review article 천식과 후성유전학 · 2013-04-10 · 전학(epigenetics)이다....

4� http://www.aard.or.kr

천식과 후성유전학배다정, 박춘식

순천향대학교부천병원 호흡기알레르기내과

Asthma and epigenetics Da-Jeong Bae, Choon-Sik Park

Division�of�Allergy�and�Respiratory�Medicine,�Genome�Research�Center�for�Allergy�and�Respiratory�Disease,�Soonchunhyang�University�Bucheon�Hospital,�Bucheon,�Korea

For�the�past�two�decades,�a�huge�number�of�genetic�studies�have�been�conducted�to�identify�the�genetic�variants�responsible�for�asthma�risk.�Several�types�of�genetic�and�genomic�approaches,�including�linkage�analysis,�candidate�gene�single�nucleotide�poly-morphism�studies,�and�whole�genome-wide�association�studies�have�been�applied.�However,�the�genetic�impacts�of�these�studies�are�minimal�because�asthma�is�a�complex�syndrome�affected�by�interaction�with�many�environmental�factors�mediated�by�epi-genetics.�Epigenetics�is�alteration�of�genetic�expression�without�changes�of�DNA�sequence.�Three�major�forms�of�epigenetic�is�DNA�methylation,�histone�modfications�and�specific�microRNA�expression�that�are�known�to�have�vast�effects�on�gene�expression.�How-ever,�knowledge�regarding�the�epigenetic�effect�on�the�development�of�asthma�and�its�traits�is�limited�up�to�date.�Recently,�new�data�on�epigenetics�have�been�brought�up�to�explain�the�phenotypic�alterations�of�asthma.�In�this�review,�we�present�general�con-cept�of�epigenetics,�environmental�factors�inducting�epigenetic�changes�and�the�background�mechanisms�in�epigenetics�behind�development�asthma�and�epigenetic�therapy.�(��(��(��

Keywords:�Asthma,�Epigenetics,�Gene,�DNA�methylation,�Genome

서 론

2차세계대전말1944년에서1945년에걸친네덜란드의대기근

(Dutchhongerwinter)으로1일500calorie이하의영양섭취로약1만8천여명이기아로인해사망했는데,이기근당시에태어난아이들이성인이되었을때당뇨병,비만,심장병,암발생,정신분열증등에의이환율이다른코호트에비해유의한정도로증가되었다.이런현상은1968–1970년Biafra기아,1958–1961년중국의대기근후태어난세대에서도관찰되고있다.우리나라도1950년에서51년에태어난세대에서상기병들이증가되어있는지를조사해보는것도흥미있는일이될것이다.산모가기아로영양결핍을겪었기때문에그당시태어난아이

또한영양상태가좋지않아많은질환이잘이환되는것은충분히이해가되나,그들의손자,손녀에서도대조군에비해유의하게낮

은저체중으로태어난다는것은세대간각인에대한중요한예시

로볼수있다.영양결핍이라는환경적영향이산모의F1세대자식

뿐만아니라F2세대인손자대까지전달된다는것은일반적인유전

적현상으로는매우설명이어렵다.1,2)후성유전학에서세대간각인은어미개체가직접적인영향을받지않았음에도불구하고,여러가지현상이다음세대에게로대물림되는현상을의미한다.그러나최근에는환경에의한개체의영향이당대에형질의변화를유발하는현상도후생유전으로설명하고있다.여기서는후생유전

의기전과천식및알레르기질환에서후생유전학적현상과배경기

전,그리고앞으로의전망을소개하고자한다.

후성유전학(epigenetis)이란?

DNA염기서열자체에는변화가없으나세포가분열되는동안

Allergy�Asthma�Respir�Dis�1(1):4-10,�March�2013� http://dx.doi.org/10.4168/aard.2013.1.1.4

pISSN:�2288-0402eISSN:�2288-0410

REVIEW ARTICLE

Correspondence to: Choon-Sik Park Division of Allergy and Respiratory Medicine, Genome Research Center for Allergy and Respiratory Disease, Soonchunhyang University Bucheon Hospital, 170 Jomaru-ro, Wonmi-gu, Bucheon 420-767, Korea Tel: +82-32-621-5105, FAX: +82-32-621-5023, E-mail: [email protected] Received: March 18, 2013 Accepted: March 25, 2013

© 2013 The Korean Academy of Pediatric Allergy and Respiratory DiseaseThe Korean Academy of Asthma, Allergy and Clinical Immunology

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License

(http://creativecommons.org/licenses/by-nc/3.0/).

배다정과 박춘식 • 천식과 후성유전학

http://dx.doi.org/10.4168/aard.2013.1.1.4��5

Allergy�Asthma�Respir�Dis

DNA염기의부속구조또는크로마틴의변형을통하여유전자의발현양상이변하여표현형의변화가생기며,다음세대로전달될수있는현상을후성유전이라하며이를연구하는학문이후성유

전학(epigenetics)이다.후성유전은발생과분화,X염색체의불활성

화,유전자각인(imprinting)에중요한역할을한다.즉태어날때부모로부터물려받은얻은DNA와유전자가어떤환경에서,어떻

게생활하느냐에따라발현의양상이달라진다.이런현상은유전

적으로동일한DNA를가지며,같은환경에서자랐는데도불구하

고,일란성쌍둥이가때로는현격한차이를보이는경우에서명확

하게관찰된다.3)고전적인유전학의개념으론설명하기가쉽지않다.하지만이러한현상에는후성유전적변화가해답을주고있다.

후성유전학의 기전

유전자의발현을조절하는후성유전의기전에는DNA메틸화(methylation),히스톤변형과noncodingRNA(ncRNA)에의하여유전자발현이조절된다(Fig.1).

1. DNA 메틸화

DNA메틸화는DNA염기중,cytosin이메틸기의공유결합을통해5′methylcytosine이된다(Fig.1).DNA메틸화는CpG에서이루어지며인간체세포에는메틸싸이토신이전체DNA염기중의1%를차지하며,인간DNA의CpG염기중70–80%가메틸화되어있다.4)CpG는주로유전자의5′promoter에집중적으로관찰되며전사의시작을조절하여유전자발현을유도한다.CpG가많이모여있는CpGisland에대한현재의정의는크기가500bp이상,CGcontent55%이상,observedCpG/ExpectedCpG비율은0.65이상

으로정의하고있으나,예외도있다.CpG의메틸화에관련된효소로는대표적으로DNAmethyl-

transferase(DNMT1),DNMT3a,DNMT3b가있다(Fig.2).DNMT1은repeatedsequences의CpG메틸화의유지를,DNMT3a,DN-MT3b는CpGislands의메틸화를유도한다.5)CpGislands의메틸

화는histone변형까지일련의변화를유도한다.DNMT3에의하여CpGislands에메틸화가증가하면,이부위로methylCpGbindingproteins(MBP)의결합이증가한다.MBP는histonedeacetyase를핵내로유도하여히스톤의탈아세틸화를유발하여,히스톤의메틸화를증가시켜heterochromatin상태가되어유전자발현이억제된다(Fig.2).

2. 히스톤 변형과 크로마틴 리모델링(histone modification and

chromatin remodeling)

크로마틴은뉴클레오솜의사슬로구성되어있고,뉴글레오솜은히스톤H2A,H2B,H3,H4각각2분자로이루어진다(Fig.3).146개의핵산DNA가감고있는단위구조인누클레오소옴이연결된것이다(Fig.1).각각의히스톤단백은뉴클레오솜에서돌출되어있는아미노산꼬리(amino-terminaltail)를가지고있는데히스톤꼬리부위에서아세틸화(acetylation),메틸화(dimethylation),인산화

(phosphorylation)등의아미노산변형을통해RNApolymeraseII와전사인자의DNA에접근을조절함으로써유전자의전사조절

Fig. 2. DNA metylation, chromatin remodeling of the gene expression. (A) The DNA methylation machinery interacts with the histone modification machinery. (B) DN-MTs, MeCP2, HDAC3 and MBPs recognized by other transcriptional regulators. TF, transcription Factor; PolII, DNA polymerase II; HAT, histone acetyltransferase; MBP, methyl-bindg protein; MeCP2, methyl CpG binding protein; DNMT, DNA methyl transferase; HDAC, histone deacetylases.

A BMethylationAcethylation

Euchromatin

Heterochromatin

Gene down regulation

Gene silencing

Gene down regulation

Fig. 1. Three mechanisms of epigenetics. SAM, S-Adenosylmethionine; DNMT, DNA methyl transferase.

DNA Methylation miRNAmRNA

MethylationAcethylation

5-MethylationmiRNA

Translation repression

mRNAdegradation

Celldifferential

Histon modification

Bae�DJ�and�Park�CS • Asthma and epigenetics

6��http://dx.doi.org/10.4168/aard.2013.1.1.4


이이루어진다(Fig.3).6)

앞에설명된것처럼,메틸화DNA,MBP에의하여핵내로유도

된histonedeacetylases(HDACs)는히스톤을탈에세틸화시켜히스톤라이신이메틸화가일어나기가용이한상태로만들어silenc-ingtranscriptionchromatinremodelingcomplexes를이루고유전

자발현을억제한다.저메틸화DNA에의하여chromatin구조가풀려히스톤에chromatinremodelingfactors인cAMPresponseelement-bindingprotein-bindingprotein(CBP,histoneacetyl-transferase[HAT])가결합을하여아세틸히스톤을증가시키고메틸화를억제하여유전자발현을유도한다.그러나히스톤의lysine위치에따라히스톤H3lysine4(H3K4)(20),H3K36(21),H3K79(22)의메틸화는유전자전사를활성하며,히스톤H3K9(23),H4K20(24),H3K27(25)의메틸화는전사를억제한다(Fig.3).7-9)

3. 마이크로 RNA (micro RNA, miRNA)

마이크로RNA는21–25개내외뉴클레오타이드로이루어진단일염기가닥의noncodingRNA이다.miRNA는mRNA의3′un-translatedregions에결합하여mRNA를분해하거나단백으로번역과정을억제하여유전자의양과단백형성을조절한다(Fig.1).10)miRNA는조직특이적으로발현된다.인체유전자의약30%정도

가miRNA에의해조절을받는것으로알려져있으며,현재까지알려진인간miRNA는1,020개정도가밝혀져있으나,훨씬더다양

할것으로생각된다.11)여러질병들에서miRNA에의해조절을받은유전자의이상발현과관련성들이보고가되고있어,질병의발생과정및향후치료에매우중요한물질로주목되고있다.12)

천식에서 관찰되는 후생유전학 현상

천식및알레르기질환은태아시절부터성인시절까지환경노출

과유전적요소에대한복합적인영향을받는다.2000년도초까지

는유전적요소중유전자의변이가주요유전적영향으로생각되

어유전자의단염기변이(singlenucleotidepolymorphisms)에대한

연구가주를이루었고,저자도단염기변이탐색(Fig.4)을하였으나위험도가2이상인SNP가별로발견되지않아,현재까지의추정결과로는소수의특정유전자보다는100개내외의유전자의SNP가천식발생과관련이있을것으로추정되어왔다.그러나약30년동안2배내지3배의천식및알레르기환자의증가는유전자의새로

운단염기변이에의한유전자발현변화보다는환경적요인에의하

여유도된후성유전적영향으로설명이가능해지고있다.13)또한아토피질환이평생을살아가면서주변환경에의하여나타나기도,또없어지기도하며여러다른형태로나타나는변화되면서나타

나는알러지행진은잘알려진현상이다.후생유전현상은반드시

Fig. 4. Odd ratio of single nucleotide mutations and genes associated with asth-ma and asthma phenotypes (2003–2010, Soonchunhyang Genome Research Center). Single base mutations of the genes involved in innate immune process-es and acquired immunity, of asthma-related risk. IL, interleukin; TLR, toll-like re-ceptors; CD4, cluster of differentiation 4; FcRI, high-affinity immunoglobulin E re-ceptor; NFAT, nuclear factor of activated T-cells; API, arrowhead proteinase in-hibitor; GATA, globin transcription factor; NFkB, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; CXCR, C-X-C chemokine receptor type; CTNNA, catenin; CSF1R, colony stimulating factor 1 receptor; PPAR, peroxisome proliferator-activated receptor; MCP3, chemokine (C-C motif) ligand; DCNP1, chromosome 5 open reading frame; RUX1, runt-related transcription factor 1; ITK, IL 2-inducible T-cell kinase; STAT, signal transducer and activator of tran-scription; ADAM, metallopeptidase domain; MYLK, myosin light chain kinase.

Fig. 3. Nucleosome structure and histone acetylation of a lysine. (A) Histones H2A, H2B, H3 and H4 are known as the core histones, this nucleosome has six N-termi-nal tail domains and two C-terminal tails. (B) Histone acetyltransferases histone acetyltransferases and histone deacetylases histone deacetylases recognized by oth-er transcriptional regulators. K, lysine; P, phosphate; Ub, ubiquitin; S, serine; E, glutamic acid; C, carboxyl terminus; N, amino terminus; H, histone.

A B

MethylationAcethylation




환경적요인이관련이된다.

1. 환경 요인

후생유전과관련된환경요인은Table1에정리되어있다.대기환경요인중제일흔하며중요한것은흡연이된다.임신중흡연은후대에서천식의발생과폐기능감소와밀접한관계가있다.14-17)흡연은폐포대식세포의histonedeacetylase(HDAC)의발현을

억제시킨다.그결과염증성유전자의발현을증가시킨다.실험적으

로담배농축액에노출된상피세포는DNMT3b발현이증가한다.그결과DNACpGmethylation이증가한다.이런현상은임신중흡연에노출된아동에서유전자전장의Alu서열과tyrosineki-nase수용체와proteintyrosinephosphatasereceptor등여러유전

자의promoter의CpG부위의메틸화가감소된것으로나타난다.자동차관련매연도중요한후생유전변화의환경요인이된다.18)Fineparticle과Blackcarbon의농도가보스톤지역의노인층의유전자전장의메틸화의시기에따른감소와관련성을보인다.임신중의polycyclicaromaticamine의노출양이천식,알레르기관련유전자의메틸화와관련이있다.19,20)여러환경요인의복합적효과

가태아발생시기도발생기와폐포확장기의후성유전적영향을미쳐소아기,성인기의천식발생의위험과관련이있다.이외에도xenobioticchemicals,내분비계손상물,모성스트레스,저용량방사선등도중요한후생유전현상의환경요인이된다.21,22)임신중vitaminE,zinc함유가적은음식,23)항생제의사용24)은소아천식

의위험도를증가시킨다.그러나,Probiotics의복용,과일,채소,생선기름의섭취는위험도를감소시킨다.25,26)

환경요인에의한후생유전현상의동물모델은다음과같이밝혀져있다.Residualoilflyash27),dieselexhaustparticles,titaniumdioxideparticle노출시28)다음세대에서천식의여러형질이나타

나며,endotoxin과probioticbacteria노출로천식이예방된다.29,30)각환경적요소에따른천식표현형의영향과후성유전적기전이다양하고천식의표현형에영향을줄수있는기전이다름을알수있으나천식과의관련기전이일부에서만확실히밝혀져있다(Ta-ble1).대표적인천식유발인자로흡연(tabaccosmoke),polycyclicaromatichydrocarbons(PAH),oxidants,lipopolysaccharide,par-ticulatematter(PM)-10,Benzopyrene을들수있다.흡연은단핵구내에서HDAC의활성화를감소시켜,염증발현주요인자(granu-locytemacrophage-colonystimulatingfactor,interleukin[IL]-8,IL-1b,andtumornecrosisfactor-α)등의활성화를유도한다.PAH의경우자손의탯줄내혈액의DNA의ACSL3유전자의프로모터

를과메틸화시키며이는소아천식의위험을증가시킨다.PM-10과oxidants역시도HAT,HDACs등에영향을주어염증싸이토카인

(IL-8,IL-6,IL-1b등)의증가를유도한다.천식과관련된산화물질

과염증전구물질은히스톤아세틸화에관여한다.31)실예로H2O2

는HAT의활성을증가시켜chromatin재구성을유발하여염증유전자발현을유도한다.32)천식환자의기도는HAT가증가,HDACs이감소하며,이현상은흡입스테로이드치료로전환된다.33)

2. 후생유전의 발생 시기와 세대를 통한 각인(trans-generational

imprint)

후생유전현상은특히DNA메틸화는세대를걸쳐후대로내려

Table 1. Environmental factors associated with epigenetics

Environmental factor Epigenetic effect Asthma Reference

Tobacco smoke GSTP1 and GSTM1 genes on susceptibility to prenatal tobacco smoke-re-lated changes in DNA methylation.

Smoking-induced asthma 48

Suppresses HDAC2 expression and overall HDAC activity in macrophages Enhances the expression of inflammatory media-tors ( IL-8, IL-1b, TNF-a)

49

Induces MAOB promoter hypomethylation in PBMCs Smoking-induced asthma 50PAH Acyl-CoA synthetase long-chain family member 3 exhibited the highest

concordance between the extent of methylation of its 5’-CGI in UCWBCsChildhood asthma 51

IFN-γ promoter methylation in cord white blood cells was associated with maternal PAH exposure in the cohort study subsample

Childhood asthma 52

The degree of unmethylation in the IL-4 gene increased in cells from pa-tients with bronchial asthma

Asthma 53

Nitric oxide synthase DNA methylation in the promoters of ARG1 and ARG2 Childhood asthma 54Oxidants Modifies the HDACs and HAT Interleukin (IL)-1β, tumor necrosis factor (TNF)-α,

and IL-6 are known to be the major cytokines important for inflammation

55–57

Maternal folic acid supple-mentation

Increased risk of wheeze and respiratory tract infections up to 18 months of age

Explains developmental reprogramming of asth-ma risk

58

GSTP1, glutathione S-transferase pi gene; GSTM1, glutathione S-transferase Mu 1; HDAC, histone deacetylase; MABO, monoamine oxidase B; IFN, interferon; PBMC, periph-eral blood mononuclear cell; PAH, polycyclic aromatic hydrocarbons; UCWBC, umbilical cord white blood cell; ARG, arginase; HAT, histone acetyltransferase.




간다.후생유전적변화는주로임신중이나,출생직후에발생하나,그후에도진행될수있다.이런후생학적변화가잘생기는기간은출생전자궁내발달기가제일중요한시기가되나,유아,소아기,성인기에서도생길수있다.34-36)2세대에걸친후생유전현상은임신중흡연에노출된5세에천식으로진단된338명의천식아동과570명의건강아동을대상으로한연구에서어머니의임신중할머

니가흡연을한경우위험도가1.8배증가되며,임신중할머니와어머니가동시에담배를핀경우위험도가2.6배증가되는것은흡연

에의한후생유전현상이2대에걸쳐지속된다.37,38)

3. 천식 발생에서 후생유전의 기전

이러한환경적요소들은천식의표현형발현에영향을주는데,기도저항성(airwayhyperresponse)의증가,기도염증반응의증가,기도의재형성과관련이된다.세가지과정에관여되는반응은Th2,Th1,Treg,Th17세포들에의한면역반응이주가되며,림프구

성면역반응외에도상피세포,혈관,괄약근,섬유아세포,호산구,대식세포등의참여로이루어진다(Fig.5).알레르기면역세포의조절은tobaccosmoke,dieselexhaustparticles,BaP,PM,PAH,blackcarbon,endotoxin,dustmite등의환경요인들과어머니로부터전달받는요소인산화,항산화,영양요소(choline,betaine,folicacid,vitaminB12,vitaminD)에의해조절이이루어진다.Retinoicacidreceptor-relatedorphanreceptorgamma,globintranscriptionfactor-3(GATA-3),T-boxtranscriptionfactor(T-bet),Foxp3등의유전자의발현을유도해IL-17,IL-4,IL-5,IL-13,IL-9,IL-2,inter-feron(IFN)-γ,transforminggrowthfactor(TGF)-β등의싸이토

카인을유도하여Th17cell,Th2cell,Th1cell,Tregcell등으로의분화를유도한다.상기염증관련유전자와이와관련된후성유전학적변화는천

식유전자중IL-4,IL-5,IL-13,TGF-β,IFN-γ,histocompatibilityantigen,Foxp3+등유전자들이후성유전적요소에의해조절된다.IL-4는GATA-3의탈메틸화,H3-K9의아세틸화와H3-K4의메틸

화그리고IL4promoter59flackingregion의탈메틸화를통해증가되며,이는IFN-γ의감소를유도한다.후성유전적요소들은알러

젠노출을통해알레르기반응을일으키는IL-5,IL-13도증가를유도한다.IFN-γ의감소는promoter부위의activatorprotein1-bind-ing(ATF2/c-Jun)결합이cis-regulatoryelement결합억제를통해유도된다.이과정에DNA메틸화,히스톤변형,miRNA가관여한

다.Th1/Th2의분화는HDAC에의해영향을받는다.HDAC은GATA-3에영향을주며Th1과Th2의균형을조절한다.기도과민아토피성천식어린이들에게서높은HAT활성과HDAC활성이감소되며,39)PAH,fineparticulatematter,그리고ozone이높은지역의천식환자는Foxp3프로모터의CpGisland의메틸화가높은것이밝혀졌다.40)

저자는후성유전체의변화가전장유전체의어떤유전자에서관찰되는가를조사하였다.41)이연구결과아스피린과민성천식환자들의비용종조직에서,과메틸화된296개의유전자에서332loci,저메틸화는141유전자에서158loci에서메틸화변화를관찰하였

고,아라키돈산물질대사경로에서,prostaglandinDsynthase,ar-achidonate5-lipoxygenase-activatingprotein,그리고leukotrieneB4receptor은저메틸화,prostaglandinEsynthase는과메틸화되어있어아라키돈산물질대사관련유전자의메틸화가아스피린천식발생과관련성을관철한바있다.최근천식과집먼지진드기관련성인천식의유전자전장메틸화분석에서6개유전자에서과메틸화가,48개유전자에서저메틸화를관찰하였으나,메틸화의정도의차이가크지않아성인천식에서기도의DNA메틸화의뚜렸한차이가천식이나,집먼지진드기감작시뚜렷하지못함을관찰하였다.42)

후성유전치료(epigenetic therapy)

지금까지설명해왔던후성유전적변화는비가역적인인체DNA의돌연변이보다매우가역적이기때문에현재많은치료방법이연구중에있다.DNA탈/메틸화효소,히스톤탈/메틸화효소등의조절을통한염색체내의메틸화의조절은특정질병관련유전자

의활성화,불활성화를유도하여이에대한질병치료의목표가될수있을것이다.43,44)현재까지는주로DNA메틸기전달효소와히스톤아세틸화효소를겨냥한치료제개발이진행중이다.45)미국FoodandDrugAdministration에서DNMT억제제인azacytidine

Fig. 5. Factors associated with the type of inflammatory cells to determine the diversity of the asthma phenotype. BaP, benzophenone; PAH, polycyclic aromat-ic hydrocarbons; DEP, diesel exhaust particles; PM, particulate matter; LPS, lipo-polysaccharide; IL, interleukin; TH cell, T helper cell; IFN, interferon; TGF-β, transforming growth factor beta; GATA, globin transcription factor; FOXP3, fork-head box P3; T-bet, T-box transcription factor.

Allergen

Tobacco smokeBaPPAHEndotoxin (e.g. LPS)DEPPMBlack carbonDust mite

Airwayepithelium

IL-2IFN-γ




이2004년에,decitabine이2006년에승인되었다.이후여러유도체

가개발되었고,최근zebularine,5-fluoro-2′-deoxycytidine가항암치료제로연구되고있다.46,47)

결 론

환경적영향을많이받는질환인알레르기질환과천식에서후생

유전학적영향과기전이밝혀져가고있으나,아직은해결되어야할문제점이많다.유전자의단염기변화와메틸화,miRNA와의복합

적관계분석이이들Omics가질병에미치는영향을종합적으로분석하는필수조건으로생각된다.임상적으로밝혀야할사항중하나는이들환경요인에의한후성유전영향이몇세대에걸쳐지속발현되는것인지에대한해답을줄수있는역학코호트연구의결과및광범위한동물실험결과가아직없다는것이다.앞으로천식발생에서후생유전학의정확한영향의규모와기전연구가진행

되면이를이용한예방및제어방법이개발될것으로기대된다.

REFERENCES

1. AhmedF.Epigenetics:talesofadversity.Nature2010;468:S20.2. CortessisVK,ThomasDC,LevineAJ,BretonCV,MackTM,Siegmund

KD,etal.Environmentalepigenetics:prospectsforstudyingepigeneticmediationofexposure-responserelationships.HumGenet2012;131:1565-89.

3. BellJT,SpectorTD.Atwinapproachtounravelingepigenetics.TrendsGenet2011;27:116-25.

4. TurkerMS,BestorTH.Formationofmethylationpatternsinthemam-maliangenome.MutatRes1997;386:119-30.

5. OkitsuCY,HsiehCL.DNAmethylationdictateshistoneH3K4methyla-tion.MolCellBiol2007;27:2746-57.

6. PetersonCL,LanielMA.Histonesandhistonemodifications.CurrBiol2004;14:R546-51.

7. KitamotoS,YamadaN,YokoyamaS,HoujouI,HigashiM,GotoM,etal.DNAmethylationandhistoneH3-K9modificationscontributetoMUC17expression.Glycobiology2011;21:247-56.

8. StewartMD,LiJ,WongJ.RelationshipbetweenhistoneH3lysine9methylation,transcriptionrepression,andheterochromatinprotein1re-cruitment.MolCellBiol2005;25:2525-38.

9. CedarH,BergmanY.LinkingDNAmethylationandhistonemodifica-tion:patternsandparadigms.NatRevGenet2009;10:295-304.

10. ChuangJC,JonesPA.EpigeneticsandmicroRNAs.PediatrRes2007;61(5Pt2):24R-29R.

11. ChenK,RajewskyN.TheevolutionofgeneregulationbytranscriptionfactorsandmicroRNAs.NatRevGenet2007;8:93-103.

12. SayedD,AbdellatifM.MicroRNAsindevelopmentanddisease.PhysiolRev2011;91:827-87.

13. MillerRL,HoSM.Environmentalepigeneticsandasthma:currentcon-ceptsandcallforstudies.AmJRespirCritCareMed2008;177:567-73.

14. GillilandFD,BerhaneK,LiYF,RappaportEB,PetersJM.Effectsofearlyonsetasthmaandinuteroexposuretomaternalsmokingonchildhoodlungfunction.AmJRespirCritCareMed2003;167:917-24.

15. LiYF,LangholzB,SalamMT,GillilandFD.Maternalandgrandmaternal

smokingpatternsareassociatedwithearlychildhoodasthma.Chest2005;127:1232-41.

16. MagnussonLL,OlesenAB,WennborgH,OlsenJ.Wheezing,asthma,hayfever,andatopiceczemainchildhoodfollowingexposuretotobaccosmokeinfetallife.ClinExpAllergy2005;35:1550-6.

17. AlatiR,AlMamunA,O'CallaghanM,NajmanJM,WilliamsGM.Inuteroandpostnatalmaternalsmokingandasthmainadolescence.Epi-demiology2006;17:138-44.

18. KurukulaaratchyRJ,MatthewsS,ArshadSH.Doesenvironmentmediateearlieronsetofthepersistentchildhoodasthmaphenotype?Pediatrics2004;113:345-50.

19. MillerRL,GarfinkelR,HortonM,CamannD,PereraFP,WhyattRM,etal.Polycyclicaromatichydrocarbons,environmentaltobaccosmoke,andrespiratorysymptomsinaninner-citybirthcohort.Chest2004;126:1071-8.

20. EnstromJE,KabatGC.Environmentaltobaccosmokeandtobaccorelat-edmortalityinaprospectivestudyofCalifornians,1960-98.BMJ2003;326:1057.

21. DolinoyDC,WeidmanJR,JirtleRL.Epigeneticgeneregulation:linkingearlydevelopmentalenvironmenttoadultdisease.ReprodToxicol2007;23:297-307.

22. TangWY,HoSM.Epigeneticreprogrammingandimprintinginoriginsofdisease.RevEndocrMetabDisord2007;8:173-82.

23. DevereuxG,TurnerSW,CraigLC,McNeillG,MartindaleS,HarbourPJ,etal.LowmaternalvitaminEintakeduringpregnancyisassociatedwithasthmain5-year-oldchildren.AmJRespirCritCareMed2006;174:499-507.

24. JedrychowskiW,GałasA,WhyattR,PereraF.Theprenataluseofantibi-oticsandthedevelopmentofallergicdiseaseinoneyearoldinfants.Apreliminarystudy.IntJOccupMedEnvironHealth2006;19:70-6.

25. KukkonenK,SavilahtiE,HaahtelaT,Juntunen-BackmanK,KorpelaR,PoussaT,etal.Probioticsandprebioticgalacto-oligosaccharidesinthepreventionofallergicdiseases:arandomized,double-blind,placebo-controlledtrial.JAllergyClinImmunol2007;119:192-8.

26. FitzsimonN,FallonU,O'MahonyD,LoftusBG,BuryG,MurphyAW,etal.Mothers'dietarypatternsduringpregnancyandriskofasthmasymp-tomsinchildrenat3years.IrMedJ2007;100:suppl27-32.

27. HamadaK,SuzakiY,LemeA,ItoT,MiyamotoK,KobzikL,etal.Expo-sureofpregnantmicetoanairpollutantaerosolincreasesasthmasus-ceptibilityinoffspring.JToxicolEnvironHealthA2007;70:688-95.

28. FedulovAV,LemeA,YangZ,DahlM,LimR,MarianiTJ,etal.Pulmo-naryexposuretoparticlesduringpregnancycausesincreasedneonatalasthmasusceptibility.AmJRespirCellMolBiol2008;38:57-67.

29. BlümerN,HerzU,WegmannM,RenzH.Prenatallipopolysaccharide-exposurepreventsallergicsensitizationandairwayinflammation,butnotairwayresponsivenessinamurinemodelofexperimentalasthma.ClinExpAllergy2005;35:397-402.

30. BlumerN,SelS,VirnaS,PatrascanCC,ZimmermannS,HerzU,etal.PerinatalmaternalapplicationofLactobacillusrhamnosusGGsuppress-esallergicairwayinflammationinmouseoffspring.ClinExpAllergy2007;37:348-57.

31. RahmanI.Oxidativestress,chromatinremodelingandgenetranscrip-tionininflammationandchroniclungdiseases.JBiochemMolBiol2003;36:95-109.

32. RahmanI,MarwickJ,KirkhamP.Redoxmodulationofchromatinre-modeling:impactonhistoneacetylationanddeacetylation,NF-kappaBandpro-inflammatorygeneexpression.BiochemPharmacol2004;68:1255-67.

33. ItoK,CaramoriG,LimS,OatesT,ChungKF,BarnesPJ,etal.Expression




andactivityofhistonedeacetylasesinhumanasthmaticairways.AmJRespirCritCareMed2002;166:392-6.

34. GillilandFD,BerhaneK,McConnellR,GaudermanWJ,VoraH,Rappa-portEB,etal.Maternalsmokingduringpregnancy,environmentalto-baccosmokeexposureandchildhoodlungfunction.Thorax2000;55:271-6.

35. BushA,Menzies-GowA.Phenotypicdifferencesbetweenpediatricandadultasthma.ProcAmThoracSoc2009;6:712-9.

36. MandhanePJ,GreeneJM,CowanJO,TaylorDR,SearsMR.Sexdiffer-encesinfactorsassociatedwithchildhood-andadolescent-onsetwheeze.AmJRespirCritCareMed2005;172:45-54.

37. PereraFP,RauhV,TsaiWY,KinneyP,CamannD,BarrD,etal.Effectsoftransplacentalexposuretoenvironmentalpollutantsonbirthoutcomesinamultiethnicpopulation.EnvironHealthPerspect2003;111:201-5.

38. WindhamGC,HopkinsB,FensterL,SwanSH.Prenatalactiveorpassivetobaccosmokeexposureandtheriskofpretermdeliveryorlowbirthweight.Epidemiology2000;11:427-33.

39. SuRC,BeckerAB,KozyrskyjAL,HayglassKT.Alteredepigeneticregu-lationandincreasingseverityofbronchialhyperresponsivenessinatopicasthmaticchildren.JAllergyClinImmunol2009;124:1116-8.

40. NadeauK,McDonald-HymanC,NothEM,PrattB,HammondSK,BalmesJ,etal.AmbientairpollutionimpairsregulatoryT-cellfunctioninasthma.JAllergyClinImmunol2010;126:845-852.e10.

41. CheongHS,ParkSM,KimMO,ParkJS,LeeJY,ByunJY,etal.Genome-widemethylationprofileofnasalpolyps:relationtoaspirinhypersensi-tivityinasthmatics.Allergy2011;66:637-44.

42. LeeJS,KimJH,BaeJS,KimJY,ParkTJ,PasajeCF,etal.AssociationofCACNG6polymorphismswithaspirin-intoleranceasthmaticsinaKore-anpopulation.BMCMedGenet2010;11:138.

43. YooCB,JonesPA.Epigenetictherapyofcancer:past,presentandfuture.NatRevDrugDiscov2006;5:37-50.

44. JuergensRA,WrangleJ,VendettiFP,MurphySC,ZhaoM,ColemanB,etal.Combinationepigenetictherapyhasefficacyinpatientswithrefrac-toryadvancednon-smallcelllungcancer.CancerDiscov2011;1:598-607.

45. EggerG,LiangG,AparicioA,JonesPA.Epigeneticsinhumandiseaseandprospectsforepigenetictherapy.Nature2004;429:457-63.

46. ChenM,ShabashviliD,NawabA,YangSX,DyerLM,BrownKD,etal.DNAmethyltransferaseinhibitor,zebularine,delaystumorgrowthandinducesapoptosisinageneticallyengineeredmousemodelofbreastcancer.MolCancerTher2012;11:370-82.

47. BillamM,SobolewskiMD,DavidsonNE.EffectsofanovelDNAmeth-yltransferaseinhibitorzebularineonhumanbreastcancercells.BreastCancerResTreat2010;120:581-92.

48. BretonCV,ByunHM,WentenM,PanF,YangA,GillilandFD.Prenataltobaccosmokeexposureaffectsglobalandgene-specificDNAmethyla-tion.AmJRespirCritCareMed2009;180:462-7.

49. ItoK,LimS,CaramoriG,ChungKF,BarnesPJ,AdcockIM.Cigarettesmokingreduceshistonedeacetylase2expression,enhancescytokineex-pression,andinhibitsglucocorticoidactionsinalveolarmacrophages.FASEBJ2001;15:1110-2.

50. LaunayJM,DelPinoM,ChironiG,CallebertJ,Peoc'hK,MegnienJL,etal.Smokinginduceslong-lastingeffectsthroughamonoamine-oxidaseepigeneticregulation.PLoSOne2009;4:e7959.

51. PereraF,TangWY,HerbstmanJ,TangD,LevinL,MillerR,etal.Rela-tionofDNAmethylationof5'-CpGislandofACSL3totransplacentalexposuretoairbornepolycyclicaromatichydrocarbonsandchildhoodasthma.PLoSOne2009;4:e4488.

52. TangWY,LevinL,TalaskaG,CheungYY,HerbstmanJ,TangD,etal.Maternalexposuretopolycyclicaromatichydrocarbonsand5'-CpGmethylationofinterferon-γincordwhitebloodcells.EnvironHealthPerspect2012;120:1195-200.

53. KwonNH,KimJS,LeeJY,OhMJ,ChoiDC.DNAmethylationandtheexpressionofIL-4andIFN-gammapromotergenesinpatientswithbronchialasthma.JClinImmunol2008;28:139-46.

54. BretonCV,ByunHM,WangX,SalamMT,SiegmundK,GillilandFD.DNAmethylationinthearginase-nitricoxidesynthasepathwayisasso-ciatedwithexhalednitricoxideinchildrenwithasthma.AmJRespirCritCareMed2011;184:191-7.

55. WuW,DoreswamyV,Diaz-SanchezD,SametJM,KesicM,DaileyL,etal.GSTM1modulationofIL-8expressioninhumanbronchialepithelialcellsexposedtoozone.FreeRadicBiolMed2011;51:522-9.

56. ChibaT,MarusawaH,UshijimaT.Inflammation-associatedcancerde-velopmentindigestiveorgans:mechanismsandrolesforgeneticandepigeneticmodulation.Gastroenterology2012;143:550-63.

57. BarnesPJ,AdcockIM,ItoK.Histoneacetylationanddeacetylation:im-portanceininflammatorylungdiseases.EurRespirJ2005;25:552-63.

58. HabergSE,LondonSJ,StigumH,NafstadP,NystadW.Folicacidsupple-mentsinpregnancyandearlychildhoodrespiratoryhealth.ArchDisChild2009;94:180-4.

review article 천식과 후성유전학 · 2013-04-10 · 전학(epigenetics)이다....

Documents