Epigenetic Regulation of Skin Wound Healing

  • Andrei N. MardaryevEmail author
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Epigenetic regulators play crucial roles in coordinating gene expression and regulating cellular behavior in both skin homeostatic conditions and tissue damage. Alterations in epigenetic mechanisms contribute to the pathogenesis of many skin disorders, including chronic wounds and excessive scarring after injury. Epigenetic regulators modify chromatin structure through covalent DNA and histone modifications, ATP-dependent and higher-order chromatin remodeling, as well as noncoding RNA-dependent regulation. By changing chromatin structure, epigenetic regulators affect gene expression and are able to both stimulate and repress gene activity to transiently alter cellular phenotype and behavior in response to injury. Here, we focus on recent progress that provides insight into the epigenetic regulatory mechanisms that control the execution of reparative gene expression programs in skin epithelial, dermal and inflammatory cells during skin repair after injury.

List of Abbreviations


DNA methyltransferase


extracellular matrix


epithelial–mesenchymal transition


histone acetyltransferase


histone deacetylase


interferon γ




matrix metalloproteinase


P300/CBP-associated factor


polycomb group protein


Polycomb Repressive Complex 2


type II diabetes


ten-eleven translocation


Toll-like receptor


trichostatin A


vascular endothelial growth factor


  1. 1.
    Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453(7193):314–21. Scholar
  2. 2.
    Schafer M, Werner S. Transcriptional control of wound repair. Annu Rev Cell Dev Biol. 2007;23:69–92. Scholar
  3. 3.
    Cooper L, Johnson C, Burslem F, Martin P. Wound healing and inflammation genes revealed by array analysis of ‘macrophageless’ PU.1 null mice. Genome Biol. 2005;6(1):R5. Scholar
  4. 4.
    Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014;6(265):265sr6. Scholar
  5. 5.
    MacLeod AS, Mansbridge JN. The innate immune system in acute and chronic wounds. Adv Wound Care (New Rochelle). 2016;5(2):65–78. Scholar
  6. 6.
    Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83(3):835–70. Scholar
  7. 7.
    Bickmore WA, van Steensel B. Genome architecture: domain organization of interphase chromosomes. Cell. 2013;152(6):1270–84. Scholar
  8. 8.
    Ho L, Crabtree GR. Chromatin remodelling during development. Nature. 2010;463(7280):474–84. Scholar
  9. 9.
    Botchkarev VA, Gdula MR, Mardaryev AN, Sharov AA, Fessing MY. Epigenetic regulation of gene expression in keratinocytes. J Invest Dermatol. 2012;132(11):2505–21. Scholar
  10. 10.
    Liang Y, Chang C, Lu Q. The genetics and epigenetics of atopic dermatitis-filaggrin and other polymorphisms. Clin Rev Allergy Immunol. 2015.
  11. 11.
    Makino T, Jinnin M. Genetic and epigenetic abnormalities in systemic sclerosis. J Dermatol. 2016;43(1):10–8. Scholar
  12. 12.
    Millington GW. Epigenetics and dermatological disease. Pharmacogenomics. 2008;9(12):1835–50. Scholar
  13. 13.
    Nguyen CM, Liao W. Genomic imprinting in psoriasis and atopic dermatitis: a review. J Dermatol Sci. 2015;80(2):89–93. Scholar
  14. 14.
    Banerjee J, Sen CK. microRNA and wound healing. Adv Exp Med Biol. 2015;888:291–305. Scholar
  15. 15.
    Fahs F, Bi X, Yu FS, Zhou L, Mi QS. New insights into microRNAs in skin wound healing. IUBMB Life. 2015;67(12):889–96. Scholar
  16. 16.
    Li D, Wang A, Liu X, Meisgen F, Grunler J, Botusan IR, et al. MicroRNA-132 enhances transition from inflammation to proliferation during wound healing. J Clin Invest. 2015;125(8):3008–26. Scholar
  17. 17.
    Liu J, Luo C, Yin Z, Li P, Wang S, Chen J, et al. Downregulation of let7b promotes COL1A1 and COL1A2 expression in dermis and skin fibroblasts during heat wound repair. Mol Med Rep. 2016;13(3):2683–8. Scholar
  18. 18.
    Shaw T, Martin P. Epigenetic reprogramming during wound healing: loss of polycomb-mediated silencing may enable upregulation of repair genes. EMBO Rep. 2009;10(8):881–6. Scholar
  19. 19.
    Na J, Lee K, Na W, Shin JY, Lee MJ, Yune TY, et al. Histone H3K27 Demethylase JMJD3 in cooperation with NF-kappaB regulates keratinocyte wound healing. J Invest Dermatol. 2016;136(4):847–58. Scholar
  20. 20.
    Fitzgerald O’Connor EJ, Badshah II, Addae LY, Kundasamy P, Thanabalasingam S, Abioye D, et al. Histone deacetylase 2 is upregulated in normal and keloid scars. J Invest Dermatol. 2012;132(4):1293–6. Scholar
  21. 21.
    Italiani P, Boraschi D. From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front Immunol. 2014;5:514. Scholar
  22. 22.
    Haertel E, Werner S, Schafer M. Transcriptional regulation of wound inflammation. Semin Immunol. 2014;26(4):321–8. Scholar
  23. 23.
    Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3(2):133–46. Scholar
  24. 24.
    Cooper PR, Takahashi Y, Graham LW, Simon S, Imazato S, Smith AJ. Inflammation-regeneration interplay in the dentine-pulp complex. J Dent. 2010;38(9):687–97. Scholar
  25. 25.
    Filbin MT. How inflammation promotes regeneration. Nat Neurosci. 2006;9(6):715–7. Scholar
  26. 26.
    Delneste Y, Charbonnier P, Herbault N, Magistrelli G, Caron G, Bonnefoy JY, et al. Interferon-gamma switches monocyte differentiation from dendritic cells to macrophages. Blood. 2003;101(1):143–50. Scholar
  27. 27.
    Mills CD, Thomas AC, Lenz LL, Munder M. Macrophage: SHIP of immunity. Front Immunol. 2014;5:620. Scholar
  28. 28.
    Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. Scholar
  29. 29.
    Bosca L, Zeini M, Traves PG, Hortelano S. Nitric oxide and cell viability in inflammatory cells: a role for NO in macrophage function and fate. Toxicology. 2005;208(2):249–58. Scholar
  30. 30.
    Hayden MS, West AP, Ghosh S. NF-kappaB and the immune response. Oncogene. 2006;25(51):6758–80. Scholar
  31. 31.
    Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651. Scholar
  32. 32.
    Mitchell S, Vargas J, Hoffmann A. Signaling via the NFkappaB system. Wiley Interdiscip Rev Syst Biol Med. 2016.
  33. 33.
    Sharif O, Bolshakov VN, Raines S, Newham P, Perkins ND. Transcriptional profiling of the LPS induced NF-kappaB response in macrophages. BMC Immunol. 2007;8:1. Scholar
  34. 34.
    Hubner G, Brauchle M, Smola H, Madlener M, Fassler R, Werner S. Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokine. 1996;8(7):548–56. Scholar
  35. 35.
    Aung HT, Schroder K, Himes SR, Brion K, van Zuylen W, Trieu A, et al. LPS regulates proinflammatory gene expression in macrophages by altering histone deacetylase expression. FASEB J. 2006;20(9):1315–27. Scholar
  36. 36.
    Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. 2005;352(19):1967–76. Scholar
  37. 37.
    Villagra A, Sotomayor EM, Seto E. Histone deacetylases and the immunological network: implications in cancer and inflammation. Oncogene. 2010;29(2):157–73. Scholar
  38. 38.
    Halili MA, Andrews MR, Sweet MJ, Fairlie DP. Histone deacetylase inhibitors in inflammatory disease. Curr Top Med Chem. 2009;9(3):309–19.CrossRefPubMedGoogle Scholar
  39. 39.
    Roger T, Lugrin J, Le Roy D, Goy G, Mombelli M, Koessler T, et al. Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection. Blood. 2011;117(4):1205–17. Scholar
  40. 40.
    De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. 2007;130(6):1083–94. Scholar
  41. 41.
    De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J. 2009;28(21):3341–52. Scholar
  42. 42.
    Gallagher KA, Joshi A, Carson WF, Schaller M, Allen R, Mukerjee S, et al. Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes. 2015;64(4):1420–30. Scholar
  43. 43.
    Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585–601. Scholar
  44. 44.
    Porcheray F, Viaud S, Rimaniol AC, Leone C, Samah B, Dereuddre-Bosquet N, et al. Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol. 2005;142(3):481–9. Scholar
  45. 45.
    Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32(5):593–604. Scholar
  46. 46.
    Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20. Scholar
  47. 47.
    Mullican SE, Gaddis CA, Alenghat T, Nair MG, Giacomin PR, Everett LJ, et al. Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev. 2011;25(23):2480–8. Scholar
  48. 48.
    Ishii M, Wen H, Corsa CA, Liu T, Coelho AL, Allen RM, et al. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood. 2009;114(15):3244–54. Scholar
  49. 49.
    Salminen A, Kaarniranta K, Hiltunen M, Kauppinen A. Histone demethylase Jumonji D3 (JMJD3/KDM6B) at the nexus of epigenetic regulation of inflammation and the aging process. J Mol Med (Berl). 2014;92(10):1035–43. Scholar
  50. 50.
    Falanga V. Wound healing and its impairment in the diabetic foot. Lancet. 2005;366(9498):1736–43. Scholar
  51. 51.
    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(2):245–53. Scholar
  52. 52.
    Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ, et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med. 2005;11(12):1351–4. Scholar
  53. 53.
    Langton AK, Herrick SE, Headon DJ. An extended epidermal response heals cutaneous wounds in the absence of a hair follicle stem cell contribution. J Invest Dermatol. 2008;128(5):1311–8. Scholar
  54. 54.
    Lu C, Fuchs E. Sweat gland progenitors in development, homeostasis, and wound repair. Cold Spring Harb Perspect Med. 2014;4(2).
  55. 55.
    Hudson LG, Newkirk KM, Chandler HL, Choi C, Fossey SL, Parent AE, et al. Cutaneous wound reepithelialization is compromised in mice lacking functional Slug (Snai2). J Dermatol Sci. 2009;56(1):19–26. Scholar
  56. 56.
    Kusewitt DF, Choi C, Newkirk KM, Leroy P, Li Y, Chavez MG, et al. Slug/Snai2 is a downstream mediator of epidermal growth factor receptor-stimulated reepithelialization. J Invest Dermatol. 2009;129(2):491–5. Scholar
  57. 57.
    Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C, Gridley T, et al. Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol. 2005;202(3):858–66. Scholar
  58. 58.
    McGowan K, Coulombe PA. The wound repair-associated keratins 6, 16, and 17. Insights into the role of intermediate filaments in specifying keratinocyte cytoarchitecture. Subcell Biochem. 1998;31:173–204.PubMedGoogle Scholar
  59. 59.
    Wong P, Coulombe PA. Loss of keratin 6 (K6) proteins reveals a function for intermediate filaments during wound repair. J Cell Biol. 2003;163(2):327–37. Scholar
  60. 60.
    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(3):616–29. Scholar
  61. 61.
    Ezhkova E, Lien WH, Stokes N, Pasolli HA, Silva JM, Fuchs E. EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev. 2011;25(5):485–98. Scholar
  62. 62.
    Ezhkova E, Pasolli HA, Parker JS, Stokes N, Su IH, Hannon G, et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 2009;136(6):1122–35. Scholar
  63. 63.
    Fessing MY, Mardaryev AN, Gdula MR, Sharov AA, Sharova TY, Rapisarda V, et al. p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis. J Cell Biol. 2011;194(6):825–39. Scholar
  64. 64.
    Kashiwagi M, Morgan BA, Georgopoulos K. The chromatin remodeler Mi-2beta is required for establishment of the basal epidermis and normal differentiation of its progeny. Development. 2007;134(8):1571–82. Scholar
  65. 65.
    LeBoeuf M, Terrell A, Trivedi S, Sinha S, Epstein JA, Olson EN, et al. Hdac1 and Hdac2 act redundantly to control p63 and p53 functions in epidermal progenitor cells. Dev Cell. 2010;19(6):807–18. Scholar
  66. 66.
    Mardaryev AN, Liu B, Rapisarda V, Poterlowicz K, Malashchuk I, Rudolf J, et al. Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium. J Cell Biol. 2016;212(1).
  67. 67.
    Sen GL, Reuter JA, Webster DE, Zhu L, Khavari PA. DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature. 2010;463(7280):563–7. Scholar
  68. 68.
    Sen GL, Webster DE, Barragan DI, Chang HY, Khavari PA. Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Genes Dev. 2008;22(14):1865–70. Scholar
  69. 69.
    Roy S, Khanna S, Rink C, Biswas S, Sen CK. Characterization of the acute temporal changes in excisional murine cutaneous wound inflammation by screening of the wound-edge transcriptome. Physiol Genomics. 2008;34(2):162–84. Scholar
  70. 70.
    Dauber KL, Perdigoto CN, Valdes VJ, Santoriello FJ, Cohen I, Ezhkova E. Dissecting the roles of Polycomb repressive complex 2 subunits in the control of skin development. J Invest Dermatol. 2016.
  71. 71.
    Ching YH, Sutton TL, Pierpont YN, Robson MC, Payne WG. The use of growth factors and other humoral agents to accelerate and enhance burn wound healing. Eplasty. 2011;11:e41.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Doma E, Rupp C, Baccarini M. EGFR-ras-raf signaling in epidermal stem cells: roles in hair follicle development, regeneration, tissue remodeling and epidermal cancers. Int J Mol Sci. 2013;14(10):19361–84. Scholar
  73. 73.
    Shi Y, Shu B, Yang R, Xu Y, Xing B, Liu J, et al. Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately. Stem Cell Res Ther. 2015;6:120. Scholar
  74. 74.
    Dorighi KM, Tamkun JW. The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to counteract Polycomb group repression in Drosophila. Development. 2013;140(20):4182–92. Scholar
  75. 75.
    Miyazaki H, Higashimoto K, Yada Y, Endo TA, Sharif J, Komori T, et al. Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract polycomb silencing. PLoS Genet. 2013;9(11):e1003897. Scholar
  76. 76.
    Tanaka Y, Katagiri Z, Kawahashi K, Kioussis D, Kitajima S. Trithorax-group protein ASH1 methylates histone H3 lysine 36. Gene. 2007;397(1–2):161–8. Scholar
  77. 77.
    Li G, Ye Z, Shi C, Sun L, Han M, Zhuang Y, et al. The histone Methyltransferase Ash1l is required for epidermal homeostasis in mice. Sci Rep. 2017;7:45401. Scholar
  78. 78.
    Luis NM, Morey L, Mejetta S, Pascual G, Janich P, Kuebler B, et al. Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4. Cell Stem Cell. 2011;9(3):233–46. Scholar
  79. 79.
    Balasubramanian S, Adhikary G, Eckert RL. The Bmi-1 polycomb protein antagonizes the (−)-epigallocatechin-3-gallate-dependent suppression of skin cancer cell survival. Carcinogenesis. 2010;31(3):496–503. Scholar
  80. 80.
    Cordisco S, Maurelli R, Bondanza S, Stefanini M, Zambruno G, Guerra L, et al. Bmi-1 reduction plays a key role in physiological and premature aging of primary human keratinocytes. J Invest Dermatol. 2010;130(4):1048–62. Scholar
  81. 81.
    Lee K, Adhikary G, Balasubramanian S, Gopalakrishnan R, McCormick T, Dimri GP, et al. Expression of Bmi-1 in epidermis enhances cell survival by altering cell cycle regulatory protein expression and inhibiting apoptosis. J Invest Dermatol. 2008;128(1):9–17. Scholar
  82. 82.
    Reinisch CM, Uthman A, Erovic BM, Pammer J. Expression of BMI-1 in normal skin and inflammatory and neoplastic skin lesions. J Cutan Pathol. 2007;34(2):174–80. Scholar
  83. 83.
    Wang Q, Li WL, You P, Su J, Zhu MH, Xie DF, et al. Oncoprotein BMI-1 induces the malignant transformation of HaCaT cells. J Cell Biochem. 2009;106(1):16–24. Scholar
  84. 84.
    Ohe S, Tanaka T, Yanai H, Komai Y, Omachi T, Kanno S, et al. Maintenance of sweat glands by stem cells located in the acral epithelium. Biochem Biophys Res Commun. 2015;466(3):333–8. Scholar
  85. 85.
    Kurihara K, Isobe T, Yamamoto G, Tanaka Y, Katakura A, Tachikawa T. Expression of BMI1 and ZEB1 in epithelial-mesenchymal transition of tongue squamous cell carcinoma. Oncol Rep. 2015;34(2):771–8. Scholar
  86. 86.
    Qiao B, Chen Z, Hu F, Tao Q, Lam AK. BMI-1 activation is crucial in hTERT-induced epithelial-mesenchymal transition of oral epithelial cells. Exp Mol Pathol. 2013;95(1):57–61. Scholar
  87. 87.
    Yuan W, Yuan Y, Zhang T, Wu S. Role of Bmi-1 in regulation of ionizing irradiation-induced epithelial-mesenchymal transition and migration of breast cancer cells. PLoS One. 2015;10(3):e0118799. Scholar
  88. 88.
    Arnoux V, Côme C, Kusewitt D, Hudson L, Savagner P. Cutaneous wound reepithelialization. In: Savanger P, editor. Rise and fall of epithelial phenotype: concepts of epithelial-mesenchymal transition. Berlin: Springer; 2005. p. 111–34.CrossRefGoogle Scholar
  89. 89.
    Spallotta F, Cencioni C, Straino S, Nanni S, Rosati J, Artuso S, et al. A nitric oxide-dependent cross-talk between class I and III histone deacetylases accelerates skin repair. J Biol Chem. 2013;288(16):11004–12. Scholar
  90. 90.
    Spallotta F, Cencioni C, Straino S, Sbardella G, Castellano S, Capogrossi MC, et al. Enhancement of lysine acetylation accelerates wound repair. Commun Integr Biol. 2013;6(5):e25466. Scholar
  91. 91.
    Wang G, Badylak SF, Heber-Katz E, Braunhut SJ, Gudas LJ. The effects of DNA methyltransferase inhibitors and histone deacetylase inhibitors on digit regeneration in mice. Regen Med. 2010;5(2):201–20. Scholar
  92. 92.
    Lv L, Sun Y, Han X, Xu CC, Tang YP, Dong Q. Valproic acid improves outcome after rodent spinal cord injury: potential roles of histone deacetylase inhibition. Brain Res. 2011;1396:60–8. Scholar
  93. 93.
    Li J, Jiang TX, Hughes MW, Wu P, Yu J, Widelitz RB, et al. Progressive alopecia reveals decreasing stem cell activation probability during aging of mice with epidermal deletion of DNA methyltransferase 1. J Invest Dermatol. 2012;132(12):2681–90. Scholar
  94. 94.
    Rinaldi L, Datta D, Serrat J, Morey L, Solanas G, Avgustinova A, et al. Dnmt3a and Dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasis. Cell Stem Cell. 2016;19(4):491–501. Scholar
  95. 95.
    Rinaldi L, Avgustinova A, Martin M, Datta D, Solanas G, Prats N, et al. Loss of Dnmt3a and Dnmt3b does not affect epidermal homeostasis but promotes squamous transformation through PPAR-gamma. eLife. 2017;6.
  96. 96.
    Sun Y, Sahbaie P, Liang D, Li W, Shi X, Kingery P, et al. DNA methylation modulates nociceptive sensitization after incision. PLoS One. 2015;10(11):e0142046. Scholar
  97. 97.
    Aguilar C, Gardiner DM. DNA methylation dynamics regulate the formation of a regenerative wound epithelium during axolotl limb regeneration. PLoS One. 2015;10(8):e0134791. Scholar
  98. 98.
    Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129–33. Scholar
  99. 99.
    Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333(6047):1300–3. Scholar
  100. 100.
    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–5. Scholar
  101. 101.
    Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu GL, et al. Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. Nat Chem Biol. 2012;8(4):328–30. Scholar
  102. 102.
    Zhang J, Yang C, Wang C, Liu D, Lao G, Liang Y, et al. AGE-induced keratinocyte MMP-9 expression is linked to TET2-mediated CpG Demethylation. Wound Repair Regen. 2016.
  103. 103.
    Tan Q, Wang W, Chuan Y, Zhang J, Sun K, Luo HC, et al. Alpha-ketoglutarate is associated with delayed wound healing in diabetes. Clin Endocrinol. 2016.
  104. 104.
    Kyriakides TR, Wulsin D, Skokos EA, Fleckman P, Pirrone A, Shipley JM, et al. Mice that lack matrix metalloproteinase-9 display delayed wound healing associated with delayed reepithelization and disordered collagen fibrillogenesis. Matrix Biol. 2009;28(2):65–73. Scholar
  105. 105.
    Liu Y, Min D, Bolton T, Nube V, Twigg SM, Yue DK, et al. Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care. 2009;32(1):117–9. Scholar
  106. 106.
    Lobmann R, Zemlin C, Motzkau M, Reschke K, Lehnert H. Expression of matrix metalloproteinases and growth factors in diabetic foot wounds treated with a protease absorbent dressing. J Diabetes Complicat. 2006;20(5):329–35. Scholar
  107. 107.
    Soo C, Shaw WW, Zhang X, Longaker MT, Howard EW, Ting K. Differential expression of matrix metalloproteinases and their tissue-derived inhibitors in cutaneous wound repair. Plast Reconstr Surg. 2000;105(2):638–47.CrossRefPubMedGoogle Scholar
  108. 108.
    Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol. 2007;8(6):464–78. Scholar
  109. 109.
    Ding J, Tredget EE. The role of chemokines in fibrotic wound healing. Adv Wound Care (New Rochelle). 2015;4(11):673–86. Scholar
  110. 110.
    Xue M, Jackson CJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle). 2015;4(3):119–36. Scholar
  111. 111.
    Glenisson W, Castronovo V, Waltregny D. Histone deacetylase 4 is required for TGFbeta1-induced myofibroblastic differentiation. Biochim Biophys Acta. 2007;1773(10):1572–82. Scholar
  112. 112.
    Guo W, Shan B, Klingsberg RC, Qin X, Lasky JA. Abrogation of TGF-beta1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition. Am J Physiol Lung Cell Mol Physiol. 2009;297(5):L864–70. Scholar
  113. 113.
    Ghosh AK, Mori Y, Dowling E, Varga J. Trichostatin A blocks TGF-beta-induced collagen gene expression in skin fibroblasts: involvement of Sp1. Biochem Biophys Res Commun. 2007;354(2):420–6. Scholar
  114. 114.
    Rombouts K, Niki T, Greenwel P, Vandermonde A, Wielant A, Hellemans K, et al. Trichostatin A, a histone deacetylase inhibitor, suppresses collagen synthesis and prevents TGF-beta(1)-induced fibrogenesis in skin fibroblasts. Exp Cell Res. 2002;278(2):184–97.CrossRefPubMedGoogle Scholar
  115. 115.
    Diao JS, Xia WS, Yi CG, Wang YM, Li B, Xia W, et al. Trichostatin A inhibits collagen synthesis and induces apoptosis in keloid fibroblasts. Arch Dermatol Res. 2011;303(8):573–80. Scholar
  116. 116.
    Bai XZ, Liu JQ, Yang LL, Fan L, He T, Su LL, et al. Identification of sirtuin 1 as a promising therapeutic target for hypertrophic scars. Br J Pharmacol. 2016;173(10):1589–601. Scholar
  117. 117.
    Ikeda K, Torigoe T, Matsumoto Y, Fujita T, Sato N, Yotsuyanagi T. Resveratrol inhibits fibrogenesis and induces apoptosis in keloid fibroblasts. Wound Repair Regen. 2013;21(4):616–23. Scholar
  118. 118.
    Russell SB, Russell JD, Trupin KM, Gayden AE, Opalenik SR, Nanney LB, et al. Epigenetically altered wound healing in keloid fibroblasts. J Invest Dermatol. 2010;130(10):2489–96. Scholar
  119. 119.
    Yang E, Qipa Z, Hengshu Z. The expression of DNMT1 in pathologic scar fibroblasts and the effect of 5-aza-2-Deoxycytidine on cytokines of pathologic scar fibroblasts. Wounds. 2014;26(5):139–46.Google Scholar
  120. 120.
    Yang E, Zou QP, Zhang HS. Expression and significance of DNMT1 in human keloid fibroblast. Zhonghua Zheng Xing Wai Ke Za Zhi. 2013;29(2):117–20.PubMedGoogle Scholar
  121. 121.
    Kaluza D, Kroll J, Gesierich S, Manavski Y, Boeckel JN, Doebele C, et al. Histone deacetylase 9 promotes angiogenesis by targeting the antiangiogenic microRNA-17-92 cluster in endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33(3):533–43. Scholar
  122. 122.
    Kaluza D, Kroll J, Gesierich S, Yao TP, Boon RA, Hergenreider E, et al. Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin. EMBO J. 2011;30(20):4142–56. Scholar
  123. 123.
    Deroanne CF, Bonjean K, Servotte S, Devy L, Colige A, Clausse N, et al. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene. 2002;21(3):427–36. Scholar
  124. 124.
    Mahpatra S, Firpo MT, Bacanamwo M. Inhibition of DNA methyltransferases and histone deacetylases induces bone marrow-derived multipotent adult progenitor cells to differentiate into endothelial cells. Ethn Dis. 2010;20(1 Suppl 1):S160–4.Google Scholar
  125. 125.
    Banerjee S, Bacanamwo M. DNA methyltransferase inhibition induces mouse embryonic stem cell differentiation into endothelial cells. Exp Cell Res. 2010;316(2):172–80. Scholar
  126. 126.
    Zhang R, Wang N, Zhang LN, Huang N, Song TF, Li ZZ, et al. Knockdown of Dnmt1 and Dnmt3a promotes the angiogenesis of hMSCs leading to arterial specific differentiation. Stem Cells. 2016.
  127. 127.
    Smits M, Mir SE, Nilsson RJ, van der Stoop PM, Niers JM, Marquez VE, et al. Down-regulation of miR-101 in endothelial cells promotes blood vessel formation through reduced repression of EZH2. PLoS One. 2011;6(1):e16282. Scholar
  128. 128.
    Turunen MP, Yla-Herttuala S. Epigenetic regulation of key vascular genes and growth factors. Cardiovasc Res. 2011;90(3):441–6. Scholar
  129. 129.
    Fork C, Gu L, Hitzel J, Josipovic I, Hu J, SzeKa Wong M, et al. Epigenetic regulation of angiogenesis by JARID1B-induced repression of HOXA5. Arterioscler Thromb Vasc Biol. 2015;35(7):1645–52. Scholar
  130. 130.
    Cuevas I, Layman H, Coussens L, Boudreau N. Sustained endothelial expression of HoxA5 in vivo impairs pathological angiogenesis and tumor progression. PLoS One. 2015;10(3):e0121720. Scholar
  131. 131.
    Kachgal S, Mace KA, Boudreau NJ. The dual roles of homeobox genes in vascularization and wound healing. Cell Adhes Migr. 2012;6(6):457–70. Scholar
  132. 132.
    Liang Y, Xia L, Du Z, Sheng L, Chen H, Chen G, et al. HOXA5 inhibits keratinocytes growth and epidermal formation in organotypic cultures in vitro and in vivo. J Dermatol Sci. 2012;66(3):197–206. Scholar
  133. 133.
    Maeng YS, Kwon JY, Kim EK, Kwon YG. Heterochromatin protein 1 alpha (HP1alpha: CBX5) is a key regulator in differentiation of endothelial progenitor cells to endothelial cells. Stem Cells. 2015;33(5):1512–22. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre for Skin Sciences, School of Chemistry and Biosciences, Faculty of Life ScienceUniversity of BradfordBradfordUK

Personalised recommendations