139. Zampetaki A et al (2010) Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res 107:810–817PubMedCrossRefGoogle Scholar
  140. Zhang R, Chen HZ, Liu JJ, Jia YY, Zhang ZQ, Yang RF, Zhang Y, Xu J, Wei YS, Liu DP, Liang CC (2010) SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages. J Biol Chem 285:7097–7110PubMedCrossRefGoogle Scholar
  141. Zhang H, Liu J, Qu D, Wang L, Luo J-Y, Lau CW, Liu P, Gao Z, Tipoe GL, Lee HK (2016) Inhibition of miR-200c restores endothelial function in diabetic mice through suppression of COX-2. Diabetes 65:1196–1207PubMedCrossRefGoogle Scholar
  142. Zhang J, Xu Z, Gu J, Jiang S, Liu Q, Zheng Y, Freedman JH, Sun J, Cai L (2018) HDAC3 inhibition in diabetic mice may activate Nrf2 preventing diabetes-induced liver damage and FGF21 synthesis and secretion leading to aortic protection. Am J Physiol Endocrinol Metab 315:E150–E162PubMedCrossRefGoogle Scholar
  143. Zhang L, Chen Y, Jiang Q, Song W, Zhang L (2019) Therapeutic potential of selective histone deacetylase 3 inhibition. Eur J Med Chem 162:534–542PubMedCrossRefGoogle Scholar
  144. Zheng J, Cheng J, Zheng S, Feng Q, Xiao X (2018) Curcumin, a polyphenolic curcuminoid with its protective effects and molecular mechanisms in diabetes and diabetic cardiomyopathy. Front Pharmacol 9:472PubMedPubMedCentralCrossRefGoogle Scholar
  145. Zhong S, Goto H, Inagaki M, Dong Z (2003) Phosphorylation at serine 28 and acetylation at lysine 9 of histone H3 induced by trichostatin A. Oncogene 22:5291–5297PubMedCrossRefGoogle Scholar
  146. Zhou J, Rossi J (2017) Aptamers as targeted therapeutics: current potential and challenges. Nat Rev Drug Discov 16:181–202PubMedCrossRefGoogle Scholar
  147. Zhou S, Tang X, Chen HZ (2018) Sirtuins and insulin resistance. Front Endocrinol (Lausanne) 9:748CrossRefGoogle Scholar
  148. Zhu B, Zheng Y, Pham A-D, Mandal SS, Erdjument-Bromage H, Tempst P, Reinberg D (2005) Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. Mol Cell 20:601–611PubMedCrossRefGoogle Scholar
  149. Zhu E, Wang X, Zheng B, Wang Q, Hao J, Chen S, Zhao Q, Zhao L, Wu Z, Yin Z (2014) miR-20b suppresses Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis by targeting RORgammat and STAT3. J Immunol 192:5599–5609PubMedCrossRefGoogle Scholar
  150. Zhu X, Wu C, Qiu S, Yuan X, Li L (2017) Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: systematic review and meta-analysis. Nutr Metab 14:60CrossRefGoogle Scholar
  151. Ziesché E, Kettner-Buhrow D, Weber A, Wittwer T, Jurida L, Soelch J, Müller H, Newel D, Kronich P, Schneider H, Dittrich-Breiholz O, Bhaskara S, Hiebert SW, Hottiger MO, Li H, Burstein E, Schmitz ML, Kracht M (2013) The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB. Nucleic Acids Res 41:90–109PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Cell and Molecular Biology, School of Biology, College of ScienceUniversity of TehranTehranIran

Personalised recommendations