epigenetic: a missing paradigm in cellular and molecular pathways

Iranian Journal of Basic Medical Sciences

ijbms.mums.ac.ir

Epigenetic: A missing paradigm in cellular and molecularpathwaysofsulfurmustardlung:aprospectiveandcomparativestudy

SaberImani1,YunesPanahi1*,JafarSalimian1,JunjiangFu2,MostafaGhanei1

1 SystemsBiologyInstitute,ChemicalInjuriesResearchCenter,BaqiyatallahUniversityofMedicalSciences,Tehran,Iran2 KeyLaboratoryofEpigeneticsandOncology,theResearchCenterforPreclinicalMedicine,SichuanMedicalUniversity,Luzhou,Sichuan,China

ARTICLEINFO A BSTRACT

Articletype:Reviewarticle

Sulfur mustard (SM, bis‐ (2‐chloroethyl) sulphide) is a chemical warfare agent that causes DNAalkylation, proteinmodification andmembrane damage. SM can trigger severalmolecular pathwaysinvolvedininflammationandoxidativestress,whichcausecellnecrosisandapoptosis,andlossofcellsintegrity and function. Epigenetic regulation of gene expression is a growing research topic and isaddressed by DNA methylation, histone modification, chromatin remodeling, and noncoding RNAsexpression.ItseemsSMcaninducetheepigeneticmodificationsthataretranslatedintochangeingeneexpression. Classification of epigenetic modifications long after exposure to SM would clarify itsmechanism and paves a better strategy for the treatment of SM‐affected patients. In this study, wereview the key aberrant epigenetic modifications that have important roles in chronic obstructivepulmonarydisease(COPD)andcomparedwithmustardlung.

Articlehistory:Received:Dec9,2014Accepted:Apr20,2015

Keywords:Cellularandmolecular‐modificationEpigeneticmodificationInflammationSulfurmustard

►Pleasecitethisarticleas:Imani S,PanahiY, Salimian J, Fu J,GhaneiM.Epigenetic:Amissingparadigmincellularandmolecularpathwaysofsulfurmustard lung:aprospectiveandcomparativestudy. IranJBasicMedSci2015;18:723‐736.

IntroductionCellular and molecular mechanisms of sulfurmustard

Sulfurmustard,bis(2‐chloroethyl)sulfide,(SM),isa lethal chemical warfare agent (CWA), with highabsorbance and alkylating potential that can affecttissuessuchasthelungs,eyesandskin.Also,itcanbedistributedthroughbloodandsystemicallyaffectothertissues and organs, especially liver, brain, spleen,platelets,kidney,andwhiteandredbloodcells,(1).SMcan directly interact with DNA bases including7‐ (2‐hydroxyethylthioethyl) guanine (7‐HETE‐G) (2),position 3 of adenine and O6 position of guanine (3)(Figure 1). Several repair pathways includingpoly (ADP‐ribose) polymerase (PARP) pathway,base excision repair, nucleotide excision repair,non‐homologous and joining are activated followingSMexposure(4).SMexposureactivatesPARPpathwayindicating its direct/indirect genotoxic effect,and also activates the intracellular repair system.Simultaneously, accumulation of p53 could blockcell cycle and provide a time for up‐regulationof repair proteins such as DNA polymerase b,stimulatingofbaseexcisionrepair(BER).Afterbinding

toDNA,PARP‐1synthesizesapoly(ADP‐ribose)chainthat isrecruitmentsignals forotherrepairenzymes(5). Currently, it is proposed that PARP may be aswitcher between apoptosis and necrosis (6), andmay have regulatory function over apoptosis (7). Ifdamageisnotrepairable,apoptosiswillbefollowedandPARPwillbecleaved.Butifcellmissesitsenergy

Figure1.DNAcross‐linkingbysulfurmustard

*Corresponding authors: YunesPanahi. SystemsBiology Institute,Chemical InjuriesResearchCenter,BaqiyatallahUniversityofMedical Sciences,Molla‐

SadraAve.,VanakSq.,Tehran,Iran.Tel:+98‐21‐88211524;Fax:+98‐21‐88211524;email:[email protected]

Imanietal Epigeneticmodificationinmustardlung

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Figure2.OverviewofthemolecularandcellulareffectsofsulfurmustardSM (SulfurMustard);GADD45 (GrowthArrest andDNADamage‐inducible45); PCNA (proliferating cell nuclear antigen);XRCC1 (X‐rayrepaircross‐complementingprotein1);PARP(Poly(ADP‐ribose)polymerase); IL(Interleukin);TNF‐α(Tumornecrosis factor);TNFR‐1(tumor necrosis factor receptor‐1); MCP1 (monocyte chemotactic protein 1); CCL2 (C‐C motif chemokine 2); MMP9 (Matrixmetalloproteinase9)HAT (histone acetyltransferase); CBP (CREB‐binding protein); PcG (Polycomb Group protein); PRC1 and PRC2 (Polycomb RepressiveComplexes1and2);HMT(histonemethyltransferase);HUL(histoneubiquitinligases);MBD(Methyl‐CpG‐bindingdomain);RAT(removeracetyletages);HDAC(Histonedeacetylase);HDM(histonedemethylases)sources due to high ATP consumption of repairingsystem,necrosiswilloccur(8).SevereATPdepletionblocks cleavage of PARP by caspase‐3 that leads tocontinuousactivityofPARP(9).

Invitro and invivo studies showsomesimilaritiesbetweenSMpathophysiologyandotherdiseasessuchas chronic obstructive pulmonary disease (COPD),idiopathic pulmonary fibrosis (IPF), and brochiolitisobliterans(BO),buttheexactpathophysiologyofSMisnotyetwellunderstood(10).ItwasfirstproposedthatacidliberationandhydrolysisofSMtoHClarethemaincauses of its toxicity. At the next step, glutathione

depletion,protein inactivation, lipidperoxidation,andoxidativestresswerepostulatedasmechanismsofSMtoxicity (11, 12).Todate, it is clear that SMalkylatesnucleotides and causes intermolecular nucleotidecross‐links,whichisfollowedbygenotoxicstressesandproteins or genome modifications. Moreover, SMinterferes with natural function of proteins viamisfolding, protein oxidation, antioxidant depletion,andcross‐linkingsuchashexokinaseinactivation.Also,lipids are peroxidized when exposed to SM (lipidperoxidation).Likewise,freeradicalswillbereleasedasbyproductsoflipidperoxidation.Itissupposedthatthe

Epigeneticmodificationinmustardlung Imanietal


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firstanddirecteffectofSMexposureisoxidativestress,which is followedbyarrestofcellsignalingpathwaysandcellmembranecollapse.

Innateimmunityisthefirstdefensivelayeragainsttoxicagents.Epithelial cells andmacrophagesare theprimarylayerofcellsthatcanbeexposedtoSMinthepulmonary system. Following SM exposure, intensecellularandmolecularalterationsoccurinlung.Duringseveral days after exposure, innate immunity inducesadaptive immune system with pro‐inflammatorymediators.If theapoptosisandnecrosisrate increase,cell contents will be released into the extracellularmatrix (ECM), and immune cells will be activated.Epithelial cell detachment, cell death, fibrosis, DNArepair system activation, tissue repair induction andsystemic signaling are reported after SM exposure.Figure 2 shows the effects of SM andmolecular andcellular alterations inducedby SM innormal cell thatdescribed our current knowledge of SM inducedcellularandmolecularmodifications.Oxidativestressandinflammation

Oxidative stress has been detected in cell andtissue damages after misbalancing in physiologicalcondition (13). It is also linked with many chronicinflammatory lung diseases such as asthma, COPD,IPF, OB, and adult respiratory distress syndrome(ARDS)(14).Oxidativestresshasbeenimplicatedinthe pathogenesis of SM exposure via unidentifiedmechanisms(15‐18).Reactiveoxygenspecies(ROS)are created in organisms after stimulation withbiochemical hazardous stimulantsmolecules. Thereare several sources of exogenous and endogenousoxidants,suchassmoking,ozone,pollutants,ionizingradiation,alcohols,peroxisomes, andphagocytes, ofwhichcytochromeP450enzymes,andnicotinamideadenine dinucleotide phosphate‐oxidase (NADPHoxidases) are the most important endogenoussources of ROS production (19, 20). ROSs can bedivided into two groups: free radicals and non‐radicalcompounds.Freeradicalisanatom,moleculeorcompound,whichisunstableandtendstointeractwith non‐radical atoms, or unpaired electrons. ROSmayalter the remodelingofapoptosis, extracellularmatrix, mitochondrial respiration system,maintenanceofsurfactant,cellproliferation,theanti‐protease screen, effective alveolar repair responsesandimmunitymodulationinlung(21,22).

Superoxide anion (O2‐•) is produced underrespiratory burst, high energy requirements andincreased respiration (23). The ROS can betransformed intohighly toxic and stable substancesthroughironmediatingreactions(24).Besides,nitricoxide (NO) is a strong natural oxidant that inhibitsmast cell degranulation and histamine release.DespiteNO isastrongoxidant,butROSreactswithO2‐•andformsastableoxidantknownasproxynitrite(ONOO‐),whichcan interactwithbio‐moleculesand

induce more damages (25‐28). NO competes withenzymatic antioxidants in O2‐• consumption, as well,highNOconcentrationdisruptsenzymaticantioxidantequilibration.Moreover,SMdepletesblood,hepaticandpulmonaryglutathione(GSH)andincreasesitsoxidizedform (GSSG). Decrease in GSH content leads tothe accumulation of naturally produced ROS withincells (17, 29). ROS causesmitochondrial damage anddysfunction that can lead to apoptosis (30).Accordingly,theroleofROSasasecondmessengerisaccepted in four ways: degradation by particularenzymes,regulatedenzymaticproduction,presenceatlow concentrations that can be transiently elevateduponstimulation,andfacilitytoreactatspecificsites,for instance with metals and thiolates (31). SeveralstudieshaveshownthatthesefourcharacteristicscanbeattributedtoROSinducedbySM(18,32,33).

SMexposure triggersseveralsignalingpathwaysthat result in inflammatory cytokine secretion suchasTNF‐αfromalveolarmacrophages,IL‐6,IL‐8,andGM‐CSF(34,35).SMcauseswideningofintercellularspaces and cell‐matrix adhesion loss; therefore,mucus secretion is increased as cilia cannot beatthem up. In patient with high SM doses exposure,rarely cilia on epithelial cells are observed andintracellularvacuolesareenlarged.Mucin(Muc5Ac)isalsoincreasedinthesepatients.Thereisarelationbetweentheregulationofinflammationandalveolarmacrophages, surfactant protein‐1 (SP‐D) andalveolar type II epithelial cell in SP‐D production.After SM exposure, SP‐D is decreased drastically(18). Extracellular proteases (released from injuredcells, dead cells and immune cells) and oxidantscausetissuedestructionandremodelinginSMlung.Normally, there is an imbalance of protease/anti‐protease and oxidant/antioxidant pathways in SMvesicants(36,37).

More exactly, lipid peroxidation, protein andnucleicacidalkylation,mutation,DNAbreakageandrepair, immune system induction and activation,injury sensing by neighboring cells, and systemictissue repair systems are all reported as knownpathways linked with SM acute injury (7, 38, 39).Newly released free radicals, depletion ofantioxidants, cell content release of dead cells,unneutralized cellular ROS and RNS (reactivenitrogen species), along with immune systemactivation and inflammation will intensify the firststep of oxidative stress (40). It is concluded thatoxidativestressandinflammationinducedbySMaretwo key factors that must be controlled for bettertreatmentofSMintoxication.(Figure2).EpigeneticsIntroduction

TheepigeneticswasfirstproposedbyWaddingtonCH in 1940s (14, 41). Epigenetics describes all



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Figure3.Thisschematiccarton,showthespecifichistonemodificationBio‐machines.Writer:TheenzymestocreatemodificationsonDNAandhistone.AReaderdecipherscodesandErasereliminatesalterationsHAT (histone acetyltransferase); CBP (CREB‐binding protein); PcG (Polycomb Group protein); PRC1 and PRC2 (Polycomb RepressiveComplexes1and2);HMT(histonemethyltransferase);HUL(histoneubiquitinligases);MBD(Methyl‐CpG‐bindingdomain);RAT(removeracetyletages);HDAC(Histonedeacetylase);HDM(histonedemethylases)meioticallyandmitoticallyheritablechangesingeneexpression states that do not depend on DNAsequence(22,42,43).Theepigeneticprofileofacelloftendictatescellulardifferentiationandfate,aswellasdevelopment,aging,diseaseandcancer(44‐52).Specificepigeneticmodifications

Specificepigeneticmodificationsareclassifiedintofive general categories: DNA methylation (53), post‐translationalhistone(54),noncodingRNAs(47,50,55‐60),chromatinremodeling(ATPdependentchromatinremodeling complexes (CRCs)), histone variants(Histoneswithvaryingstabilitiesorspecificdomains).All of these modifications lead to gene activation orinactivation.

These modifications have been proceeding bythree classes of bio‐machines; a writer to createmodificationsonDNAandhistone.Areaderdecipherscodes and finally an Eraser to eliminate alterations(58, 61, 62) (Figure 3). In this paper, we focused onkey modifications i.e. DNA methylation, histonesmodificationsandnoncodingRNAthathaveimportantroles inCOPDasan inflammatoryrespiratorydiseaseandcomparedwithSMlung.

DNAmethylation

DNAmethylation isthemostpopularmodificationinDNAlevelsthatoccursapproximatelyin3%ofwholegenome of eukaryotic cell. DNA methylation occurslargely on CpG islands that are more found in genesupstream (53, 63). Methylation of CpG islandsinterfereswithbindingoftranscriptionfactorsandthensuppresses all forums of genes expression (63, 64),

especially developmental genes, repetitive sequencesandgerm‐linespecific(imprintedgenes)(65,66).DNAmethylationcatalyzestransferofamethylgroupfromS‐adenosylmethionine(SAM)toacytosineresiduetocreate5‐methylcytosine(5mC).

ThisprocessoccursbyfamilyofcloselyrelatedDNAmethyl transferases (DNMTs) as a writer (DNMT1,DNMT3a, and DNMT3b) (67). The readers ofmethylated DNA are methyl‐CpG‐binding domainproteins includingKaiso,MeCP2,andmembersof themethyl CpG‐binding domain (MBD) family (66, 68).DNAdemethylation couldbepassiveor active.ActiveDNA demethylation occurs via direct removal of amethyl group. Active DNA demethylations such asMBD2b(methylCpG‐bindingdomainprotein2b)(69),ten–eleventranslocation(Tet)enzymesTet1,Tet2,andTet3 (70, 71), and AID/APOBEC (activation‐inducedcytidine deaminase/ apolipoprotein B mRNA‐editingenzyme complex) are themost important eraser bio‐machines in DNA modifications (72‐74). The passiveprocess takes place during replication of newlysynthesized DNA strands by DNMT1. Base excisionrepairmachinery(BER),andnucleotideexcisionrepair(NER) are important passive DNA demethylation;however, there are many questions about themechanismsofthisbio‐machines(75‐77).Post‐translationalhistonemodifications

The smallest unit of chromatin, the nucleosome,consists of 146 bp DNA sequencewrapped around ahistoneoctamer(twocopiesofH2A,H2B,H3andH4)linked by exterior histone H1. This organizationguaranteedacloseortightstructuretochromatin(78).



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Figure4.FunctionalpathwaysthatHAT/HDACratioisinvolvedincellularandmolecularmechanismofinflammations.GR (glucocorticoid receptor);ER (estrogen receptor);AR (androgen receptor);PGC‐1 (PPARgammaco‐activator‐1);Rb (retinoblastomaprotein);GATA3(GATA‐bindingprotein3);HIF1(hypoxia‐induciblefactor‐1);IRFs(Interferonregulatoryfactors);Nf‐kb(nuclearfactorkappa‐light‐chain‐enhancerofactivatedBcells);AP‐1(activatingprotein‐1);HIV‐Tat(HIVtrans‐activatorprotein);HSP90((heatshockprotein90);p53MAPK(p53Mitogen‐activatedproteinkinasekinase3)

Differenthistonemodificationsarecorrelatedwith

differentfunctionsonthelysines(K)andarginines(R)‐rich tail region of histones. The H3 and H4 have acriticalregulatoryroleinmanydiseases(79‐81).Therearemanypost‐transcription or histonemodifications,including acetylation (K), phosphorylating (P),methylation (M), citrullination, ubiquitination (Ubi),butyrylation,simulation,ADP‐ribosylation,propionyla‐tion, and glycosylation of residues in the N‐terminaltailsofhistones(Table1)(82,83).

Histones are acetylated by histone acetyltrans‐ferases (HAT). The acetylated histonemarks H3K4acandH3K39ac(as importantmarksofacetylation)areassociated with transcriptional activation (84). Theacetyl groups are removed by histone deacetylases(HDACs)thatrepressesthegeneactivationbycreatingatightlyclosedchromatinstructure(78,85,86).

In contrast toacetylation,histonemethylationcancorrelate either with transcriptional activity orinactivity.Thehistonemethylationexistsinthreeformsof mono, di and tri‐methylation (87). By contrast,histonemethylations on lysines 9 and 27 (H3K9me3

and H3K27me3) transcriptionally inactivate regions,broadly the whole gene, but more commonly atfacultative heterochromatin (54, 88). The lysines (K)and arginines (R)‐rich regions are methylated byhistone methyl transferase enzyme (HMTs) and areremoved by histone demethylases (HDMs) such asmembersoftheJumonjiproteinfamily(66,67).NoncodingRNAs

Noncoding RNAs are a class of small, mid‐sizedand long RNAs, which include the microRNAs(miRNAs),piwi‐interactingRNAs(piRNAs),andlongnoncoding RNAs (lncRNAs). Noncoding RNAs arehereditary involved in regulating the genesexpression (89‐91). miRNAs (19‐24bp) play role incontrolling transposable elements and direct DNAmethylation at transposable elements. EachmaturemiRNA may target many genes and involve indevelopment, differentiation, and cancer (92). Piwi‐interactingRNAsare~24‐35ntinlengththatinvolvein silencing transposable elements in the germ lineandstemcell.TheseRNAsareinvolvedindirecting

Table1.Histonemodificationpost‐transcriptionmodification

Modificationtypes Residue(s)modified Readerdomain(s)Unmodifiedlysine Lysine PHDAcetylation Lysine BRDMethylation Lysine/Arginine Ankyrin,Chromo,MBT,PHD,Tudor,PWWP,WD40Phosphorylation Serine/Threnine 14‐3‐3,BIR,BRCTUbiquitylation Lysine BRDSumoylation Lysine ?ADP‐Ribosylation Lysine TudorGlycosylation Serine/Threonine ?Butyrylation Lysine ?Propionylation

Lysine ?

PHD(PlantHomeodomain);BRD(bromodomain);MBT(malignantbrain tumor);BIR(InhibitorofApoptosis (IAP) familyofproteins);BRCT(BRCA1CTerminus(BRCT)domain)



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DNAmethylationatmorelocithanjusttransposableelementsandmutationsinhuman.PIWIproteinsareassociated with infertility. Different PIWI proteinshave non‐redundant roles (93, 94). lncRNAs (>200nt) are expressed in a controlled manner and areable to regulate epigenetic processes such as Xinactivation, genomic imprinting, and DNA damageresponse. It was recently shown that rRNAs andpiRNAs provide a dynamic balance between geneactivationandsilencing(95,96).Epigenetic modification caused by inflammationinCOPD

Chronic inflammation is a main characteristic ofCOPDpatientswithGOLDstagesI‐IIIthatrelatedwithactivationoftheNF‐kBsignalingpathway(97).Severalstudies have been conducted on aberrant epigeneticmodifications and respiratory diseases (44, 45, 55).Intra‐andextracellularROSandNOSleadtoavariousrange of pathophysiological conditions, as well asinflammation and oxidative stress (79). On the otherhand, the fundamentalroleof inflammationandearlyaging in the development of COPD has remainedunknown (98, 99).Recent articles have reported thatinflammatory genes are regulated by transcriptionfactors of the NF‐κB, FOXP3, IRF, and STAT families,DNAmethylation,andhistonemodifications(98,100).Gene expression regulation is not only restricted topost‐translational modification (PTM) of histone, butalso is regulated by acetylation, methylation,phosphorylation,andubiquitylation.Morestudieshaveinvestigated enzymes involved in this process. Forexample,therelationofHAT/HDACenzymeshasbeenevaluated in many respiratory diseases, especially incorticosteroidresistances(101‐103).InFigure4,someimportant functions of HAT/HDAC ratio are shown.Study of HAT/HDAC ratio in induction of pro‐inflammatoryproteinssuchasNf‐κbandAp‐1isveryimportant and necessary that can control manyinflammatory processes and signaling in the cell.Acetylating is an important modification inautoimmuneandinflammatorydiseasessuchasTh17‐Threg balancing (104‐106). So, thewriter (HAT) anderaser of acetylating (HDAC) are studied in diseases,suchasasthma,COPD,cancer,autoimmunedisease,etc(107,108).

In Table 2, some important epigenetic changesare listed that involved in the process ofinflammatory diseases. Several reports have alsodemonstrated alterations in histone proteins inCOPD.Asaresult,itmustbeconsideredinoxidativestress and inflammation induced by SM as well asdiseases suchasasthmaandCOPD (102,108,109).HDACactivationduetotheeffectofSMmayleadtoanti‐inflammatory proteins and antioxidant enzymessilencing(109).HDAC‐2isthemostimportantproteinfromHDACfamilies,whichplaysaroleininflammationandoxidativestressoflungdisease.Inastudy,Barnes

etal(86)proposedthatstimulantssuchasnitricoxideand superoxide dismutase reduced HDAC‐2 levels inCOPD and asthma patients who eventually causecorticosteroids resistance (108, 110‐112). Dependingonthecause,thepathwayisdifferentandeachpathwayofHDAC‐2 is reducedeventually (113,114).Blockingthe inflammatory gene expression pathway byinhibitingDNMTisthelogicaltherapeuticapproachininflammatorydiseases(85,109).SMandpossibleepigeneticmodificationsinlung

Several pathophysiological studies on SM exposedpatient have shown significant imbalances andalterations in inflammatorymediators. This variationreflects the inflammatory roles of SM in the chronicphase(18,115‐117).Pro‐inflammatorycytokinessuchas IL‐1α, ‐8, ‐6, ‐13(34),TNF‐α(35), IFN‐α(34,118),GM‐CSF(119)andstressinducedproteinsi.e.HSP27,‐70, ‐90 (120), SWI/SNF, iNOS, and MIP‐1 (121) aretrace in serum and tissue samples of SM patients.RegardingtheinflammatoryroleofSM,itseems,nearlyallepigeneticcodsforexpressionofpro‐inflammationproteinscanbealteredinepithelialandimmunecells.These alterations consist of hypo and hypermethylationofCpGislands,histonemodifications,longnoncoding RNA expression, and chromosomeremodeling.

Moreover,someclinicalmanifestationsanddiseasesforexample,COPD(33),lungcancer(1,122,123),andchronicbronchitis(124,125)havebeenreportedpostexposure to toxic inhalators such as SM. This datapropose that SM could induce epigenetic changes incells and tissues (126). The pathophysiologicalsimilarities between pulmonary fibrosis and SM‐induced lung toxicity , aswell asbronchiectasis (125,127) has been determined by previous studies (119,127,128).Thepathogenesisoffibrosisisinfluencedbyaberrant epigenetic modifications. Most of thedemethyltions occur in promoter regions of differentgenes encoding autocrine growth and differentiationfactors of fibroblast cells (129). Therefore, it isspeculated that SM‐induced toxicitymaybemediatedby epigenetic perturbations at least in lung tissue,demonstrating a need to investigate protease/anti‐proteaseimbalanceinmustardlung(109).Methylationof tumor suppressor genes leads to activation ofoncogenes that promotes growth factor–independentproliferationoffibroblasts.ExpressionofmiR‐21isanexample of this type of aberrant modifications thatleadstothedegradationoftumorsuppressorgenesinfibroblasts (129). So, it is necessary to measure theexpression of micro‐RNA and DNA methylation ofpromoterinbronchoalveolarlavage(BAL)andtissueofmustard lung (130). Futuremolecular studieswill berecognized the pathophysiological mechanism of thisdisease.IncreasedacutephasereactantproteinsinSMexposed patients, for instance amyloid A1 andhaptoglobinhavebeenreportedinstudiesofMehrani



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Table2.Importantepigeneticeventsininflammation

etal(33).Inanotherstudy,Shahriayetalshowedthatin addition to inflammation, a protease/anti‐proteaseimbalance exists as well. In this way, endoplasmicreticulum (ER)‐60 protease, S100 CBP A9, serpin B1,andglutathione‐S‐transferaseweresignificantlyaltered(33).

Severalkeyepigeneticmodificationsarerecognizedin repair and remodeling pathways of airwayinflammatory lung diseases. Some of these importantchanges are selective inhibition of iNOS, cyclooxy‐genase‐2, and MMPs, especially the MMP‐9 (147).MMP‐9isepigeneticcross‐talkandinterferingproteinin suppression of NF‐κB cascade pathways or p300‐HAT expression within the nucleus (148). Similarly, Norani etal have shown thatmetallothioneins (MTs)(149)andSODs(150)arehigherinthecontrolgroupcompared to SM‐exposed groups. This can be due to

oxidative stress pathways as a result of mustard gastoxicity in airway wall of SM exposed patients.Hypermucosalsecretionisanotherpathophysiologicalproblemofmustardlungpatients(18,126,149).Asaprospective investigation, the study of epigeneticmodificationsliketheDNAhypomethayltionofSMDorMMPs(32)canbeanovelmolecularexplanationandtherapeuticguidelineformustardlung(151).

ItseemsthecomplexityofpostSMexposuresuchasinflammation,oxidative stress,protease/anti‐proteaseimbalancing,shouldberesolvedepigeneticallyview;inparticular, DNA methylation and tissue‐specificpatterns. Despite, a few data are currently availableregardingthepossibilityofanepigeneticbasisfortheeffectsofSM,someevidenceshaveshownthepotentialrole of downregulation of pro‐inflammatory genes,alterations in histone modifications, and gene

DNAMethylation

Typeofmodification Function Ref

Promoterhypomethylation

IncreaseinTLR2geneexpressionandincreasedpro‐inflammatoryresponse. (131)

Histonedeacetylation+DNAmethylation

IncreaseinTLR4genemaintenanceofhomeostasisintheintestinalimmunecommensalsystem (132)

DNAdemethylates ImportantroleintheestablishmentoftheepigeneticlandscapeacrosstheTNFαlocus (133)

DNAmethylation DecreaseexpressionofRunx3ingastricepithelialcells (134)

DNAmethylationPcGproteins(asMBPs)bindtotheregulatoryregionsoftar‐getgenesandrecruitDNMTsformoreefficientrepressioninchronicinflammations

(135)

Histonemodifications

DemethylationofH3K27me3

Jmjd3asaHDMsproteinis inducedinmacrophagesandinflammatorycytokines,whereitbindsthePcGtargetgenesandregulatestheirH3K27me3levelsandtranscriptionalactivity

(136)

DemethylationofH3K27me3

ActivationofSTAT6byremovalofH3K27methylationmarksbyJmjd3triggersexpressionofspecificinflammatorygenes

(137)

trimethylationH3K9me3H3K9me3 recruitment of heterochromatin protein 1 (HP1), that HP1 and G9a form a repressivecomplex at the promoters of RelB‐dependent genes and silenced the severe systemic inflammation(SSI)

(138)

Acetylationofpro‐inflammatorycytokines

Promoter’sacetylationsofseveralpro‐inflammatorycytokines(IL‐1,IL‐2,IL‐8,andIL‐12)arerapidlyacetylatedbyCBP/p300, leading to transcriptional activation and display reducedHDACactivity inchronicinflammation

(139)

AcetylateshistoneH3atLys9

IKK‐α(responsetocytokinetreatment)bindstotheNF‐κB‐dependentpromoterswiththeassistanceofthepolymeraseIIcomplexandCBP,whereitacetylateshistoneH3atLys9

(140)

phosphorylateshistoneH3atSer10

IKK‐αbindstotheNF‐κB‐dependentpromoterswiththeassistanceofthepolymeraseIIcomplexandCBP,whereitphosphorylateshistoneH3atSer10

(70)

MicroRNAsmodification

miR‐146a miR‐146alimitsToll‐likereceptorsignalingbyblockingthesignalingmoleculeTRAF6 (141)

miR‐155 miR‐155targetsthelipidphosphataseSHIP1;animportantsignalformacrophageactivation (142)

miR‐147 TLRstimulationinducesmiR‐147andrequiresactivationofbothNF‐κBandIRF3 (143)

miR‐105 miR‐105wasshowntomodulateTLR‐2translationinhumangingivalkeratinocytes (72)

miR‐29 miR‐29canreverseaberrantmethylationinlungcancerbytargetingDNMT3aandDNMT3b (144)

miR‐29 miR‐29promotesosteogenesisbytargetingHDAC4 (145)

miR‐2861 miR‐2861controlsosteoblastdifferentiationbyrepressingHDAC5 (139)

miR‐140 Thecartilage‐specificmiR‐140regulatesHDAC (146)



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expression changes in chromatin regulatory enzymesas potentially epigenetics modifications in chronicphaseofSM(40,81).

TheFigure5listedthepossibleepigeneticschangeinNF‐kBsignalingpathway.Forinstance,increasingofATP remodeling, increasing the HAT activity (forinduction of pro‐inflammatory proteins), andincreasingH4k9andH4k16acetylation(for secretionof pro‐inflammation factors) can be importantepigeneticmodification.Hypomethylationofrepetitivegenes,andCpGpoorpromotersandlocusspecificDNA

hypomethylation inp52‐RelBproteinbinding site aresome of the DNA modification. Finally, all thismodificationcantriggerpro‐inflammationfactorssuchasIL‐1β,‐8,‐6,‐13,TNF‐αandiNOS(152).FuturedirectionsinresearchareaofSM

Overall, our previous study highlights thatSMgenerally stimulates inflammationandoxidativestress pathways in chronic phase (153). OurfindingssuggestthatmolecularmechanismsofSMintoxicationingeneexpressionoccurindependently

Figure5.Sulfurmustardandpossibleepigeneticmodificationsinchronicphase.p53MAPK(p53Mitogen‐activatedproteinkinasekinase3);Nf‐kb(nuclearfactorkappa‐light‐chain‐enhancerofactivatedBcells);Ap‐1(Activatorprotein1);HAT(histoneacetyltransferase);IL(interleukin); TNFα (tumor necrosis factor alpha); Inf‐α (Interferon alpha); HSP 27 (heat shock protein 27); p53MAPK (p53Mitogen‐activated protein kinase kinase 3); iNOS(Inducible nitric oxide synthase); MIP‐1 (Macrophage Inflammatory Proteins 1); GM‐CSF(Granulocyte‐macrophagecolony‐stimulatingfactor)



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of changes in the DNA sequence (32, 33). Theseepigenetic mechanisms include PTM of nucleosomalhistone,DNAmethylation,andregulationbynoncodingRNAs (154,155).Here,wediscussed the relationshipbetween the latest achievements in this area withepigenetics through biology systems approach.Thereversible epigenetic modifications are prospecttherapeutickeyof inflammatoryairwaydiseasessuchas COPD. Evidently, to hypothesize that epigeneticchangesplayaroleininflammationofCOPD (88), oxidative stress (113, 121), and otherinflammatory disorders (10, 156), it is necessary toclarifywhatcausestheepigeneticchanges.Ontheotherhand, it has beenproved that thepatterns of cellularandmolecularchangesofSMpoisoningaresimilartosuch diseases (157). Data presented here suggestprecise mechanism of SM poisoning to achieve thecorrectperspectiveindiagnosticsortherapeutics(157,158).Attheclinicallevel,molecularstudieswillhelpusto find out the pathogenesis of SM lung and effectivemolecular treatment. The HDACi or cyclooxygenaseinhibitors canbe themain treatment options for SM‐lung patients (158). The study ofwhole genome andepigenetics modification, as well as next generationassays may give an integrated view of the uniqueintegrative framework for the complexity andpathologicdiversityofSM.Concludingremarks

In summary, several epigenetics modificationsoccur in lung inflammatory diseases such as COPD,asthma,IPF,andeveninSManimalmodelsthatthesechangestriggerthecomplexmolecularpathwayssuchas NF‐kB, PARP, Jack‐Stat, inflammation, proteinssignaling pathway, mitochondrial metabolism, andoxidative stress. To achieve themissing link betweenclinicalandmolecularfindingsandeffectivemoleculartherapies, these epigenetics modifications should bereviewedmoreindepthasabiologicalsystem.

Acknowledgment

Theauthorswouldliketoexpresstheirappreciationof Dr Sadegh azimzadeh jal kandi and Mr HojatBorna for their assistance in the articles. The resultsdescribedinthisstudywerepartofPhDthesisthatwasconducted at Baqiyatallah University of MedicalScience,Tehran,Iran.References

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epigenetic: a missing paradigm in cellular and molecular pathways

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