Taehoon Chun · 2013-03-07 · tion of target gene, (C) Either histone deacetylation or DNA methyla-tion by polycomb proteins blocks the transcription of target gene. PRC2 complex

© 2013 Hanyang University College of Medicine 33http://www.e-hmr.org

Influence of Polycomb Proteins and Epigenetic Transcriptional Modifiers on the Development and Activation of T Lymphocytes Taehoon Chun

Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea

서  론

후생학적유전(epigenetics)이란크로마틴(chromatin)의구조에따라특정유전자의전사(transcription)개시가달라진다는뜻으

로,동일한유전자형을가지고태어난일란성쌍둥이에서도환경에따라다르게나타나는표현형을해석하기위한일환으로연구되었

다.크로마틴의구조는유전정보인DNA와유전정보와결합하는단백질간의상호작용변화에따라달라지며,이러한변화는특정유전자의전사뿐만아니라,핵분열(mitosis),유전자복제(DNAreplication)등을결정하는데매우중요한요인으로작용한다[1].따라서크로마틴의구조를변화시키는여러가지단백질들이발견

되었으며,그러한단백질의활성연구도많이진행되어있다.폴리

콤그룹(polycombgroup,PcG)단백질들은크로마틴구조를이루

고있는특정히스톤(histone)부분에메틸기(methylation)나유비

퀴틴(ubiquitin)을붙여서히스톤의구조를변화시키는단백질들

로알려져있으며,이러한결과로특정유전자의전사가개시되지않기때문에,전사저해인자로알려져있다[2,3].따라서,폴리콤그룹단백질들의활성에따라특정DNA와결합하고있는히스톤의메틸화유무에따라서특정세포의분화및활성이조절될수있다.본종설은이러한폴리콤그룹단백질들의활성이T림프구분화와활성에미치는영향에대해알아보았다.

Hanyang Med Rev 2013;33:33-38http://dx.doi.org/10.7599/hmr.2013.33.1.33

pISSN 1738-429X eISSN 2234-4446

Transcriptional regulation of a gene is not always correlated with genetic information in-herited from parents because the transcription of specific genes is often governed by the modification of chromatin structure. The study of transcriptional regulation by modifying chromatin structure is well-known as “epigenetics”. Several methods involved in the modi-fication of chromatin structure have been developed in the mammalian species during evolution. Among those methods, methylations of specific DNA region or histone are of-ten used to control specific gene transcription. Therefore, understanding the activity of proteins involved in DNA or histone methylation is an initial step to control the transcrip-tional activity of a specific gene. Polycomb group (PcG) proteins were known to be repres-sors of transcription of a specific gene by creating and maintaining methylation or ubiqui-tination of the specific region of histone. Dependent on the target histone, the activity of PcG proteins effects on the development of specific lineage cells or the activity of specific cell types. In this review, the function, expression and activity of PcG proteins related with the development or activation of T cells are discussed.

Key Words: Chromatin; Epigenomics; Histone Code; Polycomb-Group Proteins; T-Lym-phocytes

후생학적 전사조절 인자인 Polycomb 단백질들이 T 림프구 분화 및 활성에 미치는 영향전태훈

고려대학교 생명과학대학 생명공학부

Correspondence to: Taehoon Chun우136-713, 서울시 성북구 안암로 145, 고려대학교 자연계 캠퍼스 생명과학관 서관 317호 Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 317 Room, West Life Science Building, Science Campus, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 136-713, Korea Tel: +82-2-3290-3069 Fax: +82-2-3290-3507 E-mail: [email protected]

Received  15 November 2012Revised  3 January 2013Accepted  10 January 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom-mons.org/licenses/by-nc/3.0) which permits un-restricted non-commercial use, distribution, and reproduction in any medium, provided the origi-nal work is properly cited.

Hanyang Med Rev 2013;33:33-3834 http://www.e-hmr.org

Taehoon Chun • Influence of Polycomb Proteins on T cellsHMR

본  론

1. 폴리콤 단백질들의 종류, 발현, 기능

PolycombGroup(PcG)단백질은초파리의돌연변이실험을통하여,초파리초기발달과정에중요한역할을하는Hox유전자전사를억제하는것으로처음알려졌다[4].이러한기능은초파리에

서발견된TrithoraxGroup(TrxG)단백질들이특정유전자전사

를증진시키는것과는반대되는작용을하는것으로알려져있다

[5].PcG단백질들의기능이억제된돌연변이에서척추의기형성이나타남을미루어보아,척추동물에서도PcG단백질들의기능은잘보존되어있음이입증되었다[6].PcG단백질에의한유전자전사억제는특정유전자와결합하고있는히스톤(histone)의구조를변화시킴에의한다고알려져있으며,이러한PcG단백질들에의한히스톤의구조변화에사용되는방법은크게메틸기(methylation)와유비퀴틴(ubiquitin)을특정히스톤에붙이는방법에의한다[7,8].PcG단백질들에따라서PcG단백질들은methyltransferase의역할과ubiquitinligase의역할을하는효소복합체라고할수있다.또한몇몇PcG단백질들은히스톤의deacetylation을유도하거나DNAmethylation을유도하기도한다[9,10].따라서PcG단백질들

의활성에따라특정유전자의전사가억제되며,이러한기능에의해특정세포의표현형변화가일어난다.

PcG단백질들은진핵생물에서잘보존된두가지의복합체를이루며,polycombrepressivecomplex1(PRC1)과polycombrepres-sivecomplex2(PRC2)로나뉜다[11,12].PRC1에서복합체를이루

는단백질은4종류이며,BMI-1,CBX2,RING1A/B,EDR1(PHC1)등이있다[11,12].PRC2에서복합체를이루는단백질은3종류이며,EED,SUZ12,EZH2(ENX2)등이있다[11,12].PcG단백질들을연구할때가장고려해야할점은PRC1과PRC2의복합체를이루는PcG단백질들의기능적다양성과이에따른PRC1과PRC2의복합

체기능의다양성을고려해야할것이다.대부분의PcG단백질들

은RING-fingerdomain또는Zinc-fingerdomain을가지고있어DNA에결합할수있는능력을가지며,또한각단백질끼리상호작용할수있는기능을가진다[11,12].이러한각PcG단백질들의기능은어떠한단백질들이PRC1과PRC2단백질복합체조합을이루는가에따라특정targetDNA가달라질수있으며,이에따른세포표현형변화도달라질것이다.실제로PcG단백질들이PRC1과PRC2단백질복합체를이룰때,특정기능이나상황에따라,단백

질복합체의기능에꼭필요한몇몇단백질을제외하고는PRC1과PRC2단백질복합체의구성단위를이루는단백질들의조합은바뀔수있다.또한PRC1과PRC2는개별적으로또는같이일하며유전자전사를억제하는것으로알려져있다.이러한구조적기능적다양성에따라,PcG단백질들의기능은상황에따라바뀔수있으

며,단순히메틸화나유비퀴틴화에의한크로마틴구조변화의기

능에국한시켜서는안된다고생각하며,아직다른많은기능이있을것이라고추측된다.

PcG단백질들이히스톤을메틸화시켜특정유전자를억제하는기전은잘알려져있다(Fig.1A).우선PRC2단백질복합체가tar-get유전자의promoterregion에PRC1단백질복합체의이동을유도하는것이알려져있으며,PRC2단백질복합체의한subunit인EZH2가H3히스톤의lysine27번에세개의메틸기를붙이는것으로알려져있다[13,14].즉EZH2는특정히스톤에세개의메틸기

(H2K27me3)를붙이는methyltransferase이다[11,12].특정히스톤

에세개의메틸기(H2K27me3)가붙으면특정유전자의전사는억제되며,이러한예는특정세포의분화시후생학적연구에의해이미많이알려져있다.PRC2단백질복합체가target유전자의pro-moterregion에PRC1단백질복합체의이동을유도할때중요한단백질은chromobox(CBX)단백질들이다[15].CBX는메틸기가붙은lysine에결합하기때문에메틸화된히스톤과PRC1단백질복합체를연결하는매개역할을한다(Fig.1A)[11,12,15].PRC1단

Fig. 1. Transcriptional inhibition by polycomb proteins [10-17]. (A) Tri-methylation of K27 residue on H3 histone by polycomb proteins blocks the transcription of target gene, (B) Ubiquitination of K119 residue on H2A histone by polycomb proteins blocks the transcrip-tion of target gene, (C) Either histone deacetylation or DNA methyla-tion by polycomb proteins blocks the transcription of target gene.

PRC2 complex PRC1 complex

Blocking transcription

Promoter region

EED

EED

SUZ12SUZ12

EZH2 (ENX2)

BMI-1RING1A/B

CBX2

EDR1

(PHC1)

K27

EZH2 (ENX2)

Promoter region

H3 histoneH3 histone

Tri-methylation

A

PRC1 complex

Blocking transcriptionBMI-1

RING1A/BCBX2

EDR1 (PHC1)

K119

Promoter regionH2A histone

Ubquitination

B

PRC2 complex

Histone deacetylation

DNA methylation

Blocking transcription

EED

EED

EED

SUZ12

SUZ12

SUZ12

DNMT1

EZH2 (ENX2)

EZH2

(ENX2)

EZH2 (ENX2)

HDAC

C

K27

Hanyang Med Rev 2013;33:33-38 http://www.e-hmr.org 35

전태훈 • Polycomb 단백질이 T 세포에 미치는 영향 HMR

백질복합체의경우PRC1단백질복합체에의한trimethylation(H2K27me3)을유지하거나,H2A히스톤의lysine119번을유비퀴

틴화(H2AK119ub)하는것으로알려져있다[12].이때유비퀴틴li-gase역할을하는것은PRC1단백질복합체의subunit중Ring단백질들과BMI-1으로알려져있다(Fig.1B)[16].이러한특정히스

톤의유비퀴틴화(H2AK119ub)는RNApolymeraseII에의한전사과정을억제하여결과적으로특정유전자의전사를억제한다[17].

PRC1단백질복합체내의몇몇단백질은히스톤의deacetylation을유도하며,또한DNAmethylation을유도하기도한다(Fig.1C).히스톤의deacetylation을유도할때중요한단백질은EZH2와EED복합체로알려져있으며,히스톤의deacetylation역시특정유전자의전사를억제한다고알려져있다.이때EZH2와EED복합

체는histonedeacetylase(HDAC)와결합한다도알려져있다(Fig.1C)[9].DNAmethylation의경우PRC1단백질복합체가직접적

으로DNAmethylation을유도하는것이아니라히스톤의dea-cetylation을유도할때중요한단백질인EZH2와EED복합체에DNAmethyltransferaseI(DNMT1)을결합하여일어난다고보고되었다(Fig.1C)[10].또한이러한DNMT1과PRC1단백질복합체

의결합은PRC1단백질복합체의히스톤deacetylation활성에중요하다고알려져있다[10].

PcG단백질들에의한생체내조절은줄기세포분화부터암세포생성까지다양한생명현상에서연구되고있지만[11],면역세포,특히T림프구의분화및활성조절에대해서는몇몇PcG단백질들을제외하고는잘알려져있지않았다.PcG단백질중에지금까지면역세포활성에영향을주는물질은크게3가지PcG단백질(BMI-1,MEL-18,EZH2)로알려져있으며,이러한단백질들의발현및기능

이T림프구의분화및활성조절에미치는영향은다음과같다.

2. BMI-1이 T 림프구의 분화 및 활성 조절에 미치는 영향

골수내림프구발달과정에서림프구분화과정과BMI-1의발현양상은정반대의양상을보인다[18,19].즉,CD34+조혈모세포에

서는BMI-1의발현양상이높게나타나며,일단특정면역세포로분화된CD34-세포에서는BMI-1의발현이감소하는것으로알려

져있다[19].이러한결과는BMI-1이초기림프구분화과정에중요한역할을한다는것을암시한다.이러한생각을뒷받침하는예로Bmi1유전자를과발현한생쥐는림프구의발달이과도하게일어나며,결과적으로Bcelllymphoma가자연적으로생긴다[20].반면Bmi1유전자가결핍된생쥐에서는림프구발달이정상생쥐보다덜일어나게된다[21].실제로BMI-1의기능은조혈모세포의self-renewal을유지하는데중요하다고알려져있다[21,22].이때BMI-1은p16Ink4a와p19Arf의전사를억제시켜p53의존적세포사멸이나세포노화,세포분열을억제하는기능을한다[21,22].흉선내에서발달하는T림프구의발달과정을특정PcG단백질

의양상에따라분류해보면,BMI-1+/EZH2−,BMI-1+/EZH2+,BMI-1−/EZH2+이들세가지형태의세포로나뉘며,BMI-1+/EZH2−형태를나타내는T림프구전구체는주로흉선내T림프구발달초기세포인CD4-CD8-상태의전구체이며,BMI-1+/EZH2+형태를나타내

는T림프구전구체는BMI-1+/EZH2−형태를나타내는CD4−CD8−상태의전구체이후에발생한다.또한,BMI-1−/EZH2+형태를나타

내는T림프구전구체는CD4+CD8+상태의T림프구이다[23].따라

서,BMI-1의기능은T림프구발달초기세포인CD4−CD8−상태의전구체발달에중요한역할을하는것으로알려져있다.특히CD4−

CD8−상태의T림프구전구체가CD4+CD8+상태의T림프구전구

체로발달될때,BMI-1이직접적으로p16Ink4a와p19Arf의전사를억제하여세포분열을촉진시킨다는것이알려져있다[24].

BMI-1의활성은초기T림프구분화과정이후특정T림프구의활성조절에도영향을미친다는보고가나타나있다.우선BMI-1이Th2cell발달을촉진시킨다는것이알려져있으며,memoryT림프구발달에도중요한역할을한다는것이알려져있다[25,26].이러한결과는주로Bmi-1유전자가결핍된생쥐의표현형을관찰하

여알려진결과들이다[25,26].GATA-3의경우BMI-1과상호작용

을한다는것이면역침전법(immunoprecipiation)과yeast-twohy-brid(Y2H)analysis에의해입증되었다[25].이러한상호작용은GATA-3의유비퀴틴화를억제하여,결과적으로GATA-3의발현

을안정화시켜Th2cell발달을촉진시킨다[25].또한,BMI-1은me-moryT림프구에서발현하는Noxa 유전자의발현을억제하여memoryT림프구의세포사멸을억제하는것으로알려져있다

[26].Noxa유전자는림프구를비롯한여러세포에서세포사멸을유도하는유전자로알려져있으며[27],Noxa유전자의CpGisland에위치하는특정히스톤에는trimethylation(H2K27me3)이일어난다고알려져있다[26].그밖에BMI-1이흉선내상피세포(thy-micepithelialcell,TEC)의세포분열을촉진시켜생체내에서의흉선크기에영향을준다는논문도보고되었다[28].

3. MEL-18이 T 림프구의 분화 및 활성 조절에 미치는 영향

MEL-18의활성은흉선,골수,비장,림프절,Peyer’spatch등대부

분의면역기관에서활성을보이는것으로알려져있다[29].Mel18유전자가결핍된생쥐의경우대부분의면역세포가결핍을보이는현상을나타내는데,이러한이유에의해MEL-18의기능도BMI-1의역할과마찬가지로초기림프구분화과정에중요한역할을할것이라고생각된다[29].하지만MEL-18의경우BMI-1처럼조혈모

세포의self-renewal을증진시키는것이아니라,오히려조혈모세포

의self-renewal을억제하는것으로나타났다[29].이러한가설의증거는Mel18 유전자가결핍된생쥐에서Hoxb4 유전자의전사가증가되며,이에따라휴지기상태(G0stage)의조혈모세포가늘어나는현상에의한다.따라서조혈모세포에서MEL-18의기능은오히려

Hanyang Med Rev 2013;33:33-3836 http://www.e-hmr.org

Taehoon Chun • Influence of Polycomb Proteins on T cellsHMR

조혈모세포의self-renewal을억제하는것이다[29].따라서림프구분화에서MEL-18의기능은조혈모세포의self-

renewal을유지하는것보다는조혈모세포에서다른면역세포로의분화과정에서더욱중요한역할을할것이라고생각된다.특히Mel18유전자가결핍된생쥐의경우,골수내조혈모세포는IL-7에대한반응성이현저하게감소하는것으로나타났다[29].이러한이유에의해서MEL-18은IL-7수용체에의한STAT5signaling[30]에중요한역할을하는것으로알려져있다[29].또한Mel18유전자

를과발현한생쥐의경우특정cyclin과cyclindependentkinase(CDK)의활성이억제됨에따라,MEL-18이세포주기를억제하는기능을가지고있음을밝혀졌다[31].이러한연구결과는B림프구수용체에전달되는항원에의한B림프구의세포분열정도를측정

하였을때,Mel18 유전자를과발현한생쥐내에서발달하는B림프구의세포분열이정상생쥐내에서발달하는B림프구의세포분열보다억제된다는연구결과에의해알려졌다[31].

MEL-18의기능은BMI-1의기능처럼초기림프구분화과정이후특정T림프구의활성조절에도영향을미친다는보고가나타

나있다.우선BMI-1의기능과마찬가지로MEL-18이Th2cell발달

을촉진시킨다는것이알려져있다[32].Mel18유전자가결핍된생쥐에서는Th2typecytokine들인IL-4,IL-5,IL-13이감소되며,이러한결과는IL-4유전자의메틸화와GATA-3발현억제에의한다

[32].하지만MEL-18의기능이BMI-1의기능처럼memoryT림프

구의발달에중요한역할을하는지에대한연구는아직이루어져있지않다.

4. EZH2가 T 림프구의 분화 및 활성 조절에 미치는 영향

EZH2는특정히스톤에세개의메틸기(H2K27me3)를붙이는methyltransferase이기때문에PcG단백질중가장중요한기능을하며,또한그만큼많이연구되고있는단백질이다.또한EZH2는EED와함께복합체를이루어히스톤의deacetylation을유도할수있으며,DNAmethylation을유발하는DNMT1과결합하기도한다[10].EZH2의기능은면역세포보다는줄기세포나암연구에서더욱많이연구되었으며,EZH2는암세포에서높은발현양상을보이며,암세포의발달에서tumorsuppressor역할을하거나onco-gene역할을하는양면성을가진다[33,34].Ezh2유전자가결핍된생쥐의경우,개체로발달하지못하기때문에면역세포에서의EZH2의기능연구는상대적으로제한적이며,그만큼생체내에서의EZH2의기능은면역세포기능조절뿐만아니라다른세포의기능

에도중요하다는것을암시한다[35].따라서EZH2가면역세포에어떠한영향을미치는가에대한기능연구에서우선으로고려되는것은,EZH2유전자의과발현또는결핍시일어나는면역세포의표현형적특이성이아니라EZH2의표적이되는특정유전자의발굴에있다.이러한연구의예로,EZH2는Th1cell에서IL-4와IL-13

유전자의CpGisland에위치하는특정히스톤에세개의메틸기

(H2K27me3)를붙인다고알려져있으며,Th2cell에서는이러한trimethylation양상이안보인다는보고가나와있다[36].또한세포독성T림프구에서발현하는특정killerimmunoglobulin-likereceptor(KIR)유전자의CpGisland에위치하는히스톤에세개의메틸기(H2K27me3)를붙인다고알려져있다[37].또한,EZH2의tyrosineresidue를p56lck가인산화시키면,T림프구내CD3복합

체와결합하는zeta-associatedprotein-70(ZAP-70)와결합한다고알려져있다[38].하지만이들두단백질의결합에의해어떻게T림프구표현형이바뀌는지는알려져있지않다.최근에는Ezh2 유전자가결핍된생쥐에Ezh2conditionalknock

in생쥐를만들어EZH2가면역세포로의분화과정에서어떠한역할을하고있는가를연구하고있다.Ezh2conditionalknockin생쥐에서얻어진연구결과에따르면EZH2는조혈모세포내BMI-1의기능과유사하게,조혈모세포의세포사멸을억제하고,세포주기를Gostage로유지시켜self-renewal을유지하는데중요한것으로알려졌다[39].또한EZH2는조혈모세포가특정면역세포로의분화시myeloidorigin인면역세포의분화를유도하는것으로알려졌다[40].앞서기술한바와같이T림프구의발달과정을특정PcG단백질의양상에따라분류해보면,BMI-1+/EZH2−,BMI-1+/EZH2+,BMI-1−/EZH2+이들세가지형태의세포로나뉜다[23].EZH2를발현하는T림프구전구체들은주로CD4+CD8+상태의T림프구전구체이기때문에흉선내선택과정(thymicselection)이나특정lineagedifferentiation(CD4−CD8+또는CD4+CD8−thy-mocyte)발달에중요할것이라고추측된다.하지만이를뒷받침하

는증거는아직발표되어있지않다.

5. 그 밖의 PcG 단백질들이 T 림프구의 분화 및 활성 조절에

미치는 영향

그밖의PcG단백질들중면역기관의발달이나면역세포의분화및활성조절에중요한역할을하는예는CBX2,Ring1B,PHC1으로알려져있다.CBX2,Ring1B,PHC1은PRC1단백질복합체의구성단위들이다[11,12].Cbx2유전자가결핍된생쥐의경우비장내vascular또는adrenalgland의결핍현상이보이는데,이러한원인은adrenal4bindingprotein/steroidogenicfactor-1(Ad4BP/SF-1)이라는전사인자의발현이감소되기때문이라고알려졌다[40].Ring1B의경우BMI-1이나MEL-18의경우와마찬가지로Th2cell발달을촉진시킨다고알려졌으며[41],최근에는Runx1/CBFb전사

인자와직접적으로결합하여BMI-1과같이면역세포의초기분화

에중요한영향을미친다는보고가있다[42].EDR1(PHC1)의경우

도조혈모세포의self-renewal에중요한역할을한다는보고가있다[43].

Hanyang Med Rev 2013;33:33-38 http://www.e-hmr.org 37

전태훈 • Polycomb 단백질이 T 세포에 미치는 영향 HMR

결  론

PcG단백질들은크로마틴의구조를여러가지형태로변화시켜,특정유전자의발현을억제하는전사억제자(transcriptionrepres-sor)로알려져있다.PcG단백질들이특정면역세포의발달이나활성에중요한작용을한다는것은PRC1과PRC2단백질복합체내의각각의단위단백질의발현을제거한생쥐의표현형을보고그기능의유추가가능했다.그예로PRC2단백질복합체단위단백질

인BMI-1,MEL-18,Ring1B,PHC1단백질의활성이제거된생쥐에

서는면역세포분화에문제점이생기는데,이러한결과로미루어보아BMI-1,MEL-18,Ring1B,PHC1단백질들은조혈모세포에서면역세포로의분화에중요한역할을하는것으로생각된다[22,29,40,43].또한PRC2단백질복합체단위단백질들은대부분Th2cell발달을촉진시킨다고알려졌다[25,26,32].하지만이러한연구는대부분의연구가특정3가지PcG단백질(BMI-1,MEL-18,EZH2)의기능으로국한되어있으며,다른PcG단백질들이어떻게면역세포

의분화나활성에영향을미치는가에대한연구가더필요할것으로생각된다.또한앞서기술하였듯이PcG단백질들이PRC1과PRC2단백질복합체를이룰때,특정기능이나상황에따라,PRC1과PRC2단백질복합체의구성단위를이루는단백질들의조합은바뀔수있다.따라서이러한구조적기능적복잡성에따라,특정면역세포의표현형은달라질수있다.PcG단백질들의기능은지금까지생각했던것보다더욱더복잡해질수있고,면역세포내PcG단백

질들의기능에대한연구는아직걸음마단계라고생각된다.

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