Epigenetics and the overhealing wound: the role of DNA methylation in fibrosis

Fibrogenesis & Tissue Repair

John A. Baugh¹  Chris J. Watson¹  Roisin Neary¹ 

[1] UCD School of Medicine and Medical Science, Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield Dublin 4, Ireland

关键词: 5-aza-2′-deoxycytidine;    5-azacytidine;    DNA methylation;    Myofibroblast;    Fibroblast;    Fibrosis;   

Others  :  1229896
DOI  :  10.1186/s13069-015-0035-8

 received in 2015-06-10, accepted in 2015-09-04,  发布年份 2015

【 摘 要 】

Fibrosis is a progressive and potentially fatal process that can occur in numerous organ systems. Characterised by the excessive deposition of extracellular matrix proteins such as collagens and fibronectin, fibrosis affects normal tissue architecture and impedes organ function. Although a considerable amount of research has focused on the mechanisms underlying disease pathogenesis, current therapeutic options do not directly target the pro-fibrotic process. As a result, there is a clear unmet clinical need to develop new agents. Novel findings implicate a role for epigenetic modifications contributing to the progression of fibrosis by alteration of gene expression profiles.

This review will focus on DNA methylation; its association with fibroblast differentiation and activation and the consequent buildup of fibrotic scar tissue. The potential use of therapies that modulate this epigenetic pathway for the treatment of fibrosis in several organ systems is also discussed.

【 授权许可】

   
2015 Neary et al.

【 图 表 】

Fig. 1.

【 参考文献 】

• [1]Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Investig. 2007; 117(3):524-9.
• [2]Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008; 214(2):199-210.
• [3]Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012; 18(7):1028-40.
• [4]Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003; 200(4):500-3.
• [5]Ghosh AK, Quaggin SE, Vaughan DE. Molecular basis of organ fibrosis: potential therapeutic approaches. Exp Biol Med (Maywood). 2013; 238(5):461-81.
• [6]Hu B, Gharaee-Kermani M, Wu Z, Phan SH. Epigenetic regulation of myofibroblast differentiation by DNA methylation. Am J Pathol. 2010; 177(1):21-8.
• [7]Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J et al.. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012; 180(4):1340-55.
• [8]Sarrazy V, Billet F, Micallef L, Coulomb B, Desmouliere A. Mechanisms of pathological scarring: role of myofibroblasts and current developments. Wound Repair Regen. 2011; 19 Suppl 1:s10-5.
• [9]Desmouliere A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol. 1995; 146(1):56-66.
• [10]Friedman SL. Fibrogenic cell reversion underlies fibrosis regression in liver. Proc Natl Acad Sci U S A. 2012; 109(24):9230-1.
• [11]McAnulty RJ. Fibroblasts and myofibroblasts: their source, function and role in disease. Int J Biochem Cell Biol. 2007; 39(4):666-71.
• [12]Jordana M, Schulman J, McSharry C, Irving LB, Newhouse MT, Jordana G et al.. Heterogeneous proliferative characteristics of human adult lung fibroblast lines and clonally derived fibroblasts from control and fibrotic tissue. Am Rev Respir Dis. 1988; 137(3):579-84.
• [13]Hetzel M, Bachem M, Anders D, Trischler G, Faehling M. Different effects of growth factors on proliferation and matrix production of normal and fibrotic human lung fibroblasts. Lung. 2005; 183(4):225-37.
• [14]Dwivedi RS, Herman JG, McCaffrey TA, Raj DS. Beyond genetics: epigenetic code in chronic kidney disease. Kidney Int. 2011; 79(1):23-32.
• [15]Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004; 429(6990):457-63.
• [16]Das PM, Singal R. DNA methylation and cancer. J Clin Oncol. 2004; 22(22):4632-42.
• [17]Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H et al.. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology. 2010; 138(2):705-14.
• [18]Zeisberg EM, Zeisberg M. The role of promoter hypermethylation in fibroblast activation and fibrogenesis. J Pathol. 2013; 229(2):264-73.
• [19]Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W et al.. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature. 2011; 477(7366):606-10.
• [20]Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J et al.. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature. 2011; 473(7347):343-8.
• [21]Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013; 502(7472):472-9.
• [22]Zhang P, Huang B, Xu X, Sessa WC. Ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG), components of the demethylation pathway, are direct targets of miRNA-29a. Biochem Biophys Res Commun. 2013; 437(3):368-73.
• [23]Hu X, Zhang L, Mao SQ, Li Z, Chen J, Zhang RR et al.. Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming. Cell Stem Cell. 2014; 14(4):512-22.
• [24]Kinney SR, Pradhan S. Ten eleven translocation enzymes and 5-hydroxymethylation in mammalian development and cancer. Adv Exp Med Biol. 2013; 754:57-79.
• [25]Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009; 10(5):295-304.
• [26]Chuang JC, Jones PA. Epigenetics and microRNAs. Pediatr Res. 2007; 61(5 Pt 2):24R-9R.
• [27]Sato F, Tsuchiya S, Meltzer SJ, Shimizu K. MicroRNAs and epigenetics. FEBS J. 2011; 278(10):1598-609.
• [28]Dakhlallah D, Batte K, Wang Y, Cantemir-Stone CZ, Yan P, Nuovo G et al.. Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med. 2013; 187(4):397-405.
• [29]Nishigaki M, Aoyagi K, Danjoh I, Fukaya M, Yanagihara K, Sakamoto H et al.. Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays. Cancer Res. 2005; 65(6):2115-24.
• [30]Laird PW, Jaenisch R. The role of DNA methylation in cancer genetic and epigenetics. Annu Rev Genet. 1996; 30:441-64.
• [31]Wolff EM, Byun HM, Han HF, Sharma S, Nichols PW, Siegmund KD et al.. Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer. PLoS Genet. 2010; 6(4): Article ID e1000917
• [32]Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010; 28(10):1057-68.
• [33]Olson EN. MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease. Sci Transl Med. 2014; 6(239):39ps3.
• [34]Vigna E, Recchia AG, Madeo A, Gentile M, Bossio S, Mazzone C et al.. Epigenetic regulation in myelodysplastic syndromes: implications for therapy. Expert Opin Investig Drugs. 2011; 20(4):465-93.
• [35]Smith BD, Beach CL, Mahmoud D, Weber L, Henk HJ. Survival and hospitalization among patients with acute myeloid leukemia treated with azacitidine or decitabine in a large managed care population: a real-world, retrospective, claims-based, comparative analysis. Experimental Hematol Oncol. 2014; 3(1):10. BioMed Central Full Text
• [36]Schneider-Stock R, Diab-Assef M, Rohrbeck A, Foltzer-Jourdainne C, Boltze C, Hartig R et al.. 5-Aza-cytidine is a potent inhibitor of DNA methyltransferase 3a and induces apoptosis in HCT-116 colon cancer cells via Gadd45- and p53-dependent mechanisms. J Pharmacol Exp Ther. 2005; 312(2):525-36.
• [37]Fandy TE. Development of DNA methyltransferase inhibitors for the treatment of neoplastic diseases. Curr Med Chem. 2009; 16(17):2075-85.
• [38]Dastjerdi MN, Babazadeh Z, Salehi M, Hashemibeni B, Kazemi M. Comparison of the anti-cancer effect of Disulfiram and 5-Aza-CdR on pancreatic cancer cell line PANC-1. Advanced Biomedical Res. 2014; 3:156.
• [39]Christman JK. 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002; 21(35):5483-95.
• [40]Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S. A pilot pharmacokinetic study of oral azacitidine. Leukemia. 2008; 22(9):1680-4.
• [41]Garcia-Manero G, Gore SD, Cogle C, Ward R, Shi T, Macbeth KJ et al.. Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 2011; 29(18):2521-7.
• [42]Neupane YR, Sabir MD, Ahmad N, Ali M, Kohli K. Lipid drug conjugate nanoparticle as a novel lipid nanocarrier for the oral delivery of decitabine: ex vivo gut permeation studies. Nanotechnology. 2013; 24(41):415102.
• [43]Neupane YR, Srivastava M, Ahmad N, Kumar N, Bhatnagar A, Kohli K. Lipid based nanocarrier system for the potential oral delivery of decitabine: formulation design, characterization, ex vivo, and in vivo assessment. Int J Pharm. 2014; 477(1–2):601-12.
• [44]Xu RX, Xu JS, Zuo T, Shen R, Huang TH, Tweedle MF. Drug-loaded biodegradable microspheres for image-guided combinatory epigenetic therapy in cells. J Biomed Opt. 2011; 16(2):020507.
• [45]Phan SH. Biology of fibroblasts and myofibroblasts. Proc Am Thorac Soc. 2008; 5(3):334-7.
• [46]Tao H, Huang C, Yang JJ, Ma TT, Bian EB, Zhang L et al.. MeCP2 controls the expression of RASAL1 in the hepatic fibrosis in rats. Toxicology. 2011; 290(2–3):327-33.
• [47]Sanders YY, Ambalavanan N, Halloran B, Zhang X, Liu H, Crossman DK et al.. Altered DNA methylation profile in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012; 186(6):525-35.
• [48]Rabinovich EI, Kapetanaki MG, Steinfeld I, Gibson KF, Pandit KV, Yu G et al.. Global methylation patterns in idiopathic pulmonary fibrosis. PLoS One. 2012; 7(4): Article ID e33770
• [49]Zhou Y, Hagood JS, Lu B, Merryman WD, Murphy-Ullrich JE. Thy-1-integrin alphav beta5 interactions inhibit lung fibroblast contraction-induced latent transforming growth factor-beta1 activation and myofibroblast differentiation. J Biol Chem. 2010; 285(29):22382-93.
• [50]Zhou Y, Hagood JS, Murphy-Ullrich JE. Thy-1 expression regulates the ability of rat lung fibroblasts to activate transforming growth factor-beta in response to fibrogenic stimuli. Am J Pathol. 2004; 165(2):659-69.
• [51]Sanders YY, Kumbla P, Hagood JS. Enhanced myofibroblastic differentiation and survival in Thy-1(−) lung fibroblasts. Am J Respir Cell Mol Biol. 2007; 36(2):226-35.
• [52]Sanders YY, Pardo A, Selman M, Nuovo GJ, Tollefsbol TO, Siegal GP et al.. Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2008; 39(5):610-8.
• [53]Robinson CM, Neary R, Levendale A, Watson CJ, Baugh JA. Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype. Respir Res. 2012; 13:74. BioMed Central Full Text
• [54]Huang SK, Fisher AS, Scruggs AM, White ES, Hogaboam CM, Richardson BC et al.. Hypermethylation of PTGER2 confers prostaglandin E2 resistance in fibrotic fibroblasts from humans and mice. Am J Pathol. 2010; 177(5):2245-55.
• [55]Cisneros J, Hagood J, Checa M, Ortiz-Quintero B, Negreros M, Herrera I et al.. Hypermethylation-mediated silencing of p14(ARF) in fibroblasts from idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012; 303(4):L295-303.
• [56]Ko YA, Mohtat D, Suzuki M, Park AS, Izquierdo MC, Han SY et al.. Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development. Genome Biol. 2013; 14(10):R108. BioMed Central Full Text
• [57]Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ et al.. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med. 2010; 16(5):544-50.
• [58]Tampe B, Tampe D, Muller CA, Sugimoto H, LeBleu V, Xu X et al.. Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J Am Soc Nephrol. 2014; 25(5):905-12.
• [59]Bian EB, Huang C, Wang H, Chen XX, Tao H, Zhang L et al.. The role of methyl-CpG binding protein 2 in liver fibrosis. Toxicology. 2013; 309:9-14.
• [60]Mann J, Oakley F, Akiboye F, Elsharkawy A, Thorne AW, Mann DA. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. Cell Death Differ. 2007; 14(2):275-85.
• [61]Hu B, Gharaee-Kermani M, Wu Z, Phan SH. Essential role of MeCP2 in the regulation of myofibroblast differentiation during pulmonary fibrosis. Am J Pathol. 2011; 178(4):1500-8.
• [62]Komatsu Y, Waku T, Iwasaki N, Ono W, Yamaguchi C, Yanagisawa J. Global analysis of DNA methylation in early-stage liver fibrosis. BMC Med Genet. 2012; 5:5.
• [63]Watson CJ, Collier P, Tea I, Neary R, Watson JA, Robinson C et al.. Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum Mol Genet. 2013.
• [64]Turdi S, Sun W, Tan Y, Yang X, Cai L, Ren J. Inhibition of DNA methylation attenuates low-dose cadmium-induced cardiac contractile and intracellular Ca(2+) anomalies. Clin Exp Pharmacol Physiol. 2013; 40(10):706-12.
• [65]Kim YS, Kang WS, Kwon JS, Hong MH, Jeong HY, Jeong HC, et al. Protective role of 5-azacytidine on myocardial infarction is associated with modulation of macrophage phenotype and inhibition of fibrosis. J Cell Mol Med. 2014. doi:10.1111/jcmm.12248.
• [66]Watson CJ, Horgan S, Neary R, Glezeva N, Tea I, Corrigan N, et al. Epigenetic therapy for the treatment of hypertension-induced cardiac hypertrophy and fibrosis. J Cardiovasc Pharmacol Ther. 2015. doi:10.1177/1074248415591698.
• [67]Xu X, Tan X, Tampe B, Nyamsuren G, Liu X, Maier LS et al.. Epigenetic balance of aberrant Rasal1 promoter methylation and hydroxymethylation regulates cardiac fibrosis. Cardiovasc Res. 2015; 105(3):279-91.
• [68]Movassagh M, Choy MK, Goddard M, Bennett MR, Down TA, Foo RS. Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure. PLoS One. 2010; 5(1): Article ID e8564
• [69]Movassagh M, Choy MK, Knowles DA, Cordeddu L, Haider S, Down T et al.. Distinct epigenomic features in end-stage failing human hearts. Circulation. 2011; 124(22):2411-22.
• [70]Altorok N, Tsou PS, Coit P, Khanna D, Sawalha AH. Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Ann Rheum Dis. 2015; 74(8):1612-20.
• [71]Wang Y, Fan PS, Kahaleh B. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum. 2006; 54(7):2271-9.
• [72]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.
• [73]Bian EB, Huang C, Wang H, Chen XX, Zhang L, Lv XW et al.. Repression of Smad7 mediated by DNMT1 determines hepatic stellate cell activation and liver fibrosis in rats. Toxicol Lett. 2014; 224(2):175-85.
• [74]Watson CJ, Collier P, Tea I, Neary R, Watson JA, Robinson C et al.. Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype. Hum Mol Genet. 2014; 23(8):2176-88.
• [75]Tao H, Yang JJ, Chen ZW, Xu SS, Zhou X, Zhan HY et al.. DNMT3A silencing RASSF1A promotes cardiac fibrosis through upregulation of ERK1/2. Toxicology. 2014; 323C:42-50.
• [76]Norman JT, Clark IM, Garcia PL. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int. 2000; 58(6):2351-66.
• [77]Chen P, Wu R, Zhu W, Jiang Z, Xu Y, Chen H et al.. Hypoxia preconditioned mesenchymal stem cells prevent cardiac fibroblast activation and collagen production via leptin. PLoS One. 2014; 9(8): Article ID e103587
• [78]Watson JA, Watson CJ, McCann A, Baugh J. Epigenetics, the epicenter of the hypoxic response. Epigenetics. 2010; 5(4):293-6.
• [79]Watson JA, Watson CJ, McCrohan AM, Woodfine K, Tosetto M, McDaid J et al.. Generation of an epigenetic signature by chronic hypoxia in prostate cells. Hum Mol Genet. 2009; 18(19):3594-604.
• [80]Shahrzad S, Bertrand K, Minhas K, Coomber BL. Induction of DNA hypomethylation by tumor hypoxia. Epigenetics. 2007; 2(2):119-25.
• [81]Skowronski K, Dubey S, Rodenhiser D, Coomber B. Ischemia dysregulates DNA methyltransferases and p16INK4a methylation in human colorectal cancer cells. Epigenetics. 2010; 5(6):547-56.
• [82]Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011; 2(12):1117-33.
• [83]Keane MP, Belperio JA, Arenberg DA, Burdick MD, Xu ZJ, Xue YY et al.. IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol. 1999; 163(10):5686-92.
• [84]Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW et al.. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Respir Crit Care Med. 2004; 170(3):242-51.
• [85]Taura K, De Minicis S, Seki E, Hatano E, Iwaisako K, Osterreicher CH et al.. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology. 2008; 135(5):1729-38.
• [86]Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol. 2001; 12(7):1448-57.
• [87]Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E et al.. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007; 13(8):952-61.
• [88]Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005; 308(5727):1466-9.
• [89]Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature. 2010; 467(7318):963-6.
• [90]Carone BR, Fauquier L, Habib N, Shea JM, Hart CE, Li R et al.. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010; 143(7):1084-96.
• [91]Zeybel M, Hardy T, Wong YK, Mathers JC, Fox CR, Gackowska A et al.. Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat Med. 2012; 18(9):1369-77.
• [92]Mouralidarane A, Soeda J, Sugden D, Bocianowska A, Carter R, Ray S et al.. Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice. Int J Obes (Lond). 2015.
• [93]Hastings MH, Reddy AB, Maywood ES. A clockwork web: circadian timing in brain and periphery, in health and disease. Nat Rev Neurosci. 2003; 4(8):649-61.
• [94]Schibler U, Sassone-Corsi P. A web of circadian pacemakers. Cell. 2002; 111(7):919-22.
• [95]Brown SA, Kowalska E, Dallmann R. (Re)inventing the circadian feedback loop. Dev Cell. 2012; 22(3):477-87.
• [96]Dardente H, Cermakian N. Molecular circadian rhythms in central and peripheral clocks in mammals. Chronobiol Int. 2007; 24(2):195-213.
• [97]Mazzoccoli G, Pazienza V, Vinciguerra M. Clock genes and clock-controlled genes in the regulation of metabolic rhythms. Chronobiol Int. 2012; 29(3):227-51.
• [98]Joska TM, Zaman R, Belden WJ. Regulated DNA methylation and the circadian clock: implications in cancer. Biology. 2014; 3(3):560-77.
• [99]Brudnowska J, Peplonska B. Night shift work and cancer risk: a literature review. Med Pr. 2011; 62(3):323-38.
• [100]Chen ST, Choo KB, Hou MF, Yeh KT, Kuo SJ, Chang JG. Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis. 2005; 26(7):1241-6.
• [101]Taniguchi H, Fernandez AF, Setien F, Ropero S, Ballestar E, Villanueva A et al.. Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. Cancer Res. 2009; 69(21):8447-54.
• [102]Hsu MC, Huang CC, Choo KB, Huang CJ. Uncoupling of promoter methylation and expression of Period1 in cervical cancer cells. Biochem Biophys Res Commun. 2007; 360(1):257-62.
• [103]Yang MY, Chang JG, Lin PM, Tang KP, Chen YH, Lin HY et al.. Downregulation of circadian clock genes in chronic myeloid leukemia: alternative methylation pattern of hPER3. Cancer Sci. 2006; 97(12):1298-307.
• [104]Diegelmann RF, Evans MC. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci. 2004; 9:283-9.
• [105]Novak ML, Koh TJ. Phenotypic transitions of macrophages orchestrate tissue repair. Am J Pathol. 2013; 183(5):1352-63.
• [106]Weidenbusch M, Anders HJ. Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis. J Innate Immun. 2012; 4(5–6):463-77.
• [107]Yang X, Wang X, Liu D, Yu L, Xue B, Shi H. Epigenetic regulation of macrophage polarization by DNA methyltransferase 3b. Mol Endocrinol. 2014; 28(4):565-74.