Iranian Journal of Allergy, Asthma and Immunology 2017. 16(2):82-91.

Role of Epigenetics in the Pathogenesis of Asthma
Zahra Alizadeh, Esmaeil Mortaz, Ian. Adcock, Mostafa Moin


Asthma is a complex, heterogeneous and chronic airway inflammatory disease with different clinical phenotypes caused by diverse triggers and pathophysiological mechanisms. Asthma heritability has been established in many genetic studies but it is evident that only genetic elements are not responsible for the development of asthma. Increasing rate of asthma incidence during past decades has implicated the role of epigenetics in development of asthma. Environmental factors perform as initiator signals through epigenetic mechanisms. Three epigenetic mechanisms have been identified, including DNA methylation, histone modifications, and small noncoding RNAs. These mechanisms regulate the immune responses and inflammatory genes expression in asthma and allergy. This review explains the role of epigenetic modifications in controlling Th2 response and IgE production in asthma and also briefly overviews the role of environmental factors such as pollutions, allergens, prenatal exposures and diet in developing asthma. Recognizing environmental risk factors and their effects on epigenetic mechanisms would be of great interest for prognostic and preventive aspect in treatment of asthma. 


Asthma; DNA methylation; Epigenetics; Histone modification; miRNA; Environmental factors

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1. Moin M, et al. Asthma- Basic and clinical sciences. 2 ed. Tehran, Iran: Markaz Nashr Daneshgahi; In press.

2.Kabesch M, Adcock IM. Epigenetics in asthma and COPD. Biochimie. 2012;94(11):2231-41.

3. Gronbaek K, Hother C, Jones PA. Epigenetic changes in cancer. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2007;115(10):1039-59.

4. Jhala DV, Kale RK, Singh RP. Microgravity Alters Cancer Growth And Progression. Current cancer drug targets. 2014.

5.Langevin SM, Kratzke RA, Kelsey KT. Epigenetics of lung cancer. Translational research : the journal of laboratory and clinical medicine. 2014.

6. Arantes LM, de Carvalho AC, Melendez ME, Carvalho AL, Goloni-Bertollo EM. Methylation as a biomarker for head and neck cancer. Oral oncology. 2014.

7. Orozco-Solis R, Sassone-Corsi P. Epigenetic control and the circadian clock: Linking metabolism to neuronal responses. Neuroscience. 2014;264C:76-87.

8. Skinner MK, Manikkam M, Guerrero-Bosagna C. Epigenetic transgenerational actions of endocrine disruptors. Reproductive toxicology (Elmsford, NY). 2011;31(3):337-43.

9.  Liu Y, Li H, Xiao T, Lu Q. Epigenetics in immune-mediated pulmonary diseases. Clinical reviews in allergy & immunology. 2013;45(3):314-30.

10.  Karmaus W, Ziyab AH, Everson T, Holloway JW. Epigenetic mechanisms and models in the origins of asthma. Current opinion in allergy and clinical immunology. 2013;13(1):63-9.

11. Wu SC, Zhang Y. Active DNA demethylation: many roads lead to Rome. Nature reviews Molecular cell biology. 2010;11(9):607-20.

12. Adcock IM, Ford P, Ito K, Barnes PJ. Epigenetics and airways disease. Respiratory research. 2006;7:21.

13. Durham AL, Wiegman C, Adcock IM. Epigenetics of asthma. Biochimica et biophysica acta. 2011;1810(11):1103-9.

14.Munshi A, Shafi G, Aliya N, Jyothy A. Histone modifications dictate specific biological readouts. Journal of genetics and genomics = Yi chuan xue bao. 2009;36(2):75-88.

15. Seidel C, Schnekenburger M, Dicato M, Diederich M. Histone deacetylase modulators provided by Mother Nature. Genes & nutrition. 2012;7(3):357-67.

16.Yang IV, Schwartz DA. Epigenetic control of gene expression in the lung. American journal of respiratory and critical care medicine. 2011;183(10):1295-301.

17.  Yu Q, Zhou B, Zhang Y, Nguyen ET, Du J, Glosson NL, et al. DNA methyltransferase 3a limits the expression of interleukin-13 in T helper 2 cells and allergic airway inflammation. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(2):541-6.

18.  Zeng WP. 'All things considered': transcriptional regulation of T helper type 2 cell differentiation from precursor to effector activation. Immunology. 2013;140(1):31-8.

19. Kwon NH, Kim JS, Lee JY, Oh MJ, Choi DC. DNA methylation and the expression of IL-4 and IFN-gamma promoter genes in patients with bronchial asthma. Journal of clinical immunology. 2008;28(2):139-46.

20. Begin P, Nadeau KC. Epigenetic regulation of asthma and allergic disease. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. 2014;10(1):27.

21. Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009;30(1):155-67.

22.  Singh A, Yamamoto M, Ruan J, Choi JY, Gauvreau GM, Olek S, et al. Th17/Treg ratio derived using DNA methylation analysis is associated with the late phase asthmatic response. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. 2014;10(1):32.

23. Lopez-Pastrana J, Shao Y, Chernaya V, Wang H, Yang XF. Epigenetic enzymes are the therapeutic targets for CD4(+)CD25(+/high)Foxp3(+) regulatory T cells. Translational research : the journal of laboratory and clinical medicine. 2015;165(1):221-40.

24. Lu L, Ma J, Li Z, Lan Q, Chen M, Liu Y, et al. All-trans retinoic acid promotes TGF-beta-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus. PloS one. 2011;6(9):e24590.

25. Pua HH, Steiner DF, Patel S, Gonzalez JR, Ortiz-Carpena JF, Kageyama R, et al. MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production. Immunity. 2016.

26.  Simpson LJ, Patel S, Bhakta NR, Choy DF, Brightbill HD, Ren X, et al. A microRNA upregulated in asthma airway T cells promotes TH2 cytokine production. 2014;15(12):1162-70.

27. Chung KF, Adcock IM. Clinical phenotypes of asthma should link up with disease mechanisms. Current opinion in allergy and clinical immunology. 2015;15(1):56-62.

28. Tay HL, Plank M, Collison A, Mattes J, Kumar RK, Foster PS. MicroRNA: potential biomarkers and therapeutic targets for allergic asthma? Annals of medicine. 2014;46(8):633-9.

29. Chung KF, Adcock IM. How variability in clinical phenotypes should guide research into disease mechanisms in asthma. Annals of the American Thoracic Society. 2013;10(Supplement):S109-S17.

30.  Brunst KJ, Baccarelli AA, Wright RJ. Integrating mitochondriomics in children's environmental health. Journal of applied toxicology : JAT. 2015;35(9):976-91.

31. Brook PO, Perry MM, Adcock IM, Durham AL. Epigenome-modifying tools in asthma. Epigenomics. 2015;7(6):1017-32.

32. Curtin JA, Simpson A, Belgrave D, Semic-Jusufagic A, Custovic A, Martinez FD. Methylation of IL-2 promoter at birth alters the risk of asthma exacerbations during childhood. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2013;43(3):304-11.

33.Runyon RS, Cachola LM, Rajeshuni N, Hunter T, Garcia M, Ahn R, et al. Asthma discordance in twins is linked to epigenetic modifications of T cells. PloS one. 2012;7(11):e48796.

34. Berlivet S, Moussette S, Ouimet M, Verlaan DJ, Koka V, Al Tuwaijri A, et al. Interaction between genetic and epigenetic variation defines gene expression patterns at the asthma-associated locus 17q12-q21 in lymphoblastoid cell lines. Human genetics. 2012;131(7):1161-71.

35. Morales E, Bustamante M, Vilahur N, Escaramis G, Montfort M, de Cid R, et al. DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood. American journal of respiratory and critical care medicine. 2012;185(9):937-43.

36. Pascual M, Suzuki M, Isidoro-Garcia M, Padron J, Turner T, Lorente F, et al. Epigenetic changes in B lymphocytes associated with house dust mite allergic asthma. Epigenetics : official journal of the DNA Methylation Society. 2011;6(9):1131-7.

37.  Iwata M, Eshima Y, Kagechika H. Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. International immunology. 2003;15(8):1017-25.

38. Somineni HK, Zhang X, Biagini Myers JM, Kovacic MB, Ulm A, Jurcak N, et al. Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution. The Journal of allergy and clinical immunology. 2016;137(3):797-805.e5.

39.  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.

40. Gagne-Ouellet V, Guay SP, Boucher-Lafleur AM, Bouchard L, Laprise C. DNA methylation signature of interleukin 1 receptor type II in asthma. Clinical epigenetics. 2015;7(1):80.

41. Murphy TM, Wong CC, Arseneault L, Burrage J, Macdonald R, Hannon E, et al. Methylomic markers of persistent childhood asthma: a longitudinal study of asthma-discordant monozygotic twins. Clinical epigenetics. 2015;7:130.

42. Mortaz E, Masjedi MR, Barnes PJ, Adcock IM. Epigenetics and chromatin remodeling play a role in lung disease. Tanaffos. 2011;10(4):7-16.

43. Cui ZL, Gu W, Ding T, Peng XH, Chen X, Luan CY, et al. Histone modifications of notch1 promoter affect lung CD4+ T cell differentiation in asthmatic rats. International journal of immunopathology and pharmacology. 2013;26(2):371-81.

44. Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. The Journal of allergy and clinical immunology. 2013;131(3):636-45.

45.  Barnes PJ. Histone deacetylase-2 and airway disease. Therapeutic advances in respiratory disease. 2009;3(5):235-43.

46.  Stefanowicz D, Lee JY, Lee K, Shaheen F, Koo HK, Booth S, et al. Elevated H3K18 acetylation in airway epithelial cells of asthmatic subjects. Respiratory research. 2015;16:95.

47.  Clifford RL, Patel JK, John AE, Tatler AL, Mazengarb L, Brightling CE, et al. CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: regulation by BET. American journal of physiology Lung cellular and molecular physiology. 2015;308(9):L962-72.

48. Seumois G, Chavez L, Gerasimova A, Lienhard M, Omran N, Kalinke L, et al. Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility. 2014;15(8):777-88.

49. Lu TX, Hartner J, Lim EJ, Fabry V, Mingler MK, Cole ET, et al. MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity. Journal of immunology (Baltimore, Md : 1950). 2011;187(6):3362-73.

50.  Liao G, Panettieri RA, Tang DD. MicroRNA-203 negatively regulates c-Abl, ERK1/2 phosphorylation, and proliferation in smooth muscle cells. Physiological reports. 2015;3(9).

51.  Karner J, Wawrzyniak M, Tankov S, Runnel T, Aints A, Kisand K, et al. Increased microRNA-323-3p in IL-22/IL-17-producing T cells and asthma: a role in the regulation of the TGF-beta pathway and IL-22 production. Allergy. 2016.

52.    Elbehidy RM, Youssef DM, El-Shal AS, Shalaby SM, Sherbiny HS, Sherief LM, et al. MicroRNA-21 as a novel biomarker in diagnosis and response to therapy in asthmatic children. Molecular immunology. 2016;71:107-14.

53.   Dileepan M, Sarver AE, Rao SP, Panettieri RA, Jr., Subramanian S, Kannan MS. MicroRNA Mediated Chemokine Responses in Human Airway Smooth Muscle Cells. PloS one. 2016;11(3):e0150842.

54.  Rupani H, Martinez-Nunez RT, Dennison P, Lau LC, Jayasekera N, Havelock T, et al. Toll-like Receptor 7 is Reduced in Severe Asthma and Linked to Altered MicroRNA Profile. American journal of respiratory and critical care medicine. 2016.

55.  Panganiban RP, Wang Y, Howrylak J, Chinchilli VM, Craig TJ, August A, et al. Circulating microRNAs as biomarkers in patients with allergic rhinitis and asthma. The Journal of allergy and clinical immunology. 2016.

56.  Troy NM, Hollams EM, Holt PG, Bosco A. Differential gene network analysis for the identification of asthma-associated therapeutic targets in allergen-specific T-helper memory responses. BMC medical genomics. 2016;9(1):9.

57.  Rolland C, Zuberbier T, Hellings PW, Virchow JC. Diagnostic challenges of adult asthma. Allergy. 2016;22(1):38-45.

58. Comer BS, Ba M, Singer CA, Gerthoffer WT. Epigenetic targets for novel therapies of lung diseases. Pharmacology & therapeutics. 2015;147:91-110.

59. Himes BE, Weitzman ER. Innovations in health information technologies for chronic pulmonary diseases. Respiratory research. 2016;17:38.

60.  Jokay A, Farkas A, Furi P, Horvath A, Tomisa G, Balashazy I. Computer modeling of airway deposition distribution of Foster NEXThaler and Seretide Diskus dry powder combination drugs. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2016.

61.  Liang L, Willis-Owen SA, Laprise C, Wong KC, Davies GA, Hudson TJ, et al. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature. 2015;520(7549):670-4.

62.  Everson TM, Lyons G, Zhang H, Soto-Ramirez N, Lockett GA, Patil VK, et al. DNA methylation loci associated with atopy and high serum IgE: a genome-wide application of recursive Random Forest feature selection. Genome medicine. 2015;7(1):89.

63.  Koh BH, Hwang SS, Kim JY, Lee W, Kang MJ, Lee CG, et al. Th2 LCR is essential for regulation of Th2 cytokine genes and for pathogenesis of allergic asthma. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(23):10614-9.

64.  Hong X, Tsai HJ, Liu X, Arguelles L, Kumar R, Wang G, et al. Does genetic regulation of IgE begin in utero? Evidence from T(H)1/T(H)2 gene polymorphisms and cord blood total IgE. The Journal of allergy and clinical immunology. 2010;126(5):1059-67, 67.e1.

65. Lockett GA, Huoman J, Holloway JW. Does Allergy Begin In Utero? Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2015.

66.  Liang Y, Chang C, Lu Q. The Genetics and Epigenetics of Atopic Dermatitis-Filaggrin and Other Polymorphisms. Clinical reviews in allergy & immunology. 2015.

67.   Fu X, Wang X, Duan Z, Zhang C, Fu X, Yang J, et al. Histone H3k9 and H3k27 Acetylation Regulates IL-4/STAT6-Mediated Igepsilon Transcription in B Lymphocytes. Anatomical record (Hoboken, NJ : 2007). 2015;298(8):1431-9.

68.  Godava M, Vrtel R, Vodicka R. STAT6 - polymorphisms, haplotypes and epistasis in relation to atopy and asthma. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2013;157(2):172-80.

69.  Yang IV, Pedersen BS, Liu A, O'Connor GT, Teach SJ, Kattan M, et al. DNA methylation and childhood asthma in the inner city. The Journal of allergy and clinical immunology. 2015;136(1):69-80.

70.  Kabesch M, Michel S, Tost J. Epigenetic mechanisms and the relationship to childhood asthma. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 2010;36(4):950-61.

71.  de Planell-Saguer M, Lovinsky-Desir S, Miller RL. Epigenetic regulation: the interface between prenatal and early-life exposure and asthma susceptibility. Environmental and molecular mutagenesis. 2014;55(3):231-43.

72. Shang Y, Das S, Rabold R, Sham JS, Mitzner W, Tang WY. Epigenetic alterations by DNA methylation in house dust mite-induced airway hyperresponsiveness. Am J Respir Cell Mol Biol 2013; 49(2):279-87.

73.  Collison A, Mattes J, Plank M, Foster PS. Inhibition of house dust mite-induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment. The Journal of allergy and clinical immunology. 2011;128(1):160-7.e4.

74. Brand S, Kesper DA, Teich R, Kilic-Niebergall E, Pinkenburg O, Bothur E, et al. DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma. The Journal of allergy and clinical immunology. 2012;129(6):1602-10 e6.

75.  Liu J, Ballaney M, Al-alem U, Quan C, Jin X, Perera F, et al. Combined inhaled diesel exhaust particles and allergen exposure alter methylation of T helper genes and IgE production in vivo. Toxicological sciences : an official journal of the Society of Toxicology. 2008;102(1):76-81.

76. Joubert BR, Felix JF, Yousefi P, Bakulski KM, Just AC, Breton C, et al. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. Am J Hum Genet 2016; 98(4):680-96.

77.  Suter MA, Abramovici AR, Griffin E, Branch DW, Lane RH, Mastrobattista J, et al. In utero nicotine exposure epigenetically alters fetal chromatin structure and differentially regulates transcription of the glucocorticoid receptor in a rat model. Birth defects research Part A, Clinical and molecular teratology. 2015;103(7):583-8.

78.  Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an important mechanism in inflammatory lung diseases. Copd. 2005;2(4):445-55.

79. Harb H, Renz H. Update on epigenetics in allergic disease. The Journal of allergy and clinical immunology. 2015;135(1):15-24.

80.  Brunst KJ, Leung Y-K, Ryan PH, Hershey GKK, Levin L, Ji H, et al. FOXP3 hypermethylation is associated with diesel exhaust exposure and risk for childhood asthma. The Journal of allergy and clinical immunology. 2013;131(2):592.

81.  Brand S, Teich R, Dicke T, Harb H, Yildirim AO, Tost J, et al. Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. The Journal of allergy and clinical immunology. 2011;128(3):618-25.e1-7.

82.  Zhang Y, Leung DY, Goleva E. Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma. The Journal of allergy and clinical immunology. 2014;133(6):1744-52.e1.

83.  Stokholm J, Sevelsted A, Bonnelykke K, Bisgaard H. Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study. The Lancet Respiratory medicine. 2014;2(8):631-7.

84. Han YY, Blatter J, Brehm JM, Forno E, Litonjua AA, Celedon JC. Diet and asthma: vitamins and methyl donors. The Lancet Respiratory medicine. 2013;1(10):813-22.



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