Advertisement

Targeting epigenetic mechanisms in diabetic wound healing

Published:October 09, 2018DOI:https://doi.org/10.1016/j.trsl.2018.10.001
      Impaired wound healing is a major secondary complication of type 2 diabetes that often results in limb loss and disability. Normal tissue repair progresses through discrete phases including hemostasis, inflammation, proliferation, and remodeling. In diabetes, normal progression through these phases is impaired resulting in a sustained inflammatory state and dysfunctional epithelialization in the wound. Due to their plasticity, macrophages play a critical role in the transition from the inflammation phase to the proliferation phase. Diabetes disrupts macrophage function by impairing monocyte recruitment to the wound, reducing phagocytosis, and prohibiting the transition of inflammatory macrophages to an anti-inflammatory state. Diabetes also impedes keratinocyte and fibroblast function during the later phases resulting in impaired epithelialization of the wound. Several recent studies suggest that altered epigenetic regulation of both immune and structural cells in wounds may influence cell phenotypes and healing, particularly in pathologic states, such as diabetes. Specifically, it has been shown that macrophage plasticity during wound repair is partly regulated epigenetically and that diabetes alters this epigenetic regulation and contributes to a sustained inflammatory state. Epigenetic regulation is also known to regulate keratinocyte and fibroblast function during wound repair. In this review, we provide an introduction to the epigenetic mechanisms that regulate tissue repair and highlight recent findings that demonstrate, how epigenetic events are altered during the course of diabetic wound healing.

      Abbreviations:

      5caC (5’-carboxy-cytosine), 5fC (5’-fluoro-cytosine), 5hmC (5’-hydroxymethyl-cytosine), 5mC (5’-methyl-cytosine), Ac-CoA (acetyl coenzyme A), AGE (advanced glycation end-product), AGE-BSA (advanced glycation end-product – bovine serum albumin), ASH1L (absent small and homeotic disks protein 1-like), BMDM (bone marrow-derived macrophage), DAMP (damage-associated molecular pattern), DIO (diet-induced obesity), DNMT (DNA methyltransferase), ECM (extracellular matrix), eNOS (endothelial nitric oxide synthase), H3K4 (histone H3 lysine 4), H3K27 (histone H3 lysine 27), HAT (histone acetyltransferase), HDAC (histone de-acetylase), HMT (histone methyltransferase), JMJD3 (Jumonji domain-containing protein 3), LPS (lipopolysaccharide), MLL1 (mixed lineage leukemia 1), MCP-1 (macrophage chemoattractant protein 1), MMP (matrix metalloprotease), NET (neutrophil extracellular trap), NO (nitric oxide), PAD4 (peptidyl deiminase 4), PAI-1 (plasminogen activator inhibitor 1), PMN (polymorphonuclear neutrophils), SLE (systemic lupus erythematosus), T2D (type 2 diabetes), TET (ten eleven translocase)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Centers for Disease Control and Prevention
        National diabetes statistics report.
        Centers for Disease Control and Prevention, US Department of Health and Human Services, Atlanta, GA2017 (2017)
        • Guariguata L.
        • Whiting D.
        • Weil C.
        • Unwin N.
        The International Diabetes Federation diabetes atlas methodology for estimating global and national prevalence of diabetes in adults.
        Diabetes Res Clin Pract. 2011; 94: 322-332
        • Menke A.
        • Casagrande S.
        • Geiss L.
        • Cowie C.C.
        Prevalence of and trends in diabetes among adults in the United States,1988-2012.
        JAMA. 2015; 314: 1021-1029
        • Lamont P.
        • Franklyn K.
        • Rayman G.
        • Boulton A.J.
        Update on the diabetic foot 2012: the 14th biennial Malvern Diabetic Foot Conference, May 9-11, 2012.
        Int J Low Extrem Wounds. 2013; 12: 71-75
        • Theilgaard-Monch K.
        • Knudsen S.
        • Follin P.
        • Borregaard N.
        The transcriptional activation program of human neutrophils in skin lesions supports their important role in wound healing.
        J Immunol. 2004; 172: 7684-7693
        • Wynn T.A.
        • Vannella K.M.
        Macrophages in tissue repair, regeneration, and fibrosis.
        Immunity. 2016; 44: 450-462
        • Maruyama K.
        • Asai J.
        • Ii M.
        • Thorne T.
        • Losordo D.W.
        • D'Amore P.A.
        Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing.
        Am J Pathol. 2007; 170: 1178-1191
        • Willenborg S.
        • Lucas T.
        • van Loo G.
        • et al.
        CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair.
        Blood. 2012; 120: 613-625
        • Italiani P.
        • Boraschi D.
        From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation.
        Front Immunol. 2014; 5: 514
        • Boniakowski A.E.
        • Kimball A.S.
        • Jacobs B.N.
        • Kunkel S.L.
        • Gallagher K.A.
        Macrophage-mediated inflammation in normal and diabetic wound healing.
        J Immunol. 2017; 199: 17-24
        • Gallagher K.A.
        • Joshi A.
        • Carson W.F.
        • et al.
        Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes.
        Diabetes. 2015; 64: 1420-1430
        • Murray P.J.
        • Allen J.E.
        • Biswas S.K.
        • et al.
        Macrophage activation and polarization: nomenclature and experimental guidelines.
        Immunity. 2014; 41: 14-20
        • Sica A.
        • Mantovani A.
        Macrophage plasticity and polarization: in vivo veritas.
        J Clin Invest. 2012; 122: 787-795
        • Kimball A.S.
        • Joshi A.
        • Carson W.F.t.
        • et al.
        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. 2017; 66: 2459-2471
        • Wang X.
        • Cao Q.
        • Yu L.
        • Shi H.
        • Xue B.
        • Shi H.
        Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity.
        JCI Insight. 2016; 1: e87748
        • Yan J.
        • Tie G.
        • Wang S.
        • et al.
        Diabetes impairs wound healing by DNMT1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages.
        Nat Commun. 2018; 9: 33
        • De Santa F.
        • Totaro M.G.
        • 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: 1083-1094
        • Peppa M.
        • Brem H.
        • Ehrlich P.
        • et al.
        Adverse effects of dietary glycotoxins on wound healing in genetically diabetic mice.
        Diabetes. 2003; 52: 2805-2813
        • Zhu P.
        • Yang C.
        • Chen L.H.
        • Ren M.
        • Lao G.J.
        • Yan L.
        Impairment of human keratinocyte mobility and proliferation by advanced glycation end products-modified BSA.
        Arch Dermatol Res. 2011; 303: 339-350
        • Lerman O.Z.
        • Galiano R.D.
        • Armour M.
        • Levine J.P.
        • Gurtner G.C.
        Cellular dysfunction in the diabetic fibroblast: impairment in migration, vascular endothelial growth factor production, and response to hypoxia.
        Am J Pathol. 2003; 162: 303-312
        • Xuan Y.H.
        • Huang B.B.
        • Tian H.S.
        • et al.
        High-glucose inhibits human fibroblast cell migration in wound healing via repression of bFGF-regulating JNK phosphorylation.
        PLoS One. 2014; 9e108182
        • Zhang J.
        • Yang C.
        • Wang C.
        • et al.
        AGE-induced keratinocyte MMP-9 expression is linked to TET2-mediated CpG demethylation.
        Wound Repair Regen. 2016; 24: 489-500
        • Ling L.
        • Ren M.
        • Yang C.
        • et al.
        Role of site-specific DNA demethylation in TNFalpha-induced MMP9 expression in keratinocytes.
        J Mol Endocrinol. 2013; 50: 279-290
        • Park L.K.
        • Maione A.G.
        • Smith A.
        • et al.
        Genome-wide DNA methylation analysis identifies a metabolic memory profile in patient-derived diabetic foot ulcer fibroblasts.
        Epigenetics. 2014; 9: 1339-1349
        • Diegelmann R.F.
        • Evans M.C.
        Wound healing: an overview of acute, fibrotic and delayed healing.
        Front Biosci. 2004; 9: 283-289
        • Nurden A.T.
        • Nurden P.
        • Sanchez M.
        • Andia I.
        • Anitua E.
        Platelets and wound healing.
        Front Biosci. 2008; 13: 3532-3548
        • Jaramillo M.
        • Olivier M.
        Hydrogen peroxide induces murine macrophage chemokine gene transcription via extracellular signal-regulated kinase- and cyclic adenosine 5′-monophosphate (cAMP)-dependent pathways: involvement of NF-kappa B, activator protein 1, and cAMP response element binding protein.
        J Immunol. 2002; 169: 7026-7038
        • Razzell W.
        • Evans I.R.
        • Martin P.
        • Wood W.
        Calcium flashes orchestrate the wound inflammatory response through DUOX activation and hydrogen peroxide release.
        Curr Biol. 2013; 23: 424-429
        • Niethammer P.
        • Grabher C.
        • Look A.T.
        • Mitchison T.J.
        A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish.
        Nature. 2009; 459: 996-999
        • Tang D.
        • Kang R.
        • Xiao W.
        • Jiang L.
        • Liu M.
        • Shi Y.
        • et al.
        Nuclear heat shock protein 72 as a negative regulator of oxidative stress (hydrogen peroxide)-induced HMGB1 cytoplasmic translocation and release.
        J Immunol. 2007; 178: 7376-7384
        • Rani M.
        • Nicholson S.E.
        • Zhang Q.
        • Schwacha M.G.
        Damage-associated molecular patterns (DAMPs) released after burn are associated with inflammation and monocyte activation.
        Burns. 2017; 43: 297-303
        • Barrientos S.
        • Stojadinovic O.
        • Golinko M.S.
        • Brem H.
        • Tomic-Canic M.
        Growth factors and cytokines in wound healing.
        Wound Repair Regen. 2008; 16: 585-601
        • Reinke J.M.
        • Sorg H.
        Wound repair and regeneration.
        Eur Surg Res. 2012; 49: 35-43
        • Kimball A.
        • Schaller M.
        • Joshi A.
        • et al.
        Ly6C(Hi) blood monocyte/macrophage drive chronic inflammation and impair wound healing in diabetes mellitus.
        Arterioscler Thromb Vasc Biol. 2018; 38: 1102-1114
        • Olingy C.E.
        • San Emeterio C.L.
        • Ogle M.E.
        • et al.
        Non-classical monocytes are biased progenitors of wound healing macrophages during soft tissue injury.
        Sci Rep. 2017; 7: 447
        • Hesketh M.
        • Sahin K.B.
        • West Z.E.
        • Murray R.Z.
        Macrophage phenotypes regulate scar formation and chronic wound healing.
        Int J Mol Sci. 2017; 18: 1545
        • Vagesjo E.
        • Ohnstedt E.
        • Mortier A.
        • et al.
        Accelerated wound healing in mice by on-site production and delivery of CXCL12 by transformed lactic acid bacteria.
        Proc Natl Acad Sci U S A. 2018; 115: 1895-1900
        • Landen N.X.
        • Li D.
        • Stahle M.
        Transition from inflammation to proliferation: a critical step during wound healing.
        Cell Mol Life Sci. 2016; 73: 3861-3885
        • Martinez F.O.
        • Gordon S.
        The M1 and M2 paradigm of macrophage activation: time for reassessment.
        F1000Prime Rep. 2014; 6: 13
        • Martinez F.O.
        • Sica A.
        • Mantovani A.
        • Locati M.
        Macrophage activation and polarization.
        Front Biosci. 2008; 13: 453-461
        • Gabbiani G.
        The myofibroblast in wound healing and fibrocontractive diseases.
        J Pathol. 2003; 200: 500-503
        • Dinh T.
        • Tecilazich F.
        • Kafanas A.
        • et al.
        Mechanisms involved in the development and healing of diabetic foot ulceration.
        Diabetes. 2012; 61: 2937-2947
        • Ward J.D.
        • Boulton A.J.
        • Simms J.M.
        • Sandler D.A.
        • Knight G.
        Venous distension in the diabetic neuropathic foot physical sign of arteriovenous shunting.
        J R Soc Med. 1983; 76: 1011-1014
        • Rayman G.
        • Williams S.A.
        • Spencer P.D.
        • Smaje L.H.
        • Wise P.H.
        • Tooke J.E.
        Impaired microvascular hyperaemic response to minor skin trauma in type I diabetes.
        Br Med J (Clin Res Ed). 1986; 292: 1295-1298
        • Gallagher K.A.
        • Liu Z.J.
        • Xiao M.
        • Chen H.
        • et al.
        Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha.
        J Clin Invest. 2007; 117: 1249-1259
        • Undas A.
        • Wiek I.
        • Stepien E.
        • Zmudka K.
        • Tracz W.
        Hyperglycemia is associated with enhanced thrombin formation, platelet activation, and fibrin clot resistance to lysis in patients with acute coronary syndrome.
        Diabetes Care. 2008; 31: 1590-1595
        • Juhan-Vague I.
        • Roul C.
        • Alessi M.C.
        • Ardissone J.P.
        • Heim M.
        • Vague P.
        Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients-relationship with plasma insulin.
        Thromb Haemost. 1989; 61: 370-373
        • Forstermann U.
        • Mugge A.
        • Alheid U.
        • Haverich A.
        • Frolich J.C.
        Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries.
        Circ Res. 1988; 62: 185-190
        • Bucala R.
        • Tracey K.J.
        • Cerami A.
        Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes.
        J Clin Invest. 1991; 87: 432-438
        • Tessari P.
        • Cecchet D.
        • Cosma A.
        • et al.
        Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy.
        Diabetes. 2010; 59: 2152-2159
        • Hanses F.
        • Park S.
        • Rich J.
        • Lee J.C.
        Reduced neutrophil apoptosis in diabetic mice during staphylococcal infection leads to prolonged TNFalpha production and reduced neutrophil clearance.
        PLoS One. 2011; 6: e23633
        • Karima M.
        • Kantarci A.
        • Ohira T.
        • et al.
        Enhanced superoxide release and elevated protein kinase C activity in neutrophils from diabetic patients: association with periodontitis.
        J Leukoc Biol. 2005; 78: 862-870
        • Wong S.L.
        • Demers M.
        • Martinod K.
        • et al.
        Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.
        Nat Med. 2015; 21: 815-819
        • Wetzler C.
        • Kampfer H.
        • Stallmeyer B.
        • Pfeilschifter J.
        • Frank S.
        Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair.
        J Invest Dermatol. 2000; 115: 245-253
        • Loots M.A.
        • Lamme E.N.
        • Zeegelaar J.
        • Mekkes J.R.
        • Bos J.D.
        • Middelkoop E.
        Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds.
        J Invest Dermatol. 1998; 111: 850-857
        • Friggeri A.
        • Banerjee S.
        • Biswas S.
        • et al.
        Participation of the receptor for advanced glycation end products in efferocytosis.
        J Immunol. 2011; 186: 6191-6198
        • He M.
        • Kubo H.
        • Morimoto K
        • et al.
        Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells.
        EMBO Rep. 2011; 12: 358-364
        • Ignarro L.J.
        • Buga G.M.
        • Wood K.S.
        • Byrns R.E.
        • Chaudhuri G.
        Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.
        Proc Natl Acad Sci U S A. 1987; 84: 9265-9269
        • Veves A.
        • Akbari C.M.
        • Primavera J.
        • et al.
        Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration.
        Diabetes. 1998; 47: 457-463
        • Thum T.
        • Fraccarollo D.
        • Schultheiss M.
        • et al.
        Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes.
        Diabetes. 2007; 56: 666-674
        • Lan C.C.
        • Liu I.H.
        • Fang A.H.
        • Wen C.H.
        • Wu C.S.
        Hyperglycaemic conditions decrease cultured keratinocyte mobility: implications for impaired wound healing in patients with diabetes.
        Br J Dermatol. 2008; 159: 1103-1115
        • Werner S.
        • Breeden M.
        • Hubner G.
        • Greenhalgh D.G.
        • Longaker M.T.
        Induction of keratinocyte growth factor expression is reduced and delayed during wound healing in the genetically diabetic mouse.
        J Invest Dermatol. 1994; 103: 469-473
        • Pollok S.
        • Pfeiffer A.C.
        • Lobmann R.
        • et al.
        Connexin 43 mimetic peptide Gap27 reveals potential differences in the role of Cx43 in wound repair between diabetic and non-diabetic cells.
        J Cell Mol Med. 2011; 15: 861-873
        • Lan C.C.
        • Wu C.S.
        • Huang S.M.
        • Wu I.H.
        • Chen G.S.
        High-glucose environment enhanced oxidative stress and increased interleukin-8 secretion from keratinocytes: new insights into impaired diabetic wound healing.
        Diabetes. 2013; 62: 2530-2538
        • Lu W.
        • Li J.
        • Ren M.
        • et al.
        Role of the mevalonate pathway in specific CpG site demethylation on AGEs-induced MMP9 expression and activation in keratinocytes.
        Mol Cell Endocrinol. 2015; 411: 121-129
        • Robert I.
        • Aussems M.
        • Keutgens A.
        • et al.
        Matrix Metalloproteinase-9 gene induction by a truncated oncogenic NF-kappaB2 protein involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes.
        Oncogene. 2009; 28: 1626-1638
        • Hu S.C.
        • Lan C.E.
        High-glucose environment disturbs the physiologic functions of keratinocytes: Focusing on diabetic wound healing.
        J Dermatol Sci. 2016; 84: 121-127
        • Usui M.L.
        • Mansbridge J.N.
        • Carter W.G.
        • Fujita M.
        • Olerud J.E.
        Keratinocyte migration, proliferation, and differentiation in chronic ulcers from patients with diabetes and normal wounds.
        J Histochem Cytochem. 2008; 56: 687-696
        • Becker D.L.
        • Thrasivoulou C.
        • Phillips A.R.
        Connexins in wound healing; perspectives in diabetic patients.
        Biochim Biophys Acta. 2012; 1818: 2068-2075
        • Desta T.
        • Li J.
        • Chino T.
        • Graves D.T.
        Altered fibroblast proliferation and apoptosis in diabetic gingival wounds.
        J Dent Res. 2010; 89: 609-614
        • Alikhani Z.
        • Alikhani M.
        • Boyd C.M.
        • Nagao K.
        • Trackman P.C.
        • Graves D.T.
        Advanced glycation end products enhance expression of pro-apoptotic genes and stimulate fibroblast apoptosis through cytoplasmic and mitochondrial pathways.
        J Biol Chem. 2005; 280: 12087-12095
        • Okano Y.
        • Masaki H.
        • Sakurai H.
        Dysfunction of dermal fibroblasts induced by advanced glycation end-products (AGEs) and the contribution of a nonspecific interaction with cell membrane and AGEs.
        J Dermatol Sci. 2002; 29: 171-180
        • Werner S.
        • Krieg T.
        • Smola H.
        Keratinocyte-fibroblast interactions in wound healing.
        J Invest Dermatol. 2007; 127: 998-1008
        • Barrero M.J.
        • Boue S.
        • Izpisua Belmonte J.C.
        Epigenetic mechanisms that regulate cell identity.
        Cell Stem Cell. 2010; 7: 565-570
        • Portela A.
        • Esteller M.
        Epigenetic modifications and human disease.
        Nat Biotechnol. 2010; 28: 1057-1068
        • Carson W.F.t.
        • Cavassani K.A.
        • Soares E.M.
        • et al.
        The STAT4/MLL1 epigenetic axis regulates the antimicrobial functions of murine macrophages.
        J Immunol. 2017; 199: 1865-1874
        • Ishii M.
        • Wen H.
        • Corsa C.A.
        • et al.
        Epigenetic regulation of the alternatively activated macrophage phenotype.
        Blood. 2009; 114: 3244-3254
        • Schaller M.
        • Ito T.
        • Allen R.M.
        • et al.
        Epigenetic regulation of IL-12-dependent T cell proliferation.
        J Leukoc Biol. 2015; 98: 601-613
        • Xia M.
        • Liu J.
        • Wu X.
        • et al.
        Histone methyltransferase Ash1l suppresses interleukin-6 production and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20.
        Immunity. 2013; 39: 470-481
        • Kruidenier L.
        • Chung C.W.
        • Cheng Z.
        • et al.
        A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.
        Nature. 2012; 488: 404-408
        • Satoh T.
        • Takeuchi O.
        • Vandenbon A.
        • et al.
        The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection.
        Nat Immunol. 2010; 11: 936-944
        • Zimmermann M.
        • Aguilera F.B.
        • Castellucci M.
        • et al.
        Chromatin remodelling and autocrine TNFalpha are required for optimal interleukin-6 expression in activated human neutrophils.
        Nat Commun. 2015; 6: 6061
        • Coit P.
        • Yalavarthi S.
        • Ognenovski M.
        • et al.
        Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils.
        J Autoimmun. 2015; 58: 59-66
        • Lewis C.J.
        • Mardaryev A.N.
        • Sharov A.A.
        • Fessing M.Y.
        • Botchkarev V.A.
        The epigenetic regulation of wound healing.
        Adv Wound Care. 2014; 3: 468-475
        • Sen G.L.
        • Webster D.E.
        • Barragan D.I.
        • Chang H.Y.
        • Khavari P.A.
        Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3.
        Genes Dev. 2008; 22: 1865-1870
        • Driskell I.
        • Oda H.
        • Blanco S.
        • Nascimento E.
        • Humphreys P.
        • Frye M.
        The histone methyltransferase Setd8 acts in concert with c-Myc and is required to maintain skin.
        EMBO J. 2012; 31: 616-629
        • Holliday R.
        • Pugh J.E.
        DNA modification mechanisms and gene activity during development.
        Science. 1975; 187: 226-232
        • Okano M.
        • Bell D.W.
        • Haber D.A.
        • Li E.
        DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.
        Cell. 1999; 99: 247-257
        • Bestor T.H.
        The DNA methyltransferases of mammals.
        Hum Mol Genet. 2000; 9: 2395-2402
        • Bestor T.H.
        • Ingram V.M.
        Two DNA methyltransferases from murine erythroleukemia cells: purification, sequence specificity, and mode of interaction with DNA.
        Proc Natl Acad Sci U S A. 1983; 80: 5559-5563
        • Takai D.
        • Jones P.A.
        Comprehensive analysis of CpG islands in human chromosomes 21 and 22.
        Proc Natl Acad Sci U S A. 2002; 99: 3740-3745
        • Li E.
        • Zhang Y.
        DNA methylation in mammals.
        Cold Spring Harb Perspect Biol. 2014; 6a019133
        • Sen G.L.
        • Reuter J.A.
        • Webster D.E.
        • Zhu L.
        • Khavari P.A.
        DNMT1 maintains progenitor function in self-renewing somatic tissue.
        Nature. 2010; 463: 563-567
        • Zhou L.
        • Wang W.
        • Yang C.
        • et al.
        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. 2018; 159: 1172-1186
        • Chen Z.
        • Miao F.
        • Paterson A.D.
        • et al.
        Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort.
        Proc Natl Acad Sci U S A. 2016; 113: E3002-E3011
        • Volkmar M.
        • Dedeurwaerder S.
        • Cunha D.A.
        • et al.
        DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients.
        EMBO J. 2012; 31: 1405-1426
        • Dhawan S.
        • Georgia S.
        • Tschen S.I.
        • Fan G.
        • Bhushan A.
        Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx.
        Dev Cell. 2011; 20: 419-429
        • Zhao J.
        • Goldberg J.
        • Bremner J.D.
        • Vaccarino V.
        Global DNA methylation is associated with insulin resistance: a monozygotic twin study.
        Diabetes. 2012; 61: 542-546
        • Dhawan S.
        • Tschen S.I.
        • Zeng C.
        • et al.
        DNA methylation directs functional maturation of pancreatic beta cells.
        J Clin Invest. 2015; 125: 2851-2860
        • Kohli R.M.
        • Zhang Y.
        TET enzymes, TDG and the dynamics of DNA demethylation.
        Nature. 2013; 502: 472-479
        • Zhu P.
        • Ren M.
        • Yang C.
        • Hu Y.X.
        • Ran J.M.
        • Yan L.
        Involvement of RAGE, MAPK and NF-kappaB pathways in AGEs-induced MMP-9 activation in HaCaT keratinocytes.
        Exp Dermatol. 2012; 21: 123-129
        • Wolffe A.P.
        • Hayes J.J.
        Chromatin disruption and modification.
        Nucleic Acids Res. 1999; 27: 711-720
        • Thomas J.O.
        • Kornberg R.D.
        Cleavable cross-links in the analysis of histone-histone associations.
        FEBS Lett. 1975; 58: 353-358
        • McGhee J.D.
        • Rau D.C.
        • Charney E.
        • Felsenfeld G.
        Orientation of the nucleosome within the higher order structure of chromatin.
        Cell. 1980; 22: 87-96
        • Allshire R.C.
        • Madhani H.D.
        Ten principles of heterochromatin formation and function.
        Nat Rev Mol Cell Biol. 2018; 19: 229-244
        • Strahl B.D.
        • Allis C.D.
        The language of covalent histone modifications.
        Nature. 2000; 403: 41-45
        • Jenuwein T.
        • Allis C.D.
        Translating the histone code.
        Science. 2001; 293: 1074-1080
        • Luger K.
        • Richmond T.J.
        The histone tails of the nucleosome.
        Curr Opin Genet Dev. 1998; 8: 140-146
        • Lauberth S.M.
        • Nakayama T.
        • Wu X.
        • et al.
        H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation.
        Cell. 2013; 152: 1021-1036
        • Ferrari K.J.
        • Scelfo A.
        • Jammula S.
        • et al.
        Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity.
        Mol Cell. 2014; 53: 49-62
        • Wang X.
        • Zhu K.
        • Li S.
        • et al.
        MLL1, a H3K4 methyltransferase, regulates the TNFalpha-stimulated activation of genes downstream of NF-kappaB.
        J Cell Sci. 2012; 125: 4058-4066
        • Morey L.
        • Helin K.
        Polycomb group protein-mediated repression of transcription.
        Trends Biochem Sci. 2010; 35: 323-332
        • Xiang Y.
        • Zhu Z.
        • Han G.
        • Lin H.
        • Xu L.
        • Chen C.D.
        JMJD3 is a histone H3K27 demethylase.
        Cell Res. 2007; 17: 850-857
        • Na J.
        • Shin J.Y.
        • Jeong H.
        • et al.
        JMJD3 and NF-kappaB-dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing.
        Sci Rep. 2017; 7: 6494
        • Shaw T.
        • Martin P.
        Epigenetic reprogramming during wound healing: loss of polycomb-mediated silencing may enable upregulation of repair genes.
        EMBO Rep. 2009; 10: 881-886
        • Gregory G.D.
        • Vakoc C.R.
        • Rozovskaia T.
        • et al.
        Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes.
        Mol Cell Biol. 2007; 27: 8466-8479
        • Tanaka Y.
        • Katagiri Z.
        • Kawahashi K.
        • Kioussis D.
        • Kitajima S.
        Trithorax-group protein ASH1 methylates histone H3 lysine 36.
        Gene. 2007; 397: 161-168
        • Li G.
        • Ye Z.
        • Shi C.
        • Sun L.
        • et al.
        The histone methyltransferase Ash1l is required for epidermal homeostasis in mice.
        Sci Rep. 2017; 7: 45401
        • Okabe J.
        • Orlowski C.
        • Balcerczyk A.
        • et al.
        Distinguishing hyperglycemic changes by Set7 in vascular endothelial cells.
        Circ Res. 2012; 110: 1067-1076
        • Local A.
        • Huang H.
        • Albuquerque C.P.
        • et al.
        Identification of H3K4me1-associated proteins at mammalian enhancers.
        Nat Genet. 2018; 50: 73-82
        • Bedford M.T.
        • Richard S.
        Arginine methylation an emerging regulator of protein function.
        Mol Cell. 2005; 18: 263-272
        • Kim D.I.
        • Park M.J.
        • Lim S.K.
        • et al.
        High-glucose-induced CARM1 expression regulates apoptosis of human retinal pigment epithelial cells via histone 3 arginine 17 dimethylation: role in diabetic retinopathy.
        Arch Biochem Biophys. 2014; 560: 36-43
        • Porta M.
        • Amione C.
        • Barutta F.
        • et al.
        The co-activator-associated arginine methyltransferase 1 (CARM1) gene is overexpressed in type 2 diabetes.
        Endocrine. 2018;
        • Kim J.K.
        • Lim Y.
        • Lee J.O.
        • et al.
        PRMT4 is involved in insulin secretion via the methylation of histone H3 in pancreatic beta cells.
        J Mol Endocrinol. 2015; 54: 315-324
        • Covic M.
        • Hassa P.O.
        • Saccani S.
        • et al.
        Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-kappaB-dependent gene expression.
        EMBO J. 2005; 24: 85-96
        • Hassa P.O.
        • Covic M.
        • Bedford M.T.
        • Hottiger M.O.
        Protein arginine methyltransferase 1 coactivates NF-kappaB-dependent gene expression synergistically with CARM1 and PARP1.
        J Mol Biol. 2008; 377: 668-678
        • Grunstein M.
        Histone acetylation in chromatin structure and transcription.
        Nature. 1997; 389: 349-352
        • Struhl K.
        Histone acetylation and transcriptional regulatory mechanisms.
        Genes Dev. 1998; 12: 599-606
        • Gregoretti I.V.
        • Lee Y.M.
        • Goodson H.V.
        Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis.
        J Mol Biol. 2004; 338: 17-31
        • Taunton J.
        • Hassig C.A.
        • Schreiber S.L.
        A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.
        Science. 1996; 272: 408-411
        • Carrer A.
        • Parris J.L.
        • Trefely S.
        • et al.
        Impact of a high-fat diet on tissue Acyl-CoA and histone acetylation levels.
        J Biol Chem. 2017; 292: 3312-3322
        • Lee J.V.
        • Carrer A.
        • Shah S.
        • et al.
        Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation.
        Cell Metab. 2014; 20: 306-319
        • Wellen K.E.
        • Hatzivassiliou G.
        • Sachdeva U.M.
        • Bui T.V.
        • Cross J.R.
        • Thompson C.B.
        ATP-citrate lyase links cellular metabolism to histone acetylation.
        Science. 2009; 324: 1076-1080
        • Zhao S.
        • Torres A.
        • Henry R.A.
        • et al.
        ATP-citrate lyase controls a glucose-to-acetate metabolic switch.
        Cell Rep. 2016; 17: 1037-1052
        • Tu P.
        • Li X.
        • Ma B.
        • et al.
        Liver histone H3 methylation and acetylation may associate with type 2 diabetes development.
        J Physiol Biochem. 2015; 71: 89-98
        • Guillam M.T.
        • Hummler E.
        • Schaerer E.
        • et al.
        Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2.
        Nat Genet. 1997; 17: 327-330
        • Seyer P.
        • Vallois D.
        • Poitry-Yamate C.
        • et al.
        Hepatic glucose sensing is required to preserve beta cell glucose competence.
        J Clin Invest. 2013; 123: 1662-1676
        • Yasuda H.
        • Ohashi A.
        • Nishida S.
        • et al.
        Exendin-4 induces extracellular-superoxide dismutase through histone H3 acetylation in human retinal endothelial cells.
        J Clin Biochem Nutr. 2016; 59: 174-181
        • Spallotta F.
        • Cencioni C.
        • Straino S.
        • et al.
        Enhancement of lysine acetylation accelerates wound repair.
        Commun Integr Biol. 2013; 6: e25466
        • Melchionna R.
        • Bellavia G.
        • Romani M.
        • et al.
        C/EBPgamma regulates wound repair and EGF receptor signaling.
        J Invest Dermatol. 2012; 132: 1908-1917
        • Cao J.
        • Yan Q.
        Histone ubiquitination and deubiquitination in transcription, DNA damage response, and cancer.
        Front Oncol. 2012; 2: 26
        • Rossetto D.
        • Avvakumov N.
        • Cote J.
        Histone phosphorylation: a chromatin modification involved in diverse nuclear events.
        Epigenetics. 2012; 7: 1098-1108
        • Weake V.M.
        • Workman J.L.
        Histone ubiquitination: triggering gene activity.
        Mol Cell. 2008; 29: 653-663
        • Vignali M.
        • Hassan A.H.
        • Neely K.E.
        • Workman J.L.
        ATP-dependent chromatin-remodeling complexes.
        Mol Cell Biol. 2000; 20: 1899-1910
        • Quinn J.
        • Fyrberg A.M.
        • Ganster R.W.
        • Schmidt M.C.
        • Peterson C.L.
        DNA-binding properties of the yeast SWI/SNF complex.
        Nature. 1996; 379: 844-847
        • Georgel P.T.
        • Tsukiyama T.
        • Wu C.
        Role of histone tails in nucleosome remodeling by Drosophila NURF.
        EMBO J. 1997; 16: 4717-4726
        • Kotwal G.J.
        • Sarojini H.
        • Chien S.
        Pivotal role of ATP in macrophages fast tracking wound repair and regeneration.
        Wound Repair Regen. 2015; 23: 724-727
        • Indra A.K.
        • Dupe V.
        • Bornert J.M.
        • et al.
        Temporally controlled targeted somatic mutagenesis in embryonic surface ectoderm and fetal epidermal keratinocytes unveils two distinct developmental functions of BRG1 in limb morphogenesis and skin barrier formation.
        Development. 2005; 132: 4533-4544