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Epigenetics: key to improve delayed wound healing in type 2 diabetes

Molecular and Cellular Biochemistry volume 477, pages 371–383 (2022)Cite this article

Abstract

Diabetes-related delayed wound healing is a multifactorial, nuanced, and intertwined complication that causes substantial clinical morbidity. The etiology of diabetes and its related microvascular complications is affected by genes, diet, and lifestyle factors. Epigenetic modifications such as DNA methylation, histone modifications, and post-transcriptional RNA regulation (microRNAs) are subsequently recognized as key facilitators of the complicated interaction between genes and the environment. Current research suggests that diabetes-persuaded dysfunction of epigenetic pathways, which results in changed expression of genes in target cells and cause diabetes-related complications including cardiomyopathy, nephropathy, retinopathy, delayed wound healing, etc., which are foremost drivers to diabetes-related adverse outcomes. In this paper, we discuss the role of epigenetic mechanisms in controlling tissue repair, angiogenesis, and expression of growth factors, as well as recent findings that show the alteration of epigenetic events during diabetic wound healing.

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Data availability

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Abbreviations

AGEs:

Advanced glycation end-products

DNMTs:

DNA methyltransferases

eNOS:

Endothelial nitric oxide synthase

EPCs:

Endothelial progenitor cells

EGF:

Epidermal growth factor

GLP1R:

Glucagon-like peptide 1 receptor

HDACs:

Histone deacetylases

HIF-1α:

Hypoxia-inducible factor 1-alpha

HMECs:

Human mammary epithelial cells

HUVECs:

Human umbilical vascular endothelial cells

IRAK1:

Interleukin-1 receptor-associated kinase 1

IGF-1:

Insulin growth factor-1

IRF-4:

Interferon regulatory factor -4

IL-1:

Interleukin-1

MMPs:

Matrix metalloproteases

MCP-1:

Monocyte chemoattractant protein 1

NRF2:

Nuclear factor erythroid 2-related factor 2

NFκB:

Nuclear factor-kappa B

NR4A:

Nuclear receptor subfamily 4 group A

PDX-1:

Pancreatic and duodenal homeobox 1

PDGF:

Platelet derived growth factor

PPARGC1α:

Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha

SAM:

S-adenosyl methionine

SOD:

Superoxide dismutase

TRAF6:

Tumor necrosis factor receptor-associated factor 6

TGF-β1:

Transforming growth factor beta 1

TNF-α:

Tumor necrosis factor alpha

VCAM- 1:

Vascular adhesion molecule-1

VEGF:

Vascular endothelial growth factor

References

  1. Ling C, Rönn T (2019) Epigenetics in human obesity and type 2 diabetes. Cell Metab 29(5):1028–1044

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Organization WH (2016) Guideline daily iron supplementation in infants and children. World Health Organization, Geneva

    Google Scholar 

  3. Prevention C (2014) National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. US Department of Health and Human Services, Atlanta

    Google Scholar 

  4. Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA (2003) The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 26(6):1790–1795

    PubMed  Google Scholar 

  5. Singh N, Armstrong DG, Lipsky BA (2005) Preventing foot ulcers in patients with diabetes. JAMA 293(2):217–228

    CAS  PubMed  Google Scholar 

  6. Wu SC, Driver VR, Wrobel JS, Armstrong DG (2007) Foot ulcers in the diabetic patient, prevention and treatment. Vasc Health Risk Manag 3(1):65

    PubMed  PubMed Central  Google Scholar 

  7. Ling C, Groop L (2009) Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes 58(12):2718–2725

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Theilgaard-Mönch K, Knudsen S, Follin P, Borregaard N (2004) The transcriptional activation program of human neutrophils in skin lesions supports their important role in wound healing. J Immunol 172(12):7684–7693

    PubMed  Google Scholar 

  9. Wynn TA, Vannella KM (2016) Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44(3):450–462

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Maruyama K, Asai J, Ii M, Thorne T, Losordo DW, D’Amore PA (2007) Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol 170(4):1178–1191

    PubMed  PubMed Central  Google Scholar 

  11. Willenborg S, Lucas T, Van Loo G, Knipper JA, Krieg T, Haase I, Brachvogel B, Hammerschmidt M, Nagy A, Ferrara N (2012) CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood 120(3):613–625

    CAS  PubMed  Google Scholar 

  12. Italiani P, Boraschi D (2014) From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front Immunol 5:514

    PubMed  PubMed Central  Google Scholar 

  13. Boniakowski AE, Kimball AS, Jacobs BN, Kunkel SL, Gallagher KA (2017) Macrophage-mediated inflammation in normal and diabetic wound healing. J Immunol 199(1):17–24

    CAS  PubMed  Google Scholar 

  14. Gallagher KA, Joshi A, Carson WF, Schaller M, Allen R, Mukerjee S, Kittan N, Feldman EL, Henke PK, Hogaboam C (2015) Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes 64(4):1420–1430

    CAS  PubMed  Google Scholar 

  15. Kimball AS, Joshi A, Carson WF, Boniakowski AE, Schaller M, Allen R, Bermick J, Davis FM, Henke PK, Burant CF (2017) The histone methyltransferase MLL1 directs macrophage-mediated inflammation in wound healing and is altered in a murine model of obesity and type 2 diabetes. Diabetes 66(9):2459–2471

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang X, Cao Q, Yu L, Shi H, Xue B, Shi H (2016) Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity. JCI Insight. https://doi.org/10.1172/jci.insight.87748

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yan J, Tie G, Wang S, Tutto A, DeMarco N, Khair L, Fazzio TG, Messina LM (2018) Diabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages. Nat Commun 9(1):1–13

    Google Scholar 

  18. De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130(6):1083–1094

    PubMed  Google Scholar 

  19. Peppa M, Brem H, Ehrlich P, Zhang J-G, Cai W, Li Z, Croitoru A, Thung S, Vlassara H (2003) Adverse effects of dietary glycotoxins on wound healing in genetically diabetic mice. Diabetes 52(11):2805–2813

    CAS  PubMed  Google Scholar 

  20. Zhu P, Yang C, Chen L-H, Ren M, Lao G-j, Yan L (2011) Impairment of human keratinocyte mobility and proliferation by advanced glycation end products-modified BSA. Arch Dermatol Res 303(5):339–350

    CAS  PubMed  Google Scholar 

  21. Lerman OZ, Galiano RD, Armour M, Levine JP, Gurtner GC (2003) Cellular dysfunction in the diabetic fibroblast: impairment in migration, vascular endothelial growth factor production, and response to hypoxia. Am J Pathol 162(1):303–312

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Xuan YH, Huang BB, Tian HS, Chi LS, Duan YM, Wang X, Zhu ZX, Cai WH, Zhu YT, Wei TM (2014) High-glucose inhibits human fibroblast cell migration in wound healing via repression of bFGF-regulating JNK phosphorylation. PLoS One 9(9):e108182

    PubMed  PubMed Central  Google Scholar 

  23. Zhang J, Yang C, Wang C, Liu D, Lao G, Liang Y, Sun K, Luo H, Tan Q, Ren M (2016) AGE-induced keratinocyte MMP-9 expression is linked to TET2-mediated CpG demethylation. Wound Repair Regen 24(3):489–500

    PubMed  Google Scholar 

  24. Ling L, Ren M, Yang C, Lao G, Chen L, Luo H, Feng Z, Yan L (2013) Role of site-specific DNA demethylation in TNFa-induced. Endocrinology 50:279–290

    CAS  Google Scholar 

  25. Park LK, Maione AG, Smith A, Gerami-Naini B, Iyer LK, Mooney DJ, Veves A, Garlick JA (2014) Genome-wide DNA methylation analysis identifies a metabolic memory profile in patient-derived diabetic foot ulcer fibroblasts. Epigenetics 9(10):1339–1349

    PubMed  PubMed Central  Google Scholar 

  26. Galkowska H, Wojewodzka U, Olszewski WL (2006) Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers. Wound Repair Regen 14(5):558–565

    PubMed  Google Scholar 

  27. Khanna S, Biswas S, Shang Y, Collard E, Azad A, Kauh C, Bhasker V, Gordillo GM, Sen CK, Roy S (2010) Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One 5(3):e9539

    PubMed  PubMed Central  Google Scholar 

  28. Gill M, Dias S, Hattori K, Rivera ML, Hicklin D, Witte L, Girardi L, Yurt R, Himel H, Rafii S (2001) Vascular trauma induces rapid but transient mobilization of VEGFR2+ AC133+ endothelial precursor cells. Circ Res 88(2):167–174

    CAS  PubMed  Google Scholar 

  29. Gallagher KA, Liu Z-J, Xiao M, Chen H, Goldstein LJ, Buerk DG, Nedeau A, Thom SR, Velazquez OC (2007) Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α. J Clin Investig 117(5):1249–1259

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Stehouwer CD, Gall M-A, Twisk JW, Knudsen E, Emeis JJ, Parving H-H (2002) Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. Diabetes 51(4):1157–1165

    CAS  PubMed  Google Scholar 

  31. Yager DR, Zhang L-Y, Liang H-X, Diegelmann RF, Cohen IK (1996) Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids. J Invest Dermatol 107(5):743–748

    CAS  PubMed  Google Scholar 

  32. Wysocki J, Wierusz-Wysocka B, Wykretowicz A, Wysocki H (1992) The influence of thymus extracts on the chemotaxis of polymorphonuclear neutrophils (PMN) from patients with insulin-dependent diabetes mellitus (IDD). Thymus 20(1):63–67

    CAS  PubMed  Google Scholar 

  33. Bitar MS, Labbad ZN (1996) Transforming growth factor-β and insulin-like growth factor-I in relation to diabetes-induced impairment of wound healing. J Surg Res 61(1):113–119

    CAS  PubMed  Google Scholar 

  34. Pradhan L, Cai X, Wu S, Andersen ND, Martin M, Malek J, Guthrie P, Veves A, LoGerfo FW (2011) Gene expression of pro-inflammatory cytokines and neuropeptides in diabetic wound healing. J Surg Res 167(2):336–342

    CAS  PubMed  Google Scholar 

  35. Teena R, Dhamodharan U, Ali D, Rajesh K, Ramkumar KM (2020) Genetic polymorphism of the Nrf2 promoter region (rs35652124) is associated with the risk of diabetic foot ulcers. Oxid Med Cell Longev. https://doi.org/10.1155/2020/9825028

    Article  PubMed  PubMed Central  Google Scholar 

  36. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277(5322):55–60

    CAS  PubMed  Google Scholar 

  37. Kim JH, Yoon NY, Kim DH, Jung M, Jun M, Park HY, Chung CH, Lee K, Kim S, Park CS (2018) Impaired permeability and antimicrobial barriers in type 2 diabetes skin are linked to increased serum levels of advanced glycation end-product. Exp Dermatol 27(8):815–823

    CAS  PubMed  Google Scholar 

  38. Deng L, Du C, Song P, Chen T, Rui S, Armstrong DG, Deng W (2021) The role of oxidative stress and antioxidants in diabetic wound healing. Oxid Med Cell Longev. https://doi.org/10.1155/2021/8852759

    Article  PubMed  PubMed Central  Google Scholar 

  39. Dam DHM, Wang X-Q, Sheu S, Vijay M, Shipp D, Miller L, Paller AS (2017) Ganglioside GM3 mediates glucose-induced suppression of IGF-1 receptor–Rac1 activation to inhibit keratinocyte motility. J Invest Dermatol 137(2):440–448

    CAS  PubMed  Google Scholar 

  40. Nowak NC, Menichella DM, Miller R, Paller AS (2021) Cutaneous innervation in impaired diabetic wound healing. Transl Res. https://doi.org/10.1016/j.trsl.2021.05.003

    Article  PubMed  Google Scholar 

  41. Moosavi A, Ardekani AM (2016) Role of epigenetics in biology and human diseases. Iran Biomed J 20(5):246

    PubMed  PubMed Central  Google Scholar 

  42. Tycko B, Ashkenas J (2000) Epigenetics and its role in disease. J Clin Investig 105(3):245–246

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zullo A, Sommese L, Nicoletti G, Donatelli F, Mancini FP, Napoli C (2017) Epigenetics and type 1 diabetes: mechanisms and translational applications. Transl Res 185:85–93

    CAS  PubMed  Google Scholar 

  44. Sommese L, Zullo A, Mancini FP, Fabbricini R, Soricelli A, Napoli C (2017) Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus. Epigenetics 12(6):401–415

    PubMed  PubMed Central  Google Scholar 

  45. Picascia A, Grimaldi V, Pignalosa O, De Pascale MR, Schiano C, Napoli C (2015) Epigenetic control of autoimmune diseases: from bench to bedside. Clin Immunol 157(1):1–15

    CAS  PubMed  Google Scholar 

  46. Li E, Beard C, Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366(6453):362–365

    CAS  PubMed  Google Scholar 

  47. Hansen RS, Stöger R, Wijmenga C, Stanek AM, Canfield TK, Luo P, Matarazzo MR, D’Esposito M, Feil R, Gimelli G (2000) Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant. Hum Mol Genet 9(18):2575–2587

    CAS  PubMed  Google Scholar 

  48. Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23(15):5293–5300

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Jia D, Jurkowska RZ, Zhang X, Jeltsch A, Cheng X (2007) Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449(7159):248–251

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Rougier N, Bourc’his D, Gomes DM, Niveleau A, Plachot M, Pàldi A, Viegas-Péquignot E (1998) Chromosome methylation patterns during mammalian preimplantation development. Genes Dev 12(14):2108–2113

    CAS  PubMed  PubMed Central  Google Scholar 

  51. He Y-F, Li B-Z, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333(6047):1303–1307

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929):930–935

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047):1300–1303

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(3):245–254

    CAS  PubMed  Google Scholar 

  55. Tammen SA, Friso S, Choi S-W (2013) Epigenetics: the link between nature and nurture. Mol Asp Med 34(4):753–764

    CAS  Google Scholar 

  56. Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D’Souza C, Fouse SD, Johnson BE, Hong C, Nielsen C, Zhao Y (2010) Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466(7303):253–257

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hodges E, Molaro A, Dos Santos CO, Thekkat P, Song Q, Uren PJ, Park J, Butler J, Rafii S, McCombie WR (2011) Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. Mol Cell 44(1):17–28

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Schmidl C, Klug M, Boeld TJ, Andreesen R, Hoffmann P, Edinger M, Rehli M (2009) Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 19(7):1165–1174

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Hirst M, Marra MA (2009) Epigenetics and human disease. Int J Biochem Cell Biol 41(1):136–146

    CAS  PubMed  Google Scholar 

  60. Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9(6):465–476

    CAS  PubMed  Google Scholar 

  61. Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M, Burton J, Cox TV, Davies R, Down TA (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38(12):1378–1385

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Lande-Diner L, Zhang J, Ben-Porath I, Amariglio N, Keshet I, Hecht M, Azuara V, Fisher AG, Rechavi G, Cedar H (2007) Role of DNA methylation in stable gene repression. J Biol Chem 282(16):12194–12200

    CAS  PubMed  Google Scholar 

  63. Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T (2003) The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278(6):4035–4040

    CAS  PubMed  Google Scholar 

  64. Tazi J, Bird A (1990) Alternative chromatin structure at CpG islands. Cell 60(6):909–920

    CAS  PubMed  Google Scholar 

  65. Agalioti T, Lomvardas S, Parekh B, Yie J, Maniatis T, Thanos D (2000) Ordered recruitment of chromatin modifying and general transcription factors to the IFN-β promoter. Cell 103(4):667–678

    CAS  PubMed  Google Scholar 

  66. McEwen KR, Ferguson-Smith AC (2010) Distinguishing epigenetic marks of developmental and imprinting regulation. Epigenetics Chromatin 3(1):1–13

    Google Scholar 

  67. Ling C, Poulsen P, Simonsson S, Rönn T, Holmkvist J, Almgren P, Hagert P, Nilsson E, Mabey AG, Nilsson P (2007) Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Investig 117(11):3427–3435

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Rönn T, Poulsen P, Hansson O, Holmkvist J, Almgren P, Nilsson P, Tuomi T, Isomaa B, Groop L, Vaag A (2008) Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle. Diabetologia 51(7):1159–1168

    PubMed  Google Scholar 

  69. Schübeler D (2015) Function and information content of DNA methylation. Nature 517(7534):321–326

    PubMed  Google Scholar 

  70. Yang BT, Dayeh TA, Volkov PA, Kirkpatrick CL, Malmgren S, Jing X, Renström E, Wollheim CB, Nitert MD, Ling C (2012) Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. Mol Endocrinol 26(7):1203–1212

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Ishikawa K, Tsunekawa S, Ikeniwa M, Izumoto T, Iida A, Ogata H, Uenishi E, Seino Y, Ozaki N, Sugimura Y (2015) Long-term pancreatic beta cell exposure to high levels of glucose but not palmitate induces DNA methylation within the insulin gene promoter and represses transcriptional activity. PLoS One 10(2):e0115350

    PubMed  PubMed Central  Google Scholar 

  72. Dayeh T, Volkov P, Salö S, Hall E, Nilsson E, Olsson AH, Kirkpatrick CL, Wollheim CB, Eliasson L, Rönn T (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(3):e1004160

    PubMed  PubMed Central  Google Scholar 

  73. Ling C, Del Guerra S, Lupi R, Rönn T, Granhall C, Luthman H, Masiello P, Marchetti P, Groop L, Del Prato S (2008) Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51(4):615–622

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Alibegovic AC, Sonne MP, Højbjerre L, Bork-Jensen J, Jacobsen S, Nilsson E, Færch K, Hiscock N, Mortensen B, Friedrichsen M (2010) Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men. Am J Physiol Endocrinol Metab 299(5):E752–E763

    CAS  PubMed  Google Scholar 

  75. Nasrin N, Wu X, Fortier E, Feng Y, Bare OC, Chen S, Ren X, Wu Z, Streeper RS, Bordone L (2010) SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 285(42):31995–32002

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Cox EJ, Marsh SA (2013) Exercise and diabetes have opposite effects on the assembly and O-GlcNAc modification of the mSin3A/HDAC1/2 complex in the heart. Cardiovasc Diabetol 12(1):1–15

    Google Scholar 

  77. Liu Z-Z, Zhao X-Z, Zhang X-S, Zhang M (2014) Promoter DNA demethylation of Keap1 gene in diabetic cardiomyopathy. Int J Clin Exp Pathol 7(12):8756

    PubMed  PubMed Central  Google Scholar 

  78. Mishra M, Kowluru RA (2015) Epigenetic modification of mitochondrial DNA in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 56(9):5133–5142

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Chen Y-T, Liao J-W, Tsai Y-C, Tsai F-J (2016) Inhibition of DNA methyltransferase 1 increases nuclear receptor subfamily 4 group A member 1 expression and decreases blood glucose in type 2 diabetes. Oncotarget 7(26):39162

    PubMed  PubMed Central  Google Scholar 

  80. Hall E, Dayeh T, Kirkpatrick CL, Wollheim CB, Nitert MD, Ling C (2013) DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets. BMC Med Genet 14(1):1–7

    Google Scholar 

  81. Mönkemann H, De Vriese A, Blom H, Kluijtmans L, Heil S, Schild H, Golubnitschaja O (2002) Early molecular events in the development of the diabetic cardiomyopathy. Amino Acids 23(1–3):331–336

    PubMed  Google Scholar 

  82. Xu F, Zhang C, Graves DT (2013) Abnormal cell responses and role of TNF-in impaired diabetic wound healing. Biomed Res Int. https://doi.org/10.1155/2013/754802

    Article  PubMed  PubMed Central  Google Scholar 

  83. Bouwmeester T, Bauch A, Ruffner H, Angrand P-O, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S (2004) A physical and functional map of the human TNF-α/NF-κB signal transduction pathway. Nat Cell Biol 6(2):97–105

    CAS  PubMed  Google Scholar 

  84. Lu W, Li J, Ren M, Zeng Y, Zhu P, Lin L, Lin D, Hao S, Gao Q, Liang J (2015) Role of the mevalonate pathway in specific CpG site demethylation on AGEs-induced MMP9 expression and activation in keratinocytes. Mol Cell Endocrinol 411:121–129

    CAS  PubMed  Google Scholar 

  85. Zhou L, Wang W, Yang C, Zeng T, Hu M, Wang X, Li N, Sun K, Wang C, Zhou J (2018) GADD45a promotes active DNA demethylation of the MMP-9 promoter via base excision repair pathway in AGEs-treated keratinocytes and in diabetic male rat skin. Endocrinology 159(2):1172–1186

    CAS  PubMed  Google Scholar 

  86. Zhu P, Ren M, Yang C, Hu YX, Ran JM, Yan L (2012) Involvement of RAGE, MAPK and NF-κB pathways in AGEs-induced MMP-9 activation in HaCaT keratinocytes. Exp Dermatol 21(2):123–129

    CAS  PubMed  Google Scholar 

  87. Wolffe AP, Hayes JJ (1999) Chromatin disruption and modification. Nucleic Acids Res 27(3):711–720

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Thomas JO, Kornberg RD (1975) Cleavable cross-links in the analysis of histone—histone associations. FEBS Lett 58(1–2):353–358

    CAS  PubMed  Google Scholar 

  89. McGhee JD, Rau DC, Charney E, Felsenfeld G (1980) Orientation of the nucleosome within the higher order structure of chromatin. Cell 22(1):87–96

    CAS  PubMed  Google Scholar 

  90. Allshire RC, Madhani HD (2018) Ten principles of heterochromatin formation and function. Nat Rev Mol Cell Biol 19(4):229

    CAS  PubMed  Google Scholar 

  91. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403(6765):41–45

    CAS  PubMed  Google Scholar 

  92. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293(5532):1074–1080

    CAS  PubMed  Google Scholar 

  93. Luger K, Richmond TJ (1998) The histone tails of the nucleosome. Curr Opin Genet Dev 8(2):140–146

    CAS  PubMed  Google Scholar 

  94. Winer DA, Luck H, Tsai S, Winer S (2016) The intestinal immune system in obesity and insulin resistance. Cell Metab 23(3):413–426

    CAS  PubMed  Google Scholar 

  95. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91

    CAS  PubMed  Google Scholar 

  96. Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246

    CAS  PubMed  Google Scholar 

  97. Biddinger SB, Kahn CR (2006) From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol 68:123–158

    CAS  PubMed  Google Scholar 

  98. 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(5):450–458

    CAS  PubMed  Google Scholar 

  99. 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(17):18091–18097

    CAS  PubMed  Google Scholar 

  100. Kadiyala CSR, Zheng L, Du Y, Yohannes E, Kao H-Y, Miyagi M, Kern TS (2012) Acetylation of retinal histones in diabetes increases inflammatory proteins: effects of minocycline and manipulation of histone acetyltransferase (HAT) and histone deacetylase (HDAC). J Biol Chem 287(31):25869–25880

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Perrone L, Devi TS, Ki H, Terasaki T, Singh LP (2009) Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions. J Cell Physiol 221(1):262–272

    CAS  PubMed  Google Scholar 

  102. Crosson CE, Mani SK, Husain S, Alsarraf O, Menick DR (2010) Inhibition of histone deacetylase protects the retina from ischemic injury. Invest Ophthalmol Vis Sci 51(7):3639–3645

    PubMed  PubMed Central  Google Scholar 

  103. Tu P, Li X, Ma B, Duan H, Zhang Y, Wu R, Ni Z, Jiang P, Wang H, Li M (2015) Liver histone H3 methylation and acetylation may associate with type 2 diabetes development. J Physiol Biochem 71(1):89–98

    CAS  PubMed  Google Scholar 

  104. Guillam M-T, Hümmler E, Schaerer E, Wu J-Y, Birnbaum MJ, Beermann F, Schmidt A, Dériaz N, Thorens B (1997) Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat Genet 17(3):327–330

    CAS  PubMed  Google Scholar 

  105. Seyer P, Vallois D, Poitry-Yamate C, Schütz F, Metref S, Tarussio D, Maechler P, Staels B, Lanz B, Grueter R (2013) Hepatic glucose sensing is required to preserve β cell glucose competence. J Clin Investig 123(4):1662–1676

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Yasuda H, Ohashi A, Nishida S, Kamiya T, Suwa T, Hara H, Takeda J, Itoh Y, Adachi T (2016) Exendin-4 induces extracellular-superoxide dismutase through histone H3 acetylation in human retinal endothelial cells. J Clin Biochem Nutr 59(3):174–181

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhong Q, Kowluru RA (2010) Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon. J Cell Biochem 110(6):1306–1313

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Kim MS, Kwon HJ, Lee YM, Baek JH, Jang J-E, Lee S-W, Moon E-J, Kim H-S, Lee S-K, Chung HY (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7(4):437–443

    PubMed  Google Scholar 

  109. Mottet D, Bellahcene A, Pirotte S, Waltregny D, Deroanne C, Lamour V, Lidereau R, Castronovo V (2007) Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis. Circ Res 101(12):1237–1246

    CAS  PubMed  Google Scholar 

  110. Patel T, Patel V, Singh R, Jayaraman S (2011) Chromatin remodeling resets the immune system to protect against autoimmune diabetes in mice. Immunol Cell Biol 89(5):640–649

    CAS  PubMed  Google Scholar 

  111. Spallotta F, Cencioni C, Straino S, Sbardella G, Castellano S, Capogrossi MC, Martelli F, Gaetano C (2013) Enhancement of lysine acetylation accelerates wound repair. Commun Integr Biol 6(5):e25466

    PubMed  PubMed Central  Google Scholar 

  112. Melchionna R, Bellavia G, Romani M, Straino S, Germani A, Di Carlo A, Capogrossi MC, Napolitano M (2012) C/EBPγ regulates wound repair and EGF receptor signaling. J Invest Dermatol 132(7):1908–1917

    CAS  PubMed  Google Scholar 

  113. 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(10):2409–2417

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Na J, Shin JY, Jeong H, Lee JY, Kim BJ, Kim WS, Yune TY, Ju B-G (2017) JMJD3 and NF-κB-dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing. Sci Rep 7(1):1–12

    Google Scholar 

  115. Shaw T, Martin P (2009) Epigenetic reprogramming during wound healing: loss of polycomb-mediated silencing may enable upregulation of repair genes. EMBO Rep 10(8):881–886

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Melton C, Judson RL, Blelloch R (2010) Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature 463(7281):621–626

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Yamakuchi M, Ferlito M, Lowenstein CJ (2008) miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci 105(36):13421–13426

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Ferguson BS (2019) Nutritional epigenomics. Academic Press, Cambridge

    Google Scholar 

  119. Guay C, Jacovetti C, Nesca V, Motterle A, Tugay K, Regazzi R (2012) Emerging roles of non-coding RNAs in pancreatic β-cell function and dysfunction. Diabetes Obes Metab 14:12–21

    CAS  PubMed  Google Scholar 

  120. Herrera B, Lockstone H, Taylor J, Ria M, Barrett A, Collins S, Kaisaki P, Argoud K, Fernandez C, Travers M (2010) Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia 53(6):1099–1109

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Poy M (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432:226–230

    CAS  PubMed  Google Scholar 

  122. Xu G, Chen J, Jing G, Shalev A (2013) Thioredoxin-interacting protein regulates insulin transcription through microRNA-204. Nat Med 19(9):1141–1146

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Bolmeson C, Esguerra JL, Salehi A, Speidel D, Eliasson L, Cilio CM (2011) Differences in islet-enriched miRNAs in healthy and glucose intolerant human subjects. Biochem Biophys Res Commun 404(1):16–22

    CAS  PubMed  Google Scholar 

  124. Sebastiani G, Po A, Miele E, Ventriglia G, Ceccarelli E, Bugliani M, Marselli L, Marchetti P, Gulino A, Ferretti E (2015) MicroRNA-124a is hyperexpressed in type 2 diabetic human pancreatic islets and negatively regulates insulin secretion. Acta Diabetol 52(3):523–530

    CAS  PubMed  Google Scholar 

  125. Tattikota SG, Rathjen T, McAnulty SJ, Wessels H-H, Akerman I, Van De Bunt M, Hausser J, Esguerra JL, Musahl A, Pandey AK (2014) Argonaute2 mediates compensatory expansion of the pancreatic β cell. Cell Metab 19(1):122–134

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Ofori JK, Salunkhe VA, Bagge A, Vishnu N, Nagao M, Mulder H, Wollheim CB, Eliasson L, Esguerra JL (2017) Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell. Sci Rep 7(1):1–15

    CAS  Google Scholar 

  127. Belgardt B-F, Ahmed K, Spranger M, Latreille M, Denzler R, Kondratiuk N, Von Meyenn F, Villena FN, Herrmanns K, Bosco D (2015) The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes. Nat Med 21(6):619–627

    CAS  PubMed  Google Scholar 

  128. Nesca V, Guay C, Jacovetti C, Menoud V, Peyot M-L, Laybutt DR, Prentki M, Regazzi R (2013) Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia 56(10):2203–2212

    CAS  PubMed  Google Scholar 

  129. Latreille M, Hausser J, Stützer I, Zhang Q, Hastoy B, Gargani S, Kerr-Conte J, Pattou F, Zavolan M, Esguerra JL (2014) MicroRNA-7a regulates pancreatic β cell function. J Clin Investig 124(6):2722–2735

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Hanna J, Hossain GS, Kocerha J (2019) The potential for microRNA therapeutics and clinical research. Front Genet 10:478

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Chan YC, Roy S, Khanna S, Sen CK (2012) Downregulation of endothelial microRNA-200b supports cutaneous wound angiogenesis by desilencing GATA binding protein 2 and vascular endothelial growth factor receptor 2. Arterioscler Thromb Vasc Biol 32(6):1372–1382

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sinha M, Ghatak S, Roy S, Sen CK (2015) microRNA–200b as a switch for inducible adult angiogenesis. Antioxid Redox Signal 22(14):1257–1272

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Detich N, Hamm S, Just G, Knox JD, Szyf M (2003) The methyl donor S-adenosylmethionine inhibits active demethylation of DNA: a candidate novel mechanism for the pharmacological effects of S-adenosylmethionine. J Biol Chem 278(23):20812–20820

    CAS  PubMed  Google Scholar 

  134. Koh TJ, DiPietro LA (2011) Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. https://doi.org/10.1017/S1462399411001943

    Article  PubMed  PubMed Central  Google Scholar 

  135. Barrows LR, Magee PN (1982) Nonenzymatic methylation of DNA by S-adenosylmethionine in vitro. Carcinogenesis 3(3):349–351

    CAS  PubMed  Google Scholar 

  136. Spijkerman A, Smulders Y, Kostense P, Henry R, Becker A, Teerlink T, Jakobs C, Dekker J, Nijpels G, Heine R (2005) S-adenosylmethionine and 5-methyltetrahydrofolate are associated with endothelial function after controlling for confounding by homocysteine: the Hoorn study. Arterioscler Thromb Vasc Biol 25(4):778–784

    CAS  PubMed  Google Scholar 

  137. Kim SY, Hong SW, Kim M-O, Kim H-S, Jang JE, Leem J, Park I-S, Lee K-U, Koh EH (2013) S-adenosyl methionine prevents endothelial dysfunction by inducing heme oxygenase-1 in vascular endothelial cells. Mol Cells 36(4):376–384

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Taganov KD, Boldin MP, Chang K-J, Baltimore D (2006) NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci 103(33):12481–12486

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Tili E, Michaille J-J, Cimino A, Costinean S, Dumitru CD, Adair B, Fabbri M, Alder H, Liu CG, Calin GA (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-α stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179(8):5082–5089

    CAS  PubMed  Google Scholar 

  140. 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(11):2904–2915

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S (2007) Role of dicer and drosha for endothelial microRNA expression and angiogenesis. Circ Res 101(1):59–68

    CAS  PubMed  Google Scholar 

  142. Wang S, Olson EN (2009) AngiomiRs—key regulators of angiogenesis. Curr Opin Genet Dev 19(3):205–211

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Yang WJ, Yang DD, Na S, Sandusky GE, Zhang Q, Zhao G (2005) Dicer is required for embryonic angiogenesis during mouse development. J Biol Chem 280(10):9330–9335

    CAS  PubMed  Google Scholar 

  144. Shilo S, Roy S, Khanna S, Sen CK (2008) Evidence for the involvement of miRNA in redox regulated angiogenic response of human microvascular endothelial cells. Arterioscler Thromb Vasc Biol 28(3):471–477

    CAS  PubMed  Google Scholar 

  145. Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, Mercatanti A, Hammond S, Rainaldi G (2006) MicroRNAs modulate the angiogenic properties of HUVECs. Blood 108(9):3068–3071

    CAS  PubMed  Google Scholar 

  146. Biswas S, Roy S, Banerjee J, Hussain S-RA, Khanna S, Meenakshisundaram G, Kuppusamy P, Friedman A, Sen CK (2010) Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds. Proc Natl Acad Sci 107(15):6976–6981

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Chang WY, Bryce DM, D’Souza SJ, Dagnino L (2004) The DP-1 transcription factor is required for keratinocyte growth and epidermal stratification. J Biol Chem 279(49):51343–51353

    CAS  PubMed  Google Scholar 

  148. Reddy MA, Zhang E, Natarajan R (2015) Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58(3):443–455

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors sincerely thank Lovely Professional University, Punjab, India for providing the necessary facilities to carry out the study.

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  1. Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University (LPU), Jalandhar—Delhi G.T. Road, 144411, Phagwara, Punjab, India

    Rupal Dubey & Jeena Gupta

  2. Department of Medical Laboratory Sciences, School of Physiotherapy and Paramedical Sciences, Lovely Professional University, 144411, Phagwara, Punjab, India

    Pranav Kumar Prabhakar

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  1. Rupal Dubey
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Dubey, R., Prabhakar, P.K. & Gupta, J. Epigenetics: key to improve delayed wound healing in type 2 diabetes. Mol Cell Biochem 477, 371–383 (2022). https://doi.org/10.1007/s11010-021-04285-0

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Keywords

  • Diabetes
  • Wound healing
  • Epigenetics
  • DNA methylation
  • Histone modifications
  • MicroRNAs