Advertisement

Epigenetics of idiopathic pulmonary fibrosis

  • Ivana V. Yang
    Correspondence
    Reprint requests: Ivana V. Yang, PhD, University of Colorado Denver, 12700 East 19th Avenue, 8611, Aurora, CO 80045.
    Affiliations
    Department of Medicine, University of Colorado School of Medicine, Aurora, Colo

    Department of Epidemiology, Colorado School of Public Health, Aurora, Colo
    Search for articles by this author
  • David A. Schwartz
    Affiliations
    Department of Medicine, University of Colorado School of Medicine, Aurora, Colo

    Department of Immunology, University of Colorado School of Medicine, Aurora, Colo
    Search for articles by this author
Published:April 02, 2014DOI:https://doi.org/10.1016/j.trsl.2014.03.011
      Idiopathic pulmonary fibrosis (IPF) is a complex lung disease of unknown etiology. Development of IPF is influenced by both genetic and environmental factors. Recent work by our and other groups has identified strong genetic predisposition factors for the development of pulmonary fibrosis, and cigarette smoke remains the most strongly associated environmental exposure risk factor. Gene expression profiling studies of IPF lung have taught us quite a bit about the biology of this fatal disease, and those of peripheral blood have provided important biomarkers. However, epigenetic marks may be the missing link that connects the environmental exposure in genetically predisposed individuals to transcriptional changes associated with disease development. Moreover, epigenetic marks represent a promising therapeutic target for IPF. In this review, the disease is introduced, genetic and gene expression studies in IPF are summarized, exposures relevant to IPF and known epigenetic changes associated with cigarette smoke exposure are discussed, and epigenetic studies conducted so far in IPF are summarized. Limitations, challenges, and future opportunities in this field are also discussed.

      Abbreviations:

      α-SMA (α-smooth muscle actin), DNMT (DNA methyltransferase), ECM (extracellular matrix), EMT (epithelial-mesenchymal transition), HDAC (histone deacetylase), IPF (idiopathic pulmonary fibrosis), MeCP2 (methyl CpG binding protein 2), miRNA (micro-RNA), MMP (matrix metalloproteinase), mRNA (messenger RNA), QTL (quantitative trait loci), TGF (transforming growth factor)
      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

        • Gross T.J.
        • Hunninghake G.W.
        Idiopathic pulmonary fibrosis.
        N Engl J Med. 2001; 345: 517-525
        • Raghu G.
        • Weycker D.
        • Edelsberg J.
        • Bradford W.Z.
        • Oster G.
        Incidence and prevalence of idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2006; 174: 810-816
        • Olson A.L.
        • Swigris J.J.
        • Lezotte D.C.
        • Norris J.M.
        • Wilson C.G.
        • Brown K.K.
        Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003.
        Am J Respir Crit Care Med. 2007; 176: 277-284
        • King T.
        • Costabel U.
        • Cordier J.-F.
        • et al.
        Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement: American Thoracic Society (ATS) and the European Respiratory Society (ERS).
        Am J Respir Crit Care Med. 2000; 161: 646-664
        • Macneal K.
        • Schwartz D.A.
        The genetic and environmental causes of pulmonary fibrosis.
        Proc Am Thorac Soc. 2012; 9: 120-125
        • King Jr., T.E.
        • Pardo A.
        • Selman M.
        Idiopathic pulmonary fibrosis.
        Lancet. 2011; 378: 1949-1961
        • Garcia C.K.
        Idiopathic pulmonary fibrosis: update on genetic discoveries.
        Proc Am Thorac Soc. 2011; 8: 158-162
        • Macneal K.
        • Schwartz D.A.
        The genetic and environmental causes of pulmonary fibrosis.
        Proc Am Thorac Soc. 2012; 9: 120-125
        • Taskar V.S.
        • Coultas D.B.
        Is idiopathic pulmonary fibrosis an environmental disease?.
        Proc Am Thorac Soc. 2006; 3: 293-298
        • Seibold M.A.
        • Schwartz D.A.
        The lung: the natural boundary between nature and nurture.
        Annu Rev Physiol. 2011; 73: 457-478
        • Ding Q.
        • Luckhardt T.
        • Hecker L.
        • et al.
        New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis.
        Drugs. 2011; 71: 981-1001
        • Chua F.
        • Gauldie J.
        • Laurent G.J.
        Pulmonary fibrosis: searching for model answers.
        Am J Respir Cell Mol Biol. 2005; 33: 9-13
        • Steele M.P.
        • Speer M.C.
        • Loyd J.E.
        • et al.
        The clinical and pathologic features of familial interstitial pneumonia (FIP).
        Am J Respir Crit Care Med. 2005; 172: 1146-1152
        • Nogee L.M.
        • Dunbar III, A.E.
        • Wert S.E.
        • Askin F.
        • Hamvas A.
        • Whitsett J.A.
        A mutation in the surfactant protein C gene associated with familial interstitial lung disease.
        N Engl J Med. 2001; 344: 573-579
        • Wang Y.
        • Kuan P.J.
        • Xing C.
        • et al.
        Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer.
        Am J Hum Genet. 2009; 84: 52-59
        • Tsakiri K.D.
        • Cronkhite J.T.
        • Kuan P.J.
        • et al.
        Adult-onset pulmonary fibrosis caused by mutations in telomerase.
        Proc Natl Acad Sci U S A. 2007; 104: 7552-7557
        • Seibold M.A.
        • Wise A.L.
        • Speer M.C.
        • et al.
        A common MUC5B promoter polymorphism and pulmonary fibrosis.
        N Engl J Med. 2011; 364: 1503-1512
        • Zhang Y.
        • Noth I.
        • Garcia J.G.
        • Kaminski N.
        A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis.
        N Engl J Med. 2011; 364: 1576-1577
        • Stock C.J.
        • Sato H.
        • Fonseca C.
        • et al.
        Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis.
        Thorax. 2013; 68: 436-441
        • Fingerlin T.E.
        • Murphy E.
        • Zhang W.
        • et al.
        Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.
        Nat Genet. 2013; 45: 613-620
        • Noth I.
        • Zhang Y.
        • Ma S.-F.
        • et al.
        Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study.
        Lancet Respir Med. 2013; 1: 309-317
        • Borie R.
        • Crestani B.
        • Dieude P.
        • et al.
        The MUC5B variant is associated with idiopathic pulmonary fibrosis but not with systemic sclerosis interstitial lung disease in the European Caucasian population.
        PLoS One. 2013; 8: e70621
      1. Helling BA, Yang IV, Keith RC, et al. MUC5B is a common link between idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. [Under review]. 2013.

        • Seibold M.A.
        • Smith R.W.
        • Urbanek C.
        • et al.
        The idiopathic pulmonary fibrosis honeycomb cyst contains a mucociliary pseudostratified epithelium.
        PLoS One. 2013; 8: e58658
        • Hunninghake G.M.
        • Hatabu H.
        • Okajima Y.
        • et al.
        MUC5B promoter polymorphism and interstitial lung abnormalities.
        N Engl J Med. 2013; 368: 2192-2200
        • Peljto A.L.
        • Zhang Y.
        • Fingerlin T.E.
        • et al.
        Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis.
        JAMA. 2013; 309: 2232-2239
        • Baumgartner K.B.
        • Samet J.M.
        • Stidley C.A.
        • Colby T.V.
        • Waldron J.A.
        Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 1997; 155: 242-248
        • Spira A.
        • Beane J.
        • Shah V.
        • et al.
        Effects of cigarette smoke on the human airway epithelial cell transcriptome.
        Proc Natl Acad Sci U S A. 2004; 101: 10143-10148
        • Garcia-Sancho Figueroa M.C.
        • Carrillo G.
        • Perez-Padilla R.
        • et al.
        Risk factors for idiopathic pulmonary fibrosis in a Mexican population: a case-control study.
        Respir Med. 2010; 104: 305-309
        • Antoniou K.M.
        • Hansell D.M.
        • Rubens M.B.
        • et al.
        Idiopathic pulmonary fibrosis: outcome in relation to smoking status.
        Am J Respir Crit Care Med. 2008; 177: 190-194
        • King Jr., T.E.
        • Tooze J.A.
        • Schwarz M.I.
        • Brown K.R.
        • Cherniack R.M.
        Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model.
        Am J Respir Crit Care Med. 2001; 164: 1171-1181
        • Kaminski N.
        Microarray analysis of idiopathic pulmonary fibrosis.
        Am J Respir Cell Mol Biol. 2003; 29: S32-S36
        • Konishi K.
        • Gibson K.F.
        • Lindell K.O.
        • et al.
        Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2009; 180: 167-175
        • Selman M.
        • Carrillo G.
        • Estrada A.
        • et al.
        Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern.
        PLoS One. 2007; 2: e482
        • Selman M.
        • Pardo A.
        • Barrera L.
        • et al.
        Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis.
        Am J Respir Crit Care Med. 2006; 173: 188-198
        • Zuo F.
        • Kaminski N.
        • Eugui E.
        • et al.
        Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans.
        Proc Natl Acad Sci U S A. 2002; 99: 6292-6297
        • Boon K.
        • Bailey N.W.
        • Yang J.
        • et al.
        Molecular phenotypes distinguish patients with relatively stable from progressive idiopathic pulmonary fibrosis (IPF).
        PLoS One. 2009; 4: e5134
        • Yang I.V.
        • Burch L.H.
        • Steele M.P.
        • et al.
        Gene expression profiling of familial and sporadic interstitial pneumonia.
        Am J Respir Crit Care Med. 2007; 175: 45-54
        • Cigna N.
        • Farrokhi Moshai E.
        • Brayer S.
        • et al.
        The hedgehog system machinery control subjects transforming growth factor-beta-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis.
        Am J Pathol. 2012; 181: 2126-2137
        • Bolanos A.L.
        • Milla C.M.
        • Lira J.C.
        • et al.
        Role of sonic hedgehog in idiopathic pulmonary fibrosis.
        Am J Physiol Lung Cell Mol Physiol. 2012; 303: L978-L990
        • Aguilar S.
        • Scotton C.J.
        • McNulty K.
        • et al.
        Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis.
        PLoS One. 2009; 4: e8013
        • Khalil N.
        • Xu Y.D.
        • O’Connor R.
        • Duronio V.
        Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-beta1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK.
        J Biol Chem. 2005; 280: 43000-43009
        • Ramos C.
        • Becerril C.
        • Montano M.
        • et al.
        FGF-1 reverts epithelial-mesenchymal transition induced by TGF-{beta}1 through MAPK/ERK kinase pathway.
        Am J Physiol Lung Cell Mol Physiol. 2010; 299: L222-L231
        • Antoniades H.N.
        • Bravo M.A.
        • Avila R.E.
        • et al.
        Platelet-derived growth factor in idiopathic pulmonary fibrosis.
        J Clin Invest. 1990; 86: 1055-1064
        • Nagaoka I.
        • Trapnell B.C.
        • Crystal R.G.
        Upregulation of platelet-derived growth factor-A and -B gene expression in alveolar macrophages of individuals with idiopathic pulmonary fibrosis.
        J Clin Invest. 1990; 85: 2023-2027
        • Chilosi M.
        • Poletti V.
        • Zamo A.
        • et al.
        Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis.
        Am J Pathol. 2003; 162: 1495-1502
        • Henderson Jr., W.R.
        • Chi E.Y.
        • Ye X.
        • et al.
        Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis.
        Proc Natl Acad Sci U S A. 2010; 107: 14309-14314
        • Konigshoff M.
        • Balsara N.
        • Pfaff E.M.
        • et al.
        Functional Wnt signaling is increased in idiopathic pulmonary fibrosis.
        PLoS One. 2008; 3: e2142
        • Konigshoff M.
        • Kramer M.
        • Balsara N.
        • et al.
        WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis.
        J Clin Invest. 2009; 119: 772-787
        • Vuga L.J.
        • Ben-Yehudah A.
        • Kovkarova-Naumovski E.
        • et al.
        WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis.
        Am J Respir Cell Mol Biol. 2009; 41: 583-589
        • Yang I.V.
        • Coldren C.D.
        • Leach S.M.
        • et al.
        Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis.
        Thorax. 2013; 68: 1114-1121
        • Rosas I.O.
        • Richards T.J.
        • Konishi K
        • et al.
        MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis.
        PLoS Med. 2008; 5: e93
        • Richards T.J.
        • Kaminski N.
        • Baribaud F.
        • et al.
        Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2012; 185: 67-76
        • Yang I.V.
        • Luna L.G.
        • Cotter J.
        • et al.
        The peripheral blood transcriptome identifies the presence and extent of disease in idiopathic pulmonary fibrosis.
        PloS One. 2012; 7: e37708
        • Herazo-Maya J.D.
        • Noth I.
        • Duncan S.R.
        • et al.
        Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis.
        Sci Transl Med. 2013; 5: 205ra136
        • Allis C.D.
        • Jenuwein T.
        • Reinberg D.
        Epigenetics.
        Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2009
        • Yang I.V.
        • Schwartz D.A.
        Epigenetic control of gene expression in the lung.
        Am J Respir Crit Care Med. 2011; 183: 1295-1301
        • Portela A.
        • Esteller M.
        Epigenetic modifications and human disease.
        Nat Biotechnol. 2010; 28: 1057-1068
        • Feinberg A.P.
        Phenotypic plasticity and the epigenetics of human disease.
        Nature. 2007; 447: 433-440
        • Feinberg A.P.
        • Tycko B.
        The history of cancer epigenetics.
        Nat Rev Cancer. 2004; 4: 143-153
        • Doi A.
        • Park I.H.
        • Wen B.
        • et al.
        Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts.
        Nat Genet. 2009; 41: 1350-1353
        • Ji H.
        • Ehrlich L.I.
        • Seita J.
        • et al.
        Comprehensive methylome map of lineage commitment from haematopoietic progenitors.
        Nature. 2010; 467: 338-342
        • Jones P.A.
        Functions of DNA methylation: islands, start sites, gene bodies and beyond.
        Nat Rev Genet. 2012; 13: 484-492
        • Kulis M.
        • Heath S.
        • Bibikova M.
        • et al.
        Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia.
        Nat Genet. 2012; 44: 1236-1242
        • Greer E.L.
        • Shi Y.
        Histone methylation: a dynamic mark in health, disease and inheritance.
        Nat Rev Genet. 2012; 13: 343-357
        • Arrowsmith C.H.
        • Bountra C.
        • Fish P.V.
        • Lee K.
        • Schapira M.
        Epigenetic protein families: a new frontier for drug discovery.
        Nat Rev Drug Discov. 2012; 11: 384-400
        • Flynt A.S.
        • Lai E.C.
        Biological principles of microRNA-mediated regulation: shared themes amid diversity.
        Nat Rev Genet. 2008; 9: 831-842
        • Lee R.C.
        • Feinbaum R.L.
        • Ambros V.
        The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.
        Cell. 1993; 75: 843-854
        • Esteller M.
        Non-coding RNAs in human disease.
        Nat Rev Genet. 2011; 12: 861-874
        • Jirtle R.L.
        • Skinner M.K.
        Environmental epigenomics and disease susceptibility.
        Nat Rev Genet. 2007; 8: 253-262
        • Waterland R.A.
        • Jirtle R.L.
        Transposable elements: targets for early nutritional effects on epigenetic gene regulation.
        Mol Cell Biol. 2003; 23: 5293-5300
        • Anway M.D.
        • Cupp A.S.
        • Uzumcu M.
        • Skinner M.K.
        Epigenetic transgenerational actions of endocrine disruptors and male fertility.
        Science. 2005; 308: 1466-1469
        • Baccarelli A.
        • Wright R.O.
        • Bollati V.
        • et al.
        Rapid DNA methylation changes after exposure to traffic particles.
        Am J Respir Crit Care Med. 2009; 179: 572-578
        • Fraga M.F.
        • Ballestar E.
        • Paz M.F.
        • et al.
        Epigenetic differences arise during the lifetime of monozygotic twins.
        Proc Natl Acad Sci U S A. 2005; 102: 10604-10609
        • Heyn H.
        • Li N.
        • Ferreira H.J.
        • et al.
        Distinct DNA methylomes of newborns and centenarians.
        Proc Natl Acad Sci U S A. 2012; 109: 10522-10527
        • Issa J.P.
        Aging and epigenetic drift: a vicious cycle.
        J Clin Invest. 2014; 124: 24-29
        • Abramowitz L.K.
        • Bartolomei M.S.
        Genomic imprinting: recognition and marking of imprinted loci.
        Curr Opin Genet Dev. 2012; 22: 72-78
        • Bell J.T.
        • Pai A.A.
        • Pickrell J.K.
        • et al.
        DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines.
        Genome Biol. 2011; 12: R10
        • Zhang D.
        • Cheng L.
        • Badner J.A.
        • et al.
        Genetic control of individual differences in gene-specific methylation in human brain.
        Am J Hum Genet. 2010; 86: 411-419
        • Gibbs J.R.
        • van der Brug M.P.
        • Hernandez D.G.
        • et al.
        Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain.
        PLoS Genet. 2010; 6: e1000952
        • Kasowski M.
        • Kyriazopoulou-Panagiotopoulou S.
        • Grubert F.
        • et al.
        Extensive variation in chromatin states across humans.
        Science. 2013; 342: 750-752
        • Kilpinen H.
        • Waszak S.M.
        • Gschwind A.R.
        • et al.
        Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription.
        Science. 2013; 342: 744-747
        • McVicker G.
        • van de Geijn B.
        • Degner J.F.
        • et al.
        Identification of genetic variants that affect histone modifications in human cells.
        Science. 2013; 342: 747-749
        • Kim D.H.
        • Nelson H.H.
        • Wiencke J.K.
        • et al.
        p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer.
        Cancer Res. 2001; 61: 3419-3424
        • Wan E.S.
        • Qiu W.
        • Baccarelli A.
        • et al.
        Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome.
        Hum Mol Genet. 2012; 21: 3073-3082
        • Philibert R.A.
        • Sears R.A.
        • Powers L.S.
        • et al.
        Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression.
        J Leukoc Biol. 2012; 92: 621-631
        • Breitling L.P.
        • Yang R.
        • Korn B.
        • Burwinkel B.
        • Brenner H.
        Tobacco-smoking-related differential DNA methylation: 27K discovery and replication.
        Am J Hum Genet. 2011; 88: 450-457
        • Tennis M.A.
        • Vanscoyk M.M.
        • Wilson L.A.
        • Kelley N.
        • Winn R.A.
        Methylation of Wnt7a is modulated by DNMT1 and cigarette smoke condensate in non-small cell lung cancer.
        PLoS One. 2012; 7: e32921
        • Buro-Auriemma L.J.
        • Salit J.
        • Hackett N.R.
        • et al.
        Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression.
        Hum Mol Genet. 2013; 22: 4726-4738
        • Chen D.
        • Fang L.
        • Li H.
        • Tang M.S.
        • Jin C.
        Cigarette smoke component acrolein modulates chromatin assembly by inhibiting histone acetylation.
        J Biol Chem. 2013; 288: 21678-21687
        • Liu F.
        • Killian J.K.
        • Yang M.
        • et al.
        Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate.
        Oncogene. 2010; 29: 3650-3664
        • Nagathihalli N.S.
        • Massion P.P.
        • Gonzalez A.L.
        • Lu P.
        • Datta P.K.
        Smoking induces epithelial-to-mesenchymal transition in non-small cell lung cancer through HDAC-mediated downregulation of E-cadherin.
        Mol Cancer Ther. 2012; 11: 2362-2372
        • Schembri F.
        • Sridhar S.
        • Perdomo C.
        • et al.
        MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium.
        Proc Natl Acad Sci U S A. 2009; 106: 2319-2324
        • Izzotti A.
        • Calin G.A.
        • Arrigo P.
        • Steele V.E.
        • Croce C.M.
        • De Flora S.
        Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke.
        FASEB J. 2009; 23: 806-812
        • Izzotti A.
        • Calin G.A.
        • Steele V.E.
        • Croce C.M.
        • De Flora S.
        Relationships of microRNA expression in mouse lung with age and exposure to cigarette smoke and light.
        FASEB J. 2009; 23: 3243-3250
        • Breton C.V.
        • Byun H.M.
        • Wenten M.
        • Pan F.
        • Yang A.
        • Gilliland F.D.
        Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation.
        Am J Respir Crit Care Med. 2009; 180: 462-467
        • Guerrero-Preston R.
        • Goldman L.R.
        • Brebi-Mieville P.
        • et al.
        Global DNA hypomethylation is associated with in utero exposure to cotinine and perfluorinated alkyl compounds.
        Epigenetics. 2010; 5: 539-546
        • Suter M.
        • Ma J.
        • Harris A.S.
        • et al.
        Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression.
        Epigenetics. 2011; 6: 1284-1294
        • Maccani M.A.
        • Avissar-Whiting M.
        • Banister C.E.
        • McGonnigal B.
        • Padbury J.F.
        • Marsit C.J.
        Maternal cigarette smoking during pregnancy is associated with downregulation of miR-16, miR-21, and miR-146a in the placenta.
        Epigenetics. 2010; 5: 583-589
        • Coward W.R.
        • Watts K.
        • Feghali-Bostwick C.A.
        • Knox A.
        • Pang L.
        Defective histone acetylation is responsible for the diminished expression of cyclooxygenase 2 in idiopathic pulmonary fibrosis.
        Mol Cell Biol. 2009; 29: 4325-4339
        • Coward W.R.
        • Watts K.
        • Feghali-Bostwick C.A.
        • Jenkins G.
        • Pang L.
        Repression of IP-10 by interactions between histone deacetylation and hypermethylation in idiopathic pulmonary fibrosis.
        Mol Cell Biol. 2010; 30: 2874-2886
        • Sanders Y.Y.
        • Pardo A.
        • Selman M.
        • et al.
        Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis.
        Am J Respir Cell Mol Biol. 2008; 39: 610-618
        • Sanders Y.Y.
        • Tollefsbol T.O.
        • Varisco B.M.
        • Hagood J.S.
        Epigenetic regulation of Thy-1 by histone deacetylase inhibitor in rat lung fibroblasts.
        Am J Respir Cell Mol Biol. 2010; 45: 16-23
        • Robinson C.M.
        • Neary R.
        • Levendale A.
        • Watson C.J.
        • Baugh J.A.
        Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype.
        Respiratory research. 2012; 13: 74
        • Cisneros J.
        • Hagood J.
        • Checa M.
        • et al.
        Hypermethylation-mediated silencing of p14(ARF) in fibroblasts from idiopathic pulmonary fibrosis.
        Am J Physiol Lung Cell Mol Physiol. 2012; 303: L295-L303
        • Huang S.K.
        • Scruggs A.M.
        • Donaghy J.
        • et al.
        Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts.
        Cell Death Dis. 2013; 4: e621
        • Hu B.
        • Gharaee-Kermani M.
        • Wu Z.
        • Phan S.H.
        Epigenetic regulation of myofibroblast differentiation by DNA methylation.
        Am J Pathol. 2010; 177: 21-28
        • Hu B.
        • Gharaee-Kermani M.
        • Wu Z.
        • Phan S.H.
        Essential role of MeCP2 in the regulation of myofibroblast differentiation during pulmonary fibrosis.
        Am J Pathol. 2011; 178: 1500-1508
        • Dakhlallah D.
        • Batte K.
        • Wang Y.
        • et al.
        Epigenetic regulation of miR-17∼92 contributes to the pathogenesis of pulmonary fibrosis.
        Am J Respir Crit Care Med. 2013; 187: 397-405
        • Rabinovich E.
        • Yakhini Z.
        • Benos P.
        • et al.
        Human CpG islands arrays reveal changes in global methylation patterns in idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2010; 181: A2017
        • Sanders Y.Y.
        • Ambalavanan N.
        • Halloran B.
        • et al.
        Altered DNA methylation profile in idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2012; 186: 525-535
        • Irizarry R.A.
        • Ladd-Acosta C.
        • Wen B.
        • et al.
        The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores.
        Nat Genet. 2009; 41: 178-186
        • Irizarry R.A.
        • Ladd-Acosta C.
        • Carvalho B.
        • et al.
        Comprehensive high-throughput arrays for relative methylation (CHARM).
        Genome Res. 2008; 18: 780-790
        • Yang I.
        • Hennessy C.
        • Davidson E.
        • et al.
        Genome-wide DNA methylation patterns in interstitial lung disease (ILD) and chronic obstructive lung disease (COPD).
        Am J Respir Crit Care Med. 2011; 183: A1049
        • Pandit K.V.
        • Corcoran D.
        • Yousef H.
        • et al.
        Inhibition and role of let-7d in idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2010; 182: 220-229
        • Liu G.
        • Friggeri A.
        • Yang Y.
        • et al.
        miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis.
        J Exp Med. 2010; 207: 1589-1597
        • Cushing L.
        • Kuang P.P.
        • Qian J.
        • et al.
        miR-29 is a major regulator of genes associated with pulmonary fibrosis.
        Am J Respir Cell Mol Biol. 2011; 45: 287-294
        • Pottier N.
        • Maurin T.
        • Chevalier B.
        • et al.
        Identification of keratinocyte growth factor as a target of microRNA-155 in lung fibroblasts: implication in epithelial-mesenchymal interactions.
        PLoS One. 2009; 4: e6718
        • Oak S.R.
        • Murray L.
        • Herath A.
        • et al.
        A micro RNA processing defect in rapidly progressing idiopathic pulmonary fibrosis.
        PLoS One. 2011; 6: e21253
        • Pandit K.V.
        • Milosevic J.
        • Kaminski N.
        MicroRNAs in idiopathic pulmonary fibrosis.
        Transl Res. 2011; 157: 191-199
        • Talikka M.
        • Sierro N.
        • Ivanov N.V.
        • et al.
        Genomic impact of cigarette smoke, with application to three smoking-related diseases.
        Crit Rev Toxicol. 2012; 42: 877-889
        • Hawkins R.D.
        • Hon G.C.
        • Ren B.
        Next-generation genomics: an integrative approach.
        Nat Rev Genet. 2010; 11: 476-486
        • Schones D.E.
        • Zhao K.
        Genome-wide approaches to studying chromatin modifications.
        Nat Rev Genet. 2008; 9: 179-191
        • Shen-Orr S.S.
        • Tibshirani R.
        • Khatri P.
        • et al.
        Cell type-specific gene expression differences in complex tissues.
        Nat Methods. 2010; 7: 287-289
        • Houseman E.A.
        • Accomando W.P.
        • Koestler D.C.
        • et al.
        DNA methylation arrays as surrogate measures of cell mixture distribution.
        BMC Bioinformatics. 2012; 13: 86
        • Koestler D.C.
        • Christensen B.
        • Karagas M.R.
        • et al.
        Blood-based profiles of DNA methylation predict the underlying distribution of cell types: a validation analysis.
        Epigenetics. 2013; 8: 816-826
        • Cedar H.
        • Bergman Y.
        Linking DNA methylation and histone modification: patterns and paradigms.
        Nat Rev Genet. 2009; 10: 295-304
        • Chodavarapu R.K.
        • Feng S.
        • Bernatavichute Y.V.
        • et al.
        Relationship between nucleosome positioning and DNA methylation.
        Nature. 2010; 466: 388-392
        • Hu J.L.
        • Zhou B.O.
        • Zhang R.R.
        • Zhang K.L.
        • Zhou J.Q.
        • Xu G.L.
        The N-terminus of histone H3 is required for de novo DNA methylation in chromatin.
        Proc Natl Acad Sci U S A. 2009; 106: 22187-22192
        • Ooi S.K.
        • Qiu C.
        • Bernstein E.
        • et al.
        DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.
        Nature. 2007; 448: 714-717
        • Montgomery S.B.
        • Dermitzakis E.T.
        From expression QTLs to personalized transcriptomics.
        Nat Rev Genet. 2011; 12: 277-282
        • Allen J.D.
        • Xie Y.
        • Chen M.
        • Girard L.
        • Xiao G.
        Comparing statistical methods for constructing large scale gene networks.
        PLoS One. 2012; 7: e29348
        • Su C.Y.
        • Bay S.N.
        • Mariani L.E.
        • Hillman M.J.
        • Caspary T.
        Temporal deletion of Arl13b reveals that a mispatterned neural tube corrects cell fate over time.
        Development. 2012; 139: 4062-4071
        • Kaminskas E.
        • Farrell A.
        • Abraham S.
        • et al.
        Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes.
        Clin Cancer Res. 2005; 11: 3604-3608
        • Saba H.I.
        Decitabine in the treatment of myelodysplastic syndromes.
        Ther Clin Risk Manage. 2007; 3: 807-817
        • Kaminskas E.
        • Farrell A.T.
        • Wang Y.C.
        • Sridhara R.
        • Pazdur R.
        FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension.
        Oncologist. 2005; 10: 176-182
        • Brock M.V.
        • Hooker C.M.
        • Ota-Machida E.
        • et al.
        DNA methylation markers and early recurrence in stage I lung cancer.
        N Engl J Med. 2008; 358: 1118-1128
        • Juergens R.A.
        • Wrangle J.
        • Vendetti F.P.
        • et al.
        Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer.
        Cancer Discov. 2011; 1: 598-607
        • Di Ruscio A.
        • Ebralidze A.K.
        • Benoukraf T.
        • et al.
        DNMT1-interacting RNAs block gene-specific DNA methylation.
        Nature. 2013; 503: 371-376
        • Wirt S.E.
        • Porteus M.H.
        Development of nuclease-mediated site-specific genome modification.
        Curr Opinion Immunol. 2012; 24: 609-616
        • Bikard D.
        • Marraffini L.A.
        Control of gene expression by CRISPR-Cas systems.
        F1000prime Rep. 2013; 5: 47
        • Huffman K.
        • Martinez E.D.
        Pre-clinical studies of epigenetic therapies targeting histone modifiers in lung cancer.
        Front Oncol. 2013; 3: 235
        • Willis B.C.
        • Liebler J.M.
        • Luby-Phelps K.
        • et al.
        Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis.
        Am J Pathol. 2005; 166: 1321-1332
        • Kim K.K.
        • Kugler M.C.
        • Wolters P.J.
        • et al.
        Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix.
        Proc Natl Acad Sci U S A. 2006; 103: 13180-13185
        • Tanjore H.
        • Xu X.C.
        • Polosukhin V.V.
        • et al.
        Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis.
        Am J Respir Crit Care Med. 2009; 180: 657-665
        • Farkas L.
        • Gauldie J.
        • Voelkel N.F.
        • Kolb M.
        Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors.
        Am J Respir Cell Mol Biol. 2011; 45: 1-15
        • Fattman C.L.
        Apoptosis in pulmonary fibrosis: too much or not enough?.
        Antioxid Redox Signal. 2008; 10: 379-385
        • Thannickal V.J.
        • Horowitz J.C.
        Evolving concepts of apoptosis in idiopathic pulmonary fibrosis.
        Proc Am Thorac Soc. 2006; 3: 350-356
        • Hecker L.
        • Vittal R.
        • Jones T.
        • et al.
        NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury.
        Nat Med. 2009; 15: 1077-1081
        • Tanjore H.
        • Cheng D.S.
        • Degryse A.L.
        • et al.
        Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress.
        J Biol Chem. 2011; 286: 30972-30980
        • Lawson W.E.
        • Cheng D.S.
        • Degryse A.L.
        • et al.
        Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs.
        Proc Natl Acad Sci U S A. 2011; 108: 10562-10567
        • Alder J.K.
        • Chen J.J.
        • Lancaster L.
        • et al.
        Short telomeres are a risk factor for idiopathic pulmonary fibrosis.
        Proc Natl Acad Sci U S A. 2008; 105: 13051-13056
        • Cronkhite J.T.
        • Xing C.
        • Raghu G.
        • et al.
        Telomere shortening in familial and sporadic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2008; 178: 729-737
        • Chilosi M.
        • Doglioni C.
        • Murer B.
        • Poletti V.
        Epithelial stem cell exhaustion in the pathogenesis of idiopathic pulmonary fibrosis.
        Sarcoidosis Vasc Diffuse Lung Dis. 2010; 27: 7-18
        • Scotton C.J.
        • Krupiczojc M.A.
        • Konigshoff M.
        • et al.
        Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury.
        J Clin Invest. 2009; 119: 2550-2563
        • Selman M.
        • Pardo A.
        • Kaminski N.
        Idiopathic pulmonary fibrosis: aberrant recapitulation of developmental programs?.
        PLoS Med. 2008; 5: e62
        • Boucher R.C.
        Idiopathic pulmonary fibrosis: a sticky business.
        N Engl J Med. 2011; 364: 1560-1561