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REVIEW Epigenetics in idiopathic pulmonary fibrosis1 Biochem. Cell Biol. Downloaded from www.nrcresearchpress.com by NEW YORK UNIVERSITY on 02/10/15 For personal use only.

Argyrios Tzouvelekis and Naftali Kaminski

Abstract: Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disorder with no effective treatment and a prognosis worse than that of lung cancer. Despite extensive research efforts, its etiology and pathogenesis still remain largely unknown. Current experimental evidence has shifted the disease paradigm from chronic inflammation towards the premise of abnormal epithelial wound repair in response to repeated epigenetic injurious stimuli in genetically predisposed individuals. Epigenetics is defined as the study of heritable changes in gene function by factors other than an individual's DNA sequence, providing valuable information regarding adaption of genes to environmental changes. Although cancer is the most studied disease with relevance to epigenetic modifications, recent data support the idea that epigenomic alterations may lead to variable disease phenotypes, including fibroproliferative lung disorders such as IPF. This review article summarizes the latest experimental and translational epigenetic studies in the research field of chronic lung disorders, mainly focusing on IPF, highlights current methodology limitations, and underlines future directions and perspectives. Key words: fibroproliferative disorders, DNA methylation, histone modification, noncoding RNAs, epigenetic treatments. Résumé : La fibrose pulmonaire idiopathique (FPI) est une maladie chronique mortelle du poumon pour laquelle il n’existe pas de traitement et dont le pronostic est pire que celui du cancer du poumon. Malgré une recherche intensive, son étiologie et sa pathogenèse demeurent encore largement méconnues. Des données expérimentales actuelles ont déplacé le paradigme de la maladie d’une inflammation chronique vers la prémisse d’une cicatrisation anormale en réponse a` des stimuli épigénétiques répétés dommageables chez des individus génétiquement prédisposés. L’épigénétique se définit comme l’étude des changements héréditaires de la fonction des gènes par des facteurs autres que la séquence d’ADN de l’individu, fournissant une information précieuse sur l’adaptation des gènes aux changements environnementaux. Même si le cancer est la maladie la plus étudiée en lien avec les modifications épigénétiques, des données récentes appuient l’idée que les modifications épigénomiques peuvent mener a` des phénotypes de maladies variés, y compris les maladies fibro-prolifératives pulmonaires comme la FPI. Cet article de revue résume les études épigénétiques expérimentales et translationnelles les plus récentes du domaine des maladies pulmonaires chroniques, se concentrant principalement sur la FPI ; il met l’accent sur les limites méthodologiques actuelles et souligne les directions a` suivre et les perspectives d’avenir. [Traduit par la Rédaction] Mots-clés : maladie fibro-proliférative, méthylation d’ADN, modification des histones, ARN non codant, traitements épigénétiques.

Introduction Over the past 10 years we have witnessed an explosion of scientific knowledge, research efforts, and international initiatives dedicated to epigenetics. The word epigenetics has its origin in the Greek word epi (meaning for, over, or above) and genetics, the science of hereditary transmission (Bonasio et al. 2010; Schwartz 2010; Yang and Schwartz 2011). The latest definition involves the study of inherited phenotypes resulting from changes in a chromosome without alterations in the DNA sequence (Goldberg et al. 2007). There are three main classes of epigenetic marks. DNA methylation DNA methylation is a highly specific biochemical process that typically involves the addition of a methyl group to the 5= position of CpG islands (Magnusdottir et al. 2012). Specific enzymes called DNA methyltransferases (DNMTs) mediate the process that leads to gene repression. Inserting methyl groups changes the appearance and structure of DNA leading to terminal modifications of the interactions of genes with the transcription machinery of the cell within the nucleus.

Histone modifications Histones are proteins that represent the primary components of chromatin, the complex of DNA and proteins that makes up chromosomes. There are two main mechanisms that can modify the structure of histones and chromatin: acetylation and methylation. These are biochemical processes that are characterized by the addition of either an acetyl or a methyl group to the amino acid lysine that is located in the histone. Histone acetylation often results in a relatively uncondensed chromatin structure. The uncondensed chromatin structure, in turn, increases the accessibility of transcription factors and is reversibly regulated by two distinct families of enzymes, called histone acetyltransferases and deacetylases. Histone methylation is catalyzed by histone methyltransferases or demethylases and favors the compaction or relaxation of chromatin based on the number of methyl groups (Helin and Dhanak 2013; Kimmins and Sassone-Corsi 2005; Klose and Zhang 2007). In addition, there are histone posttranslational modifications other than methylation and acetylation, including phosphorylation and ubiquitination, that directly or indirectly influence chromatin structure. Histone phosphorylation takes place on serine, threonine, and tyrosine residues and exerts an essential role in DNA damage response, transcription regulation,

Received 13 September 2014. Revision received 15 November 2014. Accepted 19 December 2014. A. Tzouvelekis and N. Kaminski. Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, 300 Cedar St., TAC-441 South, P.O. Box 208057, New Haven, CT 06520, USA. Corresponding author: Naftali Kaminski (e-mail: [email protected]). 1This article is part of Special Issue entitled Lung Dieases and Epigenetics and has undergone the Journal's usual peer review process. Biochem. Cell Biol. 93: 1–12 (2015) dx.doi.org/10.1139/bcb-2014-0126

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cell cycle, and apoptosis (Rossetto et al. 2012). On the other hand, histone ubiquitination represents the least understood histone modification and plays an important role in regulating transcription either through proteasome-dependent destruction of transcription factors or proteasome-independent mechanisms (Zhang 2003). Due to space limitations and the lack of data related to the main topic of this review article, we will focus on histone acetylation and methylation. Noncoding RNA regulation The recent advent and implementation of novel technologies has supported the premise that the function of RNA is more than just transmitting genetic information to the ribosomes, thereby facilitating protein expression. Many functional RNAs have been recently described, including microRNAs (miRNAs) and long noncoding RNAs (lnc-RNAs). miRNAs are small, approximately 22-nucleotide, single stranded, noncoding RNAs that function by regulating target gene expression either by silencing or degradation. miRNAs may indirectly alter gene expression through global effects on methylation and targeting of transcription factors. Notably, miRNAs can regulate upward entire gene networks and thereby modify complex disease phenotypes, suggesting them as effective disruptors of lung fibrosis and thus attractive therapeutic alternatives for this lethal disease (Nana-Sinkam et al. 2009). Lnc-RNAs represent non-protein coding transcripts longer than 200 nucleotides, a somewhat arbitrary limit that distinguishes them from small regulatory RNAs such as microRNAs. A useful framework has been proposed for the functional classification of lncRNAs:as scaffolds assembling interacting proteins, tethers linking proteins to areas of transcription (in cis), or guides bringing protein complexes to a regulated region of the genome (in trans) (Mercer et al. 2009). Various diverse functions have been suggested for lnc-RNAs, including roles in regulating DNA metabolism, chromatin structure, and gene expression, leading to diverse human diseases (Huang and Zhang 2014; Karapetyan et al. 2013; Maass et al. 2014; Shi et al. 2013; Zhang et al. 2013a).

Epigenetics in chronic lung disorders Gene–environment interactions have been demonstrated to play a pivotal role in the development and progression of carcinogenesis as well as chronic inflammatory responses and autoimmunity (Cuddapah et al. 2010; Mukasa et al. 2010; Perdomo et al. 2011, 2013; Schembri et al. 2009). A growing body of evidence from epidemiological reports has suggested an association between tumorigenesis, deregulated immune responses, and environmental stimuli, including chemical (silica, industrial agents, asbestos, smoke), physical (ionizing radiation and sunlight), and biologic agents (viral and microbial pathogens, food and other toxins) (Eilebrecht et al. 2013; Izzotti et al. 2009; Schwartz 2010; Suter et al. 2011; Yang and Schwartz 2011). Lung cancer Epigenetic abnormalities are present in all types of human cancer and are currently considered the pathogenetic hallmark of carcinogenesis. Currently the most extensively studied epigenetic event associated with tumorigenesis is DNA methylation. The recent advances of DNA methylation detection tools, including CpG islands microarrays, have resulted in the identification of aberrantly methylated gene signatures including p16, H-cadherin, RASFF1A, APC, and DAPK1 (Breton et al. 2009; Kim et al. 2001; Liu et al. 2010a). Hypermethylation of these genes contributes significantly to their transcriptional silencing, leading to genomic instability and cancer metaplasia. A therapeutic role has also been reported for the mir-29 family through restoration of aberrant DNA methylation and downregulation of DNMT 3A and DNMT 3B in lung cancer patients (Fabbri et al. 2007). Phase II clinical trials are currently ongoing and results are much anticipated. DNA meth-

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ylation alterations in both genes and miRNAs (i.e., the let-7 family) in different types of biological samples (such as peripheral blood leukocytes (Wang et al. 2010), plasma (Ostrow et al. 2010), serum (Bianchi et al. 2011), bronchoalveolar lavage (Kim et al. 2004), and sputum (Leng et al. 2012)) have been applied to cancer diagnostics as biomarkers for early differentiation of lung cancer cases from controls, identification of histological subtypes, and prediction of treatment response. These samples may provide a less invasive approach for disease detection and monitoring compared to tissues, and reduce high screening costs and unnecessary invasive procedures arising from overabundance of false positive screenings based on serial computed tomographies (National Lung Screening Trial Research Team et al. 2011). Chronic obstructive pulmonary disease (COPD) Epigenetic mechanisms have been suggested to play a crucial role in COPD, given that its pathogenesis is strongly influenced by environmental factors such as cigarette smoke and biomass fuels. Smoke-induced oxidative stress seems to alter the activity of both histone acetylates and deacetylases, thereby enhancing NF-␬Bdependent gene expression (Yang et al. 2006). A reduction of the expression of HDACs, 2, 3, 5, and 8 and an increase in the expression of HDACs 4 and 6 has been reported in patients with COPD and has been associated with increased expression of CXCL8 (Ito et al. 2005) and defensins (Andresen et al. 2011). Recently, a large genomewide analysis of methylation has been performed on 27 000 CpGs in patients with COPD and showed hypomethylation of CpG islands in the vicinity of the gene encoding for a1-antithrypsin (Qiu et al. 2012). Regarding the epigenetic control of gene expression that is coordinated by noncoding RNAs, studies have shown that miR-1 was downregulated in skeletal muscle of patients with COPD (Lewis et al. 2012), while reduced let-7 expression was inversely correlated with disease severity (Van Pottelberge et al. 2011). A profile of 14-miRs was able to differentiate patients with COPD from patients with lung cancer (Leidinger et al. 2011). Asthma Asthma represents a disease paradigm where the effect of environmental exposures, such as smoking, air pollution, diet, and stress, in disease pathogenesis may be explained by epigenetic regulation (Liu et al. 2013; Schwartz 2010; Yang and Schwartz 2011). Modifications of the DNA methylation status either in different cell subpopulations (T cells, B cells, mast and dendritic cells, or genes (b2-adrenergic receptor, interferon-receptor, and interleukins-2, 13) have been associated with asthma development and progression (Yang and Schwartz 2011, 2012). A strong association between exposure to tobacco, allergens during prenatal period, air pollution, stress, and changes in DNA methylation levels has been demonstrated by several studies (Liu et al. 2013; Schwartz 2010). Inhibitors of DNMTs such as 5=azacytidine have been also proven beneficial in experimental models of asthma through increasing regulatory T cells (Wu et al. 2013). Histone modifications have also been shown to be associated with the transcription activity of genes mediating immune responses in asthma and providing novel therapeutic targets. Likewise with other chronic lung disorders, miRs have been identified as major regulators of immune homeostasis in experimental models and patients with asthma (Liu et al. 2013). Similarly with lung cancer, COPD, and IPF, miRs of the let-7 family have been found to be significantly downregulated in patients with asthma compared with controls (Kumar et al. 2011). A beneficial role for miR-21 via a mechanism that favors Th1 versus Th2 immune responses has been demonstrated (Lu et al. 2011).

Epigenetic factors in fibrotic disorders While mechanistic studies have provided extensive insights into the pathogenetic pathways of fibrogenesis that underlie the progression of chronic fibrotic disorders, these experimental studies fail to Published by NRC Research Press

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fully explain the vast heterogeneity of the progression slopes of individual patients. Recent studies support the concept that genetic polymorphisms and epigenetic variations determine the individual susceptibility of patients to develop chronic fibrotic disorders in different organs. The use of selective inhibitors of enzymes involved in DNA methylation or histone modification has shed further light into the role of epigenetic alterations in fibroproliferative disorders in different organs such as the liver, kidneys, heart, and lungs.

through a mechanism that involves TGFb1/smad3 signaling (Zhang et al. 2014). In line with evidence derived from kidney (Patel and Noureddine 2012) and lung fibrosis (Liu et al. 2010b), miR-21 has been suggested to exert a pro-fibrotic role in cardiac fibrosis by regulation of ERK/MAPK signaling pathway in cardiac fibroblasts (Thum et al. 2008). The role of miR-21 as a peripheral biomarker in patients with myocardial fibrosis has also been reported (Villar et al. 2013).

Liver fibrosis Abundant evidence supports the pivotal role of epigenetic modifications in the transdifferentiation of hepatic stellate cells (HSC) to a profibrogenic myofibroblastic phenotype. Studies using small molecular epigenetic inhibitors such as 5=azacytidine (DNMT1) or the EZH2 (histone methyltransferase) inhibitor potently ablate HSC activation in vitro and in vivo (Mann et al. 2007, 2010). Mice lacking MeCP2, a protein that regulates DNA methylation, are protected from both liver (Mann et al. 2010) and lung fibrosis (Hu et al. 2011), while MeCP2-deficient fibroblasts exhibit various defects in their fibrogenic phenotype. Mechanistic data support the pivotal role of MeCP2 in silencing PPAR␥ and HSC transdifferentiation (Mann 2014). Changes in DNA methylation during HSC activation have been demonstrated to lead to diminished expression of tumor-suppressor genes in myofibroblasts (Yang et al. 2013). A large genome-wide association study of changes in DNA methylation, investigating 69 247 differentially methylated CpG islands in liver biopsies derived from patients with nonalcoholic fatty liver disease, stratified patients into advanced and mild disease (Murphy et al. 2013).

Contrary to the case for other chronic lung disorders, there is a significant lack of knowledge regarding epigenetic regulation and initiation of idiopathic pulmonary fibrosis (IPF) (Robinson et al. 2012; Yang 2012). In view of rapidly emerging pathogenetic pathways and in an attempt to find a rationale that may explain major discrepancies between genomic and proteomic data, scientists have focused on the investigation of the role of posttranscriptional modifications and gene–environment interactions in lung fibrogenesis (Blackwell et al. 2013; Cabrera et al. 2013; Fingerlin et al. 2013; Herazo-Maya et al. 2013; Kass and Kaminski 2011; O'Dwyer et al. 2013; Peljto et al. 2013; Seibold et al. 2011). (Fig. 1). Several observational reports have demonstrated high prevalence of multiple environmental stimuli (including smoking (Antoniou et al. 2008), gastro-esophageal reflux (Lee et al. 2013; Raghu 2011; Raghu and Meyer 2012; Raghunath et al. 2003), and viral infections (Konishi et al. 2009)) in large cohorts of patients with IPF. Additionally, evidence of immune compromise (such as downregulation of genes involved in the T cell co-stimulatory pathway) has been recently linked with a worse prognosis and shortened life span for patients with IPF, evidence that has revived the role of immune deregulation in disease pathogenesis (Kotsianidis et al. 2009).

Kidney fibrosis Original reports implicating the impact of epigenetic modifications in renal fibrogenesis emerged from the observation that experimental renal fibrosis in mice is ameliorated when the demethylating agent 5=azacytidine is administered (Tampe and Zeisberg 2013). Genome-wide methylation analyses comparing the methylation status of fibroblasts derived from fibrotic and nonfibrotic kidneys revealed 12 genes that were hypermethylated in all tested fibroblasts. Among those genes, hypermethylation of RASALI was not found not to be limited in renal fibrosis but was also present as being hypermethylated in liver fibrosis (Tao et al. 2011) and colorectal cancer (Bechtel et al. 2010). The role of histone modifications in renal fibrosis is still under investigation and preclinical data are limited to the beneficial effects of histone deacetylase inhibitors such as trichostatin (Marumo et al. 2010). Among the epigenetic mechanisms, regulation of gene expression through miRNAs is the most dynamic, because miRNAs can be therapeutically interfered with. Regarding renal fibrosis, the roles of miR-21, miR-200, and miR-29 have been best established. In particular, reports have clearly demonstrated the fibrogenic role of miR-21 and the protective anti-fibrotic contribution of miR-29 in renal fibrosis (Patel and Noureddine 2012), evidence that also extends to cardiac (Zhang et al. 2014) and lung fibrosis (Liu et al. 2010b; Xiao et al. 2012). Cardiac fibrosis Most cardiac diseases are associated with cardiac fibrosis (Tao et al. 2013). The use of histone deacetylase inhibitors was found to be associated with profound suppressive effects in experimental myocardial fibrosis (Bogaard et al. 2011), collagen production, expression of a-SMA, and TGFb1-signaling (Zhang et al. 2010). Several miRNAs are involved in the pathogenetic cascade of cardiac fibrosis. Among them miR-24, miR-29, and miR-21 have been extensively investigated (Tao et al. 2013). In particular, studies have shown upregulation of miR-24, reduced TGFb1 secretion, and smad2/3 phosphorylation (Wang et al. 2012), whereas overexpression of miR-29a lead to reduced collagen expression in cardiac fibroblasts

Epigenetic factors in IPF

DNA methylation Studies have demonstrated that the hypermethylation status of the promoter of Thy-1 is responsible for the diminished expression of Thy-1 in IPF lung fibroblasts, leading to uncontrolled generation of myofibroblasts and progressive lung scarring (Sanders et al. 2007, 2008). Differential levels of methylation of three CpG islands in the promoter of a-smooth muscle actin (a-SMA) in fibroblasts, myofibroblasts, and alveolar epithelial cells were shown to correlate with the expression of a-SMA in these cell lines (Hu et al. 2010). Pharmacological inhibition of DNMT activity induced a-SMA gene expression, while links between methyl CpG binding protein 2 and a-SMA downregulation have been also demonstrated (Hu et al. 2010). A recent study by the same group of investigators reported a binding site of MeCP2 to a-SMA gene and that regulation of MeCP2 affects a-SMA expression in lung fibroblasts (Hu et al. 2011). Hypermethylation of the promoter of several genes involved in fibroblast apoptosis, such as prostaglandin E receptor 2 gene (PTGER2) and p14 (ARF), was responsible for their diminished expression in IPF lung fibroblasts (Cisneros et al. 2012; Huang et al. 2010). Prostaglandin E2 has been also shown to increase DNMT3a activity leading to global hypermethylation and increased expression of genes that suppress cell proliferation in lung fibroblasts (Huang et al. 2012). Recently, the first study applying genome-wide methylation arrays identified an intermediate methylation profile in patients with IPF compared to lung cancer and controls. Interestingly, 402 differentially methylated CpG islands overlapped between IPF and lung cancer, highlighting common pathogenetic pathways (Rabinovich et al. 2012b). A follow-up comparative analysis of genome-wide DNA methylation using methylation arrays revealed a relatively balanced differential methylation repertoire between patients with IPF and controls encompassing a total of 870 genes (Sanders et al. 2012). The combination of methylation with gene expression data led to the detection of only 16 genes that exhibited an inverse relation between DNA methylation and Published by NRC Research Press

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Fig. 1. Idiopathic pulmonary fibrosis (IPF) transcriptome derives from an interaction between environmental and genetic factors. Epigenomic changes, including DNA methylation, histone modifications, and noncoding RNA regulation, represent an important mechanism that links environmental exposures to gene expression changes (i.e., MUC5B, TLR3, SFTPC, TOLLIP, hTERT) and may explain the various disease phenotypes in patients with IPF. A gradually increasing number of publications investigating epigenetic marks in patients with IPF will accelerate our current state of knowledge regarding this dismal disease.

gene expression matrix metalloproteinase-7 (MMP-7), secreted protein acidic, and were rich in cysteine (SPARC) and collagen 3A1. Intriguingly, TP53INP1, a p-53 inducible cell stress response protein that is being released by apoptotic cells, was one of the most hypomethylated and subsequently upregulated genes in patients with IPF (Rabinovich et al. 2012a, 2012b; Sanders et al. 2012). TP53INP1 has been extensively investigated in several types of cancer, including pancreatic, colorectal, prostate, and breast, and its circulating levels have been strongly correlated with both disease recurrence and treatment responsiveness, supporting its role as a reliable biomarker (Cano et al. 2009; Crowley et al. 2013). Although the above studies suggested that DNA methylation may alter the expression of several genes within the fibrotic lung, all of them used small sample sizes, only partially characterized the association of DNA methylation with gene expression changes that may lead to IPF phenotype, and more importantly were unable to assess methylation alterations in the CpG shores, located outside CpG islands. A recent study by Yang et al. (2014) addressed all the above concerns by applying high-throughput methylation and gene expression arrays in almost 100 IPF lung samples. On the contrary with previous studies (Rabinovich et al. 2012a, 2012b; Sanders et al. 2012), a relatively strong gene expression–methylation relationship was revealed for almost half of the differentially methylated genes, possibly attributed to the fact that methylation analysis was focused for the first time in CpG shores, where epigenetic marks appear to be more regulatory than those observed in CpG islands. Among differentially methylated and expressed genes, between IPF and controls, were genes previously implicated in disease pathogen-

esis (TOLLIP, NOTCH1, HDAC4, PDGF, SERPINF1, collagen) as well as novel candidates such as CASZ1, a transcription factor that plays an important role in vascular and cardiac or skeletal muscle developmental pathways. Histone methyltransferase EZH2 was identified as a putative mediator of methylation changes in CASZ1, further supporting its usefulness as a future therapeutic target (Table 1). Histone modification So far, several studies have shown that decreased histone acetylation in the promoter regions of anti-fibrotic or apoptoticrelated genes (including Fas-ligand, cyclooxygenase 2 (COX-2), and CXCL-10 (IP-10)) resulted in decreased production and impaired activity of the relevant proteins, leading to apoptosis resistance of fibroblasts derived from patients with IPF (Coward et al. 2009, 2010; Huang et al. 2013). Wang et al. (2009) reported that an FDAapproved histone deacetylase inhibitor is potent against TGF-b1, triggering effects in fibroblast cell lines by inhibiting their differentiation into myofibroblasts and decreasing collagen production. Results were further corroborated by Zhang et al. (2013b) in the experimental model of bleomycin-induced pulmonary fibrosis. Administration of TSA, another histone deacetylase blocker, restored Thy-1 expression in fibroblast cell lines in a time- and concentration-dependent manner (Sanders et al. 2011). In addition, TSA inhibited TGF-b1-driven differentiation into myofibroblasts, collagen production, and contractile response in normal health lung fibroblasts (Guo et al. 2009). Finally, inhibition of proliferation and differentiation of IPF fibroblasts by spiruchostatin (SpA), a selective histone deacetylase inhibitor, has been also Published by NRC Research Press

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Study (Reference)

Patients/cells

Genes

Methylation status

Expression level

Sanders et al. 2008

IPF lung fibroblasts

Thy-1

1

2

Sanders et al. 2007

IPF lung fibroblasts

Thy-1

1

2

Hu et al. 2010

Fibroblasts/myofibroblasts/ AECs

a-SMA

1

1

Hu et al. 2011

Lung fibroblasts from BLM-model IPF lung fibroblasts and lung fibroblasts from BLM-model IPF lung fibroblasts Primary fetal and adult fibroblasts Lungs from 12 patients with IPF-10 lung cancer Lungs from 12 patients with IPF

MeCP2

1

1

PTGER2

1

2

p14 (ARF) PGE2

1 1

2 1

625 differentially methylated CpG islands 870 genes including: CLDN5, ZNF467, TP53INP1, DDAH1

Global methylation changes Global methylation changes/1

12

Lungs from 94 IPF and 67 control subjects

738 differentially Expressed genes including: CASZ1, HDAC4, NOTCH1, PDGF, SERPINF1, TOLLIP

Global methylation changes

Huang et al. 2010 Cisneros et al. 2012 Huang et al. 2012 Rabinovich et al. 2012a Sanders et al. 2012

Yang et al. 2014

12

12

Pathway/effect Cell–matrix interactions, myofibroblast differentiation Myofibroblast differentiation, resistance to apoptosis Hypermethylation of 3 CpG islands in the promoter of a-SMA upregulated a-SMA expression, inhibition of DNMT led to a-SMA overexpression 1a-SMA expression, myofibroblast differentiation Increased PGE2 resistance of fibroblasts Increased apoptosis resistance PGE2 increases DNMT3a activity in lung fibroblasts Apoptosis, morphogenesis, cellular biosynthetic process Cell–cell signaling, inflammatory response, apoptosis, antigen presentation, developmental pathways Amyloid beta precursor, mesenchyme tissue development, cell–cell signaling, toll-like receptor signaling

Note: a-SMA: a-smooth muscle actin, BLM: bleomycin, DNMT: DNA methyltransferases, IPF: idiopathic pulmonary fibrosis, PTGER2: prostaglandin E receptor-2, PGE2: prostaglandin E2.

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Table 1. Studies reporting impaired DNA methylation in lung fibrosis.

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reported (Davies et al. 2012), while sirtuin, a class III histone deacetylase, has been demonstrated to promote p21 proteasomal degradation leading to attenuation of TGF-b-induced senescence of primary human bronchial epithelial cells (Minagawa et al. 2011) (Table 2). Noncoding RNA regulation A number of very recent publications investigating global miRNA profiles in IPF lung tissue identified let-7d and mir-29, while miR154, 155, and 21 appear to be upregulated (Yang 2012; Yang and Schwartz 2011). Pandit et al. (2010) used miRNA microarrays and demonstrated distinct miRNA repertoires between IPF and control lungs. Further analysis revealed a protective role of let-7d in a murine model of lung fibrosis through inhibition of Smad-3 dependent epithelial-mesenchymal transition (⌭⌴⌻). Inhibition of let-7d both in vitro and in vivo by an antagomir for the let-7d family resulted in upregulation of mesenchymal and downregulation of epithelial markers in alveolar epithelial cell lines. The latter supports a role of let-7 miRNAs in EMT. A follow-up analysis identified miR-154 as one of the most upregulated miRs in IPF lungs. Transfection of primary fibroblasts with miR-154 promoted significant increases in cell proliferation and migration through activation of a WNT pathway, indicating miR-154 as a potential therapeutic target (Milosevic et al. 2012). A therapeutic role for short noncoding RNAs has been also demonstrated in the bleomycin-model of lung fibrosis. Based on previous observations showing downregulation of miR-29 following bleomycin treatment (Cushing et al. 2011), Xiao et al. (2012) demonstrated a beneficial effect of intravenously administered miR-29 in the mouse model of pulmonary fibrosis. The miR-29 family has been extensively studied as a potential antifibrotic mediator, because it is constitutively highly expressed, is decreased in kidney, lung, liver, and myocardial fibrosis, and molecules important to fibrosis, such as collagen and connective tissue growth factor (CTGF), are among its targets (Fang et al. 2013; Pandit et al. 2010; Roderburg et al. 2011; van Rooij et al. 2008). Most importantly, a phase II clinical trial investigating the effectiveness of the latter in patients with IPF is ongoing, and results are eagerly anticipated. Experimental data have showed a significant downregulation of genes regulated by the anti-fibrotic mir-29 in normal health fibroblasts following culture with ECM components derived from patients with IPF (Parker et al. 2014). Interrupting the positive feedback loop between fibroblasts and ECM may be a more efficient therapeutic strategy than targeting only fibroblasts. Mir-21 has been shown to be upregulated in the experimental model of pulmonary fibrosis and in the lungs of patients with IPF, mainly within fibroblastic foci (Liu et al. 2010b). Pharmacological inhibition of miR-21 was found to attenuate bleomycin-induced lung fibrosis through downregulation of TGF-b1 signaling (Liu et al. 2010b). An epigenetic regulation of miR-17⬃92 was revealed in the bleomycin model of lung fibrosis (Dakhlallah et al. 2013; Rosas and Yang 2013). Treatment of mice with 5=-aza-2=-deoxycytidine led to upregulation of miR-17⬃92, reduced DNMT-1 expression, and attenuated pulmonary fibrosis (Rosas and Yang 2013). Additionally, the role of noncoding RNAs in serving as reliable biomarkers of disease severity has been investigated. Oak et al. (2011) identified a panel of miRNAs (miR-302c, miR-423, miR-210, miR-376C, and miR-185) in lung biopsies from patients with IPF that could differentiate rapid from slow progressors. Over the past two years, the contribution of lnc-RNAs in the pathogenesis of lung fibrosis has focused increased attention on this factor. A recent microarray analysis revealed distinct lnc-RNA profiles between normal and fibrotic rat lung following bleomycin treatment (Cao et al. 2013). Validation experiments localized two of the most upregulated lnc-RNAs (AJ005396 and S69206) within the fibrotic interstitium, suggesting them as potential future therapeutic targets (Cao et al. 2013). It is now clear that lncRNAs are more common and more important than previously

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appreciated, and these species appear to play various roles in coordinating transcription and other crucial cellular functions. Despite the fact that high-throughput genomic technologies, like lnc-RNA microarray and RNA-sequencing, have generated a library of lnc-RNAs of interest, little is known about the transcriptional regulation of the set of lnc-RNA genes. Several features have made the study of lnc-RNAs difficult, including poor sequence conservation in model organisms and difficulties in predicting RNA structure. Genome-wide profiling studies implementing next-generation sequencing are sorely needed to delineate the contribution of lnc-RNAs within disease etiology (Table 3).

Limitations and future challenges Epigenetic research has provided novel insights into early fibrosis development and progression, delineating new pathogenetic pathways with fruitful therapeutic applications. Our awareness of epigenetic mechanisms in fibrosis development is growing rapidly. However, further research applications are required to complete and improve our understanding (Fig. 1). To this end there are a number of challenges that should be addressed: 1. One major challenge is the dynamic nature of epigenetic marks, especially in the context of complex disease phenotypes including IPF. Discrepancies between studies using different research approaches (single-gene or genome-wide) may be attributed to the temporal and spatial heterogeneity of the disease (Yang 2012). The epigenome should be investigated taking into consideration environmental exposures, diet, and age. In addition, an analysis solely based on a single-tissue sample snapshot is incomplete and inconclusive given the dynamic range of epigenetic signatures. Different stages of the disease may present with different phenotypes. Applying nextgeneration sequencing analysis to blood or bronchoalveolar lavage samples of different time-points will help us to gain a more complete view of the lung epigenome in patients with IPF. Advanced in vivo imaging technologies such as magnetic resonance spectroscopy will facilitate depiction of dynamic chromatin structure providing us with real-time pictures of epigenetic changes. 2. The lack of intersection between epigenetic modifications and expected gene expression should challenge scientists to apply more targeted methodology techniques for collecting epigenomic profiles than those currently used. In particular, Sanders et al. (2012) used DNA immunoprecipitation arrays and revealed a distinct methylation repertoire between a limited number of patients with IPF and controls, encompassing a total of 870 genes. Surprisingly, only 16 genes have exhibited significant expression alterations, evidence that may be attributed to the fact that most epigenetic marks occur neither in promoters nor in CpG islands, but in proximal sequences up to 2 kb from the islands (known as CpG island shores), as happens in lung cancer (Liloglou et al. 2014). One of the main reasons for these discrepancies and also a major limitation in many epigenetic studies is the use of the mixture of cells in whole lung tissue specimens, instead of investigating epigenetic profiles in selectively isolated cell lines from IPF lung samples including fibroblasts, alveolar epithelial, inflammatory (macrophages, neutrophils, lymphocytes), and endothelial cells. Although the isolation of enough material for specific cell types may be not feasible in many studies, one way to overcome this barrier is to apply methods to decompose whole-tissue expression into cell specific components (Shen-Orr et al. 2010) as well as laser capture microdissection approaches. The latter would be very useful to better understand the role of epigenetics in disease pathogenesis, since epigenetic marks are cell-specific and variable. Another important issue arising from this evidence is choosing the right control lung specimens. This is vital since all the current studies have used either lung transplant Published by NRC Research Press

Tissue/cells

Genes

Histone modification

Huang et al. 2013

IPF lung fibroblasts

Fas

H3 and H4 acetylation H3K9 hypermethylation

2

Coward et al. 2010

IPF lung fibroblasts

IP-10

H3 and H4 deacetylation H3K9 hypermethylation

2

Coward et al. 2009

IPF lung fibroblasts

COX-2

H3 and H4 deacetylation

2

Wang et al. 2009

Fetal, adult and IPF lung fibroblasts

Histone deacetylase

H3 hyperacetylation

2

Zhang et al. 2013b

Histone deacetylase

H3 hyperacetylation

2

Sanders et al. 2011

IPF lung fibroblasts BLM-model of PF Rat lung fibroblasts

Histone deacetylase

H3 hyperacetylation

2

Guo et al. 2009

NHLFs

Histone deacetylase

H3 hyperacetylation

2

Davies et al. 2012

IPF lung fibroblasts

Histone deacetylase

H3 hyperacetylation

2

Minagawa et al. 2011

Primary bronchial Epithelial cells

p21

H3 deacetylation

2

Pagination not final (cite DOI) / Pagination provisoire (citer le DOI)

Expression level

Study (Reference)

Pathway/effect Histone deacetylation is responsible for decreased Fas expression and apoptosis resistance in IPF lung fibroblasts Histone deacetylation and hypermethylation at the IP-10 promoter results in targeted repression of the gene in IPF lung fibroblasts Histone deacetylation leads to reduced COX-2 expression in IPF lung fibroblasts SAHA, a broad spectrum histone deacetylase inhibitor induces TGF-b induced myofibroblast differentiation, inhibits collagen and MMP-1 production SAHA treatment reduces collagen synthesis Trichostatin restored Thy-1 expression in rat lung fibroblasts Trichostatin abrogates differentiation of fibroblasts to myofibroblasts and collagen expression SpA a selective histone deacetylase inhibitor inhibits proliferation and differentiation of IPF lung fibroblasts Sirtuin, a class III histone deacetylase, promotes p21 degradation and attenuates TGF-b-induced senescence of primary bronchial epithelial cells

Note: COX-2: cycloxygenase-2, IPF: idiopathic pulmonary fibrosis, MMP: matrix metalloproteinase, NHLFs; normal human lung fibroblasts, PGE2: prostaglandin E2, SAHA: suberoylanilide hydroxamic acid, SpA: spiruchostatin, TERT: telomerase reverse transcriptase, TGF-b: transforming growth factor-␤.

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Table 2. Studies reporting aberrant histone-modification in lung fibrosis.

Tissue/cells

Noncoding RNAs

Expression level

Target genes

Pathway/effect

Pandit et al. 2010

10 IPF and 10 control lungs

Let-7d

2

Smad3-TGF-b

Milosevic et al. 2012

13 IPF and 12 control lungs

miR-154

1

CDKN2B

Cushing et al. 2011

BLM-model, Human fetal lung fibroblasts

miR-29

2

Collagen, integrins, laminins, MMP-12, 19, IL-1 R, genes involved in ECM formation

Xiao et al. 2012

Primary lung fibroblasts from BLM-induced model of lung fibrosis

miR-29

2

Smad3-TGF-b-CTGF

Parker et al. 2014

IPF and normal lung fibroblasts

miR-29

1

ECM genes

Liu et al. 2010b

Lung fibroblasts from BLM-model and patients with IPF

miR-21

1

Smad/Smad7-TGF-b

Dakhlallah et al. 2013

Lungs from patients with IPF

miR-17⬃92

2

COL1A1, TGF-b, MMP, 1, 7, 9

Oak et al. 2011

Surgical lung biopsies from patients with IPF

miR-302c, miR-423, miR-210, miR-376 C, and miR-185

2

EMT-associated genes (CD44, COL1A2, VIM, FOXC1)

Cao et al. 2013

BLM-model of lung fibrosis

210 lnc-RNAs/358 lnc-RNAs

1/2

Pro-fibrotic genes

TGF-b driven downregulation of let-7d results to overexpression of EMTassociated genes. Let-7d overexpression abrogates this effect WNT/b-catenin Increase in cell proliferation and migration Knock-down of mir-29 in human fetal lung fibroblasts regulates the overexpression of several profibrotic genes through TGF-b TGF-b and CTGF negatively regulate mir-29 expression through Smad3 pathway. MiR-29 administration attenuated BLM-induced lung fibrosis Culture of fibroblasts with IPF derived ECM results in downregulation of miR-29 and upregulation of fibrotic ECM genes TGF-b enhances miR-21 expression through Smad, Smad7. Blocking mir-21 attenuates experimental lung fibrosis Hypermethylation of the promoter of miR-17⬃92 in patients with IPF resulted in decreased expression leading to overexpression of profibrotic genes Downregulation of miRs in the IPF lungs of rapid versus slow progressors results into overexpression of EMT-associated genes Two of the most upregulated lncRNAs (AJ005396 and S69206) were localized within the fibrotic interstitium

Note: BLM: bleomycin, CDKN2B: cyclin-dependent kinase inhibitor 2b, COL: collagen, ECM: extracellular matrix, miRs: micro-RNAs, ECM: extracellular matrix EMT: epithelial-mesenchymal-transition, FOXC1: forkhead box C1 protein, IPF: idiopathic pulmonary fibrosis, lnc: long noncoding RNA MMP: metalloproteinase, TGF: transforming growth factor, VIM: vimentin.

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Study (Reference)

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Table 3. Studies reporting noncoding RNA regulation in lung fibrosis.

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rejects or normal parts of lungs from patients with lung cancer (Yang and Schwartz 2011; Yang et al. 2014). 3. Closely related to the poor overlap results between genetic variants and epigenetic marks, is the evidence that the role of epigenetic modifications in disease pathogenesis has been, so far, largely underrated. Besides already identified epigenetic marks there are additional methylation- or acetylation-expression relationships that have not been discovered. One alternative approach would be to apply more sophisticated data analysis techniques to integrate expression and methylation/acetylation profiles. It should be emphasized that one of the future developments may be an analysis that allows the integration of all epigenetic modifications including methylation, acetylation, phosphorylation, and ubiquitination to explain expression, even at the single gene level but also in terms of pathways and genomically. 4. Implementing personalized medicine therapeutic approaches based on analysis of surrogate tissues represents the most fruitful application of epigenetics in chronic fibrotic lung diseases. Given the lack of effective treatment and the unpredictable nature of IPF, it seems imperative to stratify patients into appropriate regimes and treat only those more likely to respond, sparing those who would gain no benefit from side effects (i.e., administer a specific microRNA only in patients with IPF that exhibits low levels of this particular microRNA). To this end, development and validation of a companion diagnostic and strategies to assess treatment response based on epigenetic marks sounds both promising and challenging. 5. Epigenetic alterations will also need to be considered in the context of genetic variation. So far, it is largely unknown whether epigenetic inheritance also occurs in humans and mammals as it happens with plants and fungi. It is largely known that most of the epigenetic tags are erased during early development so that a healthy embryo can be born. Nevertheless, data show that some epigenetic marks overcome the reprogramming barrier during gestational time and pass unchanged from parents to offspring, e.g., gestational diabetes and risk of development of diabetes mellitus (Heard and Martienssen 2014). It is therefore conceivable that genes do have “memory and experience”, and that the lives of our grandparents, their nutrition, the air they breathed, whether they were passive and (or) active smokers, their occupational exposures, may affect our lives, despite the fact that we have never experienced these things ourselves. Extrapolating the above notion, cases of familial IPF may be explained by inheritance of epigenetic tags influencing the regulation of genes that render siblings highly susceptible to fibrotic lung disease, as happens with telomerase mutations in families with IPF. Identifying the epigenetic processes that buffer genetic variation in patients with IPF represents an exciting possibility. In summary, conducting large scale meaningful epigenome-wide association studies will be challenging, as epigenetic signatures are highly plastic and dynamic, display differences on a cell- or tissue-specific manner, and are modified by aging and multiple environmental factors. However, epigenome-wide association studies offer the reward of a holistic overview of disease pathology, improved patient stratification, and new prognostic tools. Contrary to genetic fingerprints of the disease, unhealthy epigenetic modifications may be therapeutically modified, thus offering the potential for epigenetic treatments.

Acknowledgement AT has no financial interests to disclose relevant to the topic of this review. NK has been a paid consultant for Sanofi, Stromedix, Vertex, Takeda, Promedior, and InterMune; is a recipient of investigator-initiated grants from Celgene and Gilead; and is an

9

inventor on a patent application on the use of peripheral blood proteins in prediction of IPF outcomes.

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Biochem. Cell Biol. Vol. 93, 2015

Published by NRC Research Press

Epigenetics in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disorder with no effective treatment and a prognosis worse than that of lung cancer. Desp...
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