Cohesin結(jié)構(gòu)及功能研究進展

張雨，方玉達

綜述

Cohesin結(jié)構(gòu)及功能研究進展

張雨，方玉達

上海交通大學農(nóng)業(yè)與生物學院單細胞生物學聯(lián)合研究中心，上海 200240

Cohesin是一類在真核生物進化過程中保守的蛋白復合體，由4個重要亞基相互作用形成環(huán)狀結(jié)構(gòu)，在細胞分裂過程中參與維持染色體的有序排布。在動物中研究發(fā)現(xiàn)cohesin還可以作為分子間的連結(jié)器介導絕緣子/增強子–啟動子間長距離交互，導致基因表達增強或者抑制，但在植物中關于cohesin在調(diào)控基因表達和維持染色體構(gòu)象方面的研究卻相對滯后。本文介紹了cohesin的結(jié)構(gòu)特點和主要組成亞基，對調(diào)控cohesin在染色質(zhì)上動態(tài)變化的相關因子進行了總結(jié)，并結(jié)合近年來植物中cohesin的功能研究和動物中cohesin在三維基因組及轉(zhuǎn)錄調(diào)控中的重要作用，展望了植物中cohesin在轉(zhuǎn)錄調(diào)控中的潛在功能。

SMC；cohesin；細胞周期；三維基因組；轉(zhuǎn)錄調(diào)控

細胞核是細胞遺傳與代謝的調(diào)控中心，遺傳物質(zhì)DNA有序且密集地分布其中。人類細胞核基因組的物理長度約102 cm，即使基因組較小的擬南芥()，其細胞核基因組也有3.8 cm，而這些DNA通過折疊濃縮后儲存在僅有幾微米的細胞核內(nèi)。染色體經(jīng)過折疊形成有序的三維結(jié)構(gòu)，這一過程很大程度上依賴染色體結(jié)構(gòu)維持蛋白(structural maintenance of chromosomes, SMC)的調(diào)控[1~3]。SMC復合體從真菌、植物到人類都非常保守，包括cohesin、condensin和SMC5/6三大類。Condensin的功能主要與染色體內(nèi)部的凝聚相關，當人類細胞敲除condensin后，導致染色體不能凝聚，不能形成正常姐妹染色單體，在分裂后期姐妹染色單體也不能正常分離。SMC5/6功能主要與DNA的損傷修復相關。關于cohesin的功能，早期人們研究發(fā)現(xiàn)其在酵母細胞有絲分裂和減數(shù)分裂過程中都發(fā)揮重要功能。在分裂過程中，cohesin可以維持染色體的正常形態(tài)，保證姐妹染色單體及同源染色體在細胞的不同分裂時期正確分布[4~6]。而在間期，cohesin維持染色質(zhì)形成不同的空間結(jié)構(gòu)，調(diào)控基因表達，還與DNA復制、DNA損傷修復相關[5,7~9]。最近的研究還發(fā)現(xiàn)cohesin介導的染色質(zhì)環(huán)擠出動態(tài)過程對RAG (recombination-activating gene)掃描損傷位點起到促進作用，并在數(shù)量眾多的V(D)J (variable- diversity-joining)重排和交錯轉(zhuǎn)化重組(cross switch recombination, CSR)過程中發(fā)揮重要作用[10]。

Cohesin在維持染色質(zhì)構(gòu)象及調(diào)控轉(zhuǎn)錄方面的研究也成為三維基因組學和表觀遺傳學研究的熱點。本文在介紹cohesin結(jié)構(gòu)特點、主要組成亞基及其功能的基礎上，對cohesin在染色質(zhì)上從招募到穩(wěn)定結(jié)合，再到解離過程中調(diào)控其動態(tài)變化的作用因子進行了總結(jié)，并結(jié)合近年來在哺乳動物及酵母中的相關研究，討論了cohesin在植物與動物中功能的保守程度，對植物cohesin在基因表達調(diào)控中的潛在功能進行了展望。

1 Cohesin結(jié)構(gòu)

1.1 SMC蛋白復合體的結(jié)構(gòu)特點

真核生物的SMC復合體都是在兩個SMC蛋白組成的異源二聚體基礎上形成的[11~13]。每個SMC 蛋白由1000~1500個氨基酸組成，中間是球狀的鉸鏈(hinge)結(jié)構(gòu)域，鉸鏈結(jié)構(gòu)域兩側(cè)延伸形成卷曲螺旋(coiled-coils)結(jié)構(gòu)域[14]，卷曲螺旋結(jié)構(gòu)域終端分別為Walker A和Walker B結(jié)構(gòu)域，即SMC蛋白N端的Walker A和C端的Walker B結(jié)構(gòu)域。Walker A含有核苷酸結(jié)合結(jié)構(gòu)域(nucleotide-binding domain, NBD)，Walker B含有與典型ATP酶同源的ATP結(jié)合結(jié)構(gòu)域(ATP-binding cassette, ABC)。單個SMC蛋白以hinge結(jié)構(gòu)為中心，兩側(cè)的coiled-coils結(jié)構(gòu)域反向平行相互作用在一起，這使得SMC的N端Walker A和C端Walker B結(jié)構(gòu)域相互靠近在一起,形成有功能ATP酶(ATPase)結(jié)構(gòu)域(圖1，A和B)[15~17]。SMC的ATPase位點對于整個SMC蛋白復合體在DNA上的結(jié)合和解離至關重要[18]。

1.2 Cohesin主要亞基

Cohesin是SMC復合體中的一類，由SMC1、SMC3和SCC3 (在動物中是Rad21)以及kleisin亞基組成的環(huán)狀套索結(jié)構(gòu)[14,19]。其中，SMC1與SMC3是典型的SMC 蛋白，SMC1和SMC3的hinge結(jié)構(gòu)域相互作用形成V形的異源二聚體，底部由kleisin亞基將兩個SMC蛋白的ATP酶結(jié)構(gòu)域連接形成閉合環(huán)狀V形復合體(圖1B)[20,21]。Kleisin亞基與SCC3亞基相互作用，進而招募SCC3形成完整的cohesin蛋白復合體[22]。酵母中發(fā)現(xiàn)SCC3 (SA2)的C端與kleisin相結(jié)合。蛋白結(jié)構(gòu)分析發(fā)現(xiàn)，SCC3內(nèi)部凹面可以與kleisin (Rad21/Scc1-M)亞基中間很大一段相互作用[23]。目前在植物中還沒有關于cohesin各亞基間相互作用的報道。

擬南芥cohesin的AtSMC1和AtSMC3亞基與酵母和哺乳動物SMC家族相比蛋白同源性很高。擬南芥和單突純合突變體種子在發(fā)育過程中胚和胚乳都存在嚴重缺陷[24~26]，胚胎發(fā)育早期就死亡，由此可見cohesin在胚胎發(fā)育早期即已經(jīng)發(fā)揮著重要作用。擬南芥中AtSCC3不存在基因冗余現(xiàn)象，與酵母中SCC3蛋白有40%的同源性。動物中SCC3亞基含有HEAT-repeat (Huntingtin, elongation factor 3, protein phosphatase 2A)結(jié)構(gòu)域[27]，而擬南芥中AtSCC3卻不含有HEAT-repeat結(jié)構(gòu)域。擬南芥純合突變體在胚胎發(fā)育早期缺陷致死，Chelysheva等[28]發(fā)現(xiàn)Ws(Wassileskija)擬南芥弱的突變體植株與野生型相比表現(xiàn)出矮小、晚花、育性降低、有絲分裂及減數(shù)分裂均發(fā)生異常。

圖1 SMC類蛋白及cohesin的結(jié)構(gòu)示意圖

A：SMC類蛋白保守結(jié)構(gòu)域示意圖；B：Cohesin結(jié)構(gòu)示意圖。根據(jù)參考文獻[18]繪制。

Kleisin亞基在擬南芥、水稻(L.)和玉米(L.)中均有研究。在擬南芥和水稻中kleisin 亞基的4個同源蛋白相對保守，玉米中僅有AFD1一個同源蛋白，釀酒酵母()及脊椎動物中kleisin 亞基有RAD21和REC8兩個同源蛋白(表1)[29]。擬南芥中Kleisin亞基的4個同源蛋白分別為：AtSYN1、AtSYN2、AtSYN3和AtSYN4[30~33]。突變體雌雄配子不育，但其營養(yǎng)生長等生長發(fā)育過程均正常[34,35]，表明AtSYN1蛋白主要在減數(shù)分裂形成配子過程中發(fā)揮重要功能[34,36]。最近研究發(fā)現(xiàn)，擬南芥第一次減數(shù)分裂過程中cohesin維持在著絲粒區(qū)域依賴兩個蛋白磷酸化酶對AtSYN1的去磷酸化作用[37,38]。AtSYN3主要定位在核仁，與rDNA結(jié)構(gòu)維持及rRNA轉(zhuǎn)錄和加工成熟有關[33]。AtSYN2和AtSYN4在有絲分裂中發(fā)揮重要功能。AtSYN2與種子萌發(fā)過程中DNA損傷后修復相關[35]，而AtSYN4與苗期體細胞DNA損傷修復相關[39]。酵母雙雜交實驗證明，AtSYN4 也可以與磷酸化酶PP2A B'α、PP2AB'β和PP2AB'ζ相互作用，磷酸化酶與AtSYN4的相互作用可能與有絲分裂過程中cohesin在著絲粒上的維持相關[37,38]。

水稻中RAD21-4/OsREC8是酵母中REC8的同源蛋白，OsREC8在減數(shù)分裂過程中保證同源染色體正確的配對及聯(lián)會(表1)。突變體及RNAi植株在營養(yǎng)生長階段與野生型相比無明顯差異，但育性均顯著降低[40,41]。在水稻各組織中均有表達，但在花和芽中表達明顯高于葉和根。在花中高表達。RNAi植株的花粉有絲分裂異常，染色體不能正常分離，且花粉活力嚴重降低，但花粉的減數(shù)分裂并無異常，表明OsRAD21-3在花粉減數(shù)分裂后的有絲分裂過程中發(fā)揮作用[42]。通過原位雜交發(fā)現(xiàn)多在細胞分裂旺盛的組織中高表達，且異位表達后水稻細胞生長遲緩、植株發(fā)育異常[43]。

玉米AFD1是REC8的同源蛋白，其功能與同源染色體配對、聯(lián)會復合體的形成及RAD51在染色體上的分布有關。AFD1會影響染色體在細線期及偶線期的分布。突變體中染色體在偶線期不能呈“花束”形態(tài)(bouquet formation)分布，減數(shù)分裂發(fā)生異常[44]。

2 調(diào)節(jié)cohesin在染色質(zhì)上動態(tài)變化的因子

Cohesin在細胞分裂過程中重要的功能是維持姐妹染色單體有序地分布。在顯微鏡下可以觀察到，在細胞分裂前期到中期cohesin都結(jié)合在染色體臂以及著絲粒區(qū)域，維持兩條姐妹染色單體粘連在一起，在分裂中后期cohesin從染色體臂上解離下來，末期著絲粒上的cohesin也解離下來，姐妹染色單體得以正常分離。在轉(zhuǎn)錄過程中cohesin也隨著RNA聚合酶及轉(zhuǎn)錄因子從轉(zhuǎn)錄起始位點向轉(zhuǎn)錄終止位點移動[45,46]?？梢奵ohesin在染色質(zhì)上的結(jié)合是動態(tài)變化的。Cohesin在染色質(zhì)上的動態(tài)變化在擬南芥，酵母，線蟲()和人類()中均有相關研究[4~6,47,48]。Cohesin的動態(tài)變化依賴很多蛋白，如：SCC2負責在DNA上招募co-hesin，而cohesin在染色質(zhì)上的維持依賴CTF7/ECO1 (chro-mosome transmission fidelity/establishment of co-hesion 1)。另外，WAPL (wings apart-like protein)和PDS5 (precocious dissociation of sisters protein 5)因子與cohesin從DNA上解離有關(表1)。

2.1 Cohesin在染色質(zhì)上的加載

在DNA復制開始前，cohesin的加載因子SCC2和SCC4先在染色質(zhì)上結(jié)合，進而招募cohesin在染色質(zhì)上結(jié)合[6,47,49,50]。在釀酒酵母中，SCC4可以穩(wěn)定SCC2在染色質(zhì)上的結(jié)合[49,51]，兩者作用在一起形成cohesin的加載因子，從而招募cohesin[6,52]。Cohesin與SCC2在DNA上的結(jié)合位點并不是隨機的，兩者染色質(zhì)免疫共沉淀-高通量測序(ChIP-seq)的分析結(jié)果發(fā)現(xiàn)它們各自結(jié)合位點可能沒有重疊[53,54]，這可能由于cohesin最初是依賴SCC2與DNA的結(jié)合，但cohesin在染色質(zhì)上的結(jié)合位置是動態(tài)變化的，cohesin會在其他因子的作用下移動，如間期cohesin隨著轉(zhuǎn)錄過程中RNA聚合酶在染色質(zhì)上移動。Cohesin多分布在轉(zhuǎn)錄相對活躍的地方，且隨轉(zhuǎn)錄過程在轉(zhuǎn)錄終止區(qū)域富集[55~57]。SCC2與co-hesin結(jié)合的程度會影響cohesin在染色質(zhì)上的移動。當SCC2突變后，cohesin在轉(zhuǎn)錄起始位點的結(jié)合能力也降低[58]。SCC2和SCC4影響cohesin在染色質(zhì)上結(jié)合的具體機制還不完全清楚。酵母研究發(fā)現(xiàn)，SCC2和SCC4突變后，完整的cohesin環(huán)可以形成，但不能與DNA結(jié)合。和突變體的表型與SMC1和SMC3的ATPase結(jié)構(gòu)域突變后的表型類似，即cohesin可以形成完整的環(huán)狀復合體，但也不能結(jié)合DNA。據(jù)此推測，SCC2可以加強SMC3和SMC1的ATPase活性以及催化DNA形成容易被cohesin有效結(jié)合的拓撲異構(gòu)結(jié)構(gòu)，進而影響co-hesin在染色質(zhì)上的結(jié)合[14,21,59~61]。

表1 Cohesin亞基及相關調(diào)控因子

*根據(jù)序列比對得到的同源蛋白。根據(jù)參考文獻[29]整理。

擬南芥中cohesin加載因子的同源蛋白為AtSCC2和AtSCC4。AtSCC2與動物中同源蛋白有20%的同源性，除了有動物中共有的HEAT-repeat結(jié)構(gòu)域外，AtSCC2還有植物中特有的植物同源結(jié)構(gòu)域(plant homeodomain, PHD)。PHD結(jié)構(gòu)域與組蛋白表觀修飾以及基因表達調(diào)控相關[62,63]。在植物中，SCC2也是非常重要的蛋白。擬南芥純合突變體在種子形成過程中胚乳過度增生分裂、發(fā)育異常、胚胎早期致死[62]。擬南芥純合突變體胚胎在心形胚形成階段不能對稱分裂，胚柄處過度增生[64]。擬南芥植株中可觀察到減數(shù)分裂過程中染色體分離紊亂，同時結(jié)合在染色質(zhì)上的AtSCC3蛋白也減少，并出現(xiàn)姐妹染色單體黏連，染色體橋及分裂后細胞中染色體數(shù)目異常的現(xiàn)象[62]。在雙突變體背景下，生長素報告基因被限制在胚柄底部細胞中表達，而野生型中報告基因在胚柄頂部細胞中表達。這表明AtSCC2和AtSCC4的缺失會導致胚胎發(fā)育過程中胚柄細胞胚胎潛能的改變。植物和酵母中都發(fā)現(xiàn)，SCC4可以與SCC2的N端穩(wěn)定地相互作用在一起，但植物AtSCC4與AtSCC2之間的相互作用不會影響AtSCC4的定位。擬南芥AtSCC2的突變并沒有改變植物體細胞核中AtSCC4的定位[54]。此外，有絲分裂間期AtSCC4與kleisin亞基AtSYN4共定位[54]，而AtSCC2的主要功能被認為在減數(shù)分裂過程中影響cohesin的定位[62]，這表明在擬南芥中AtSCC4與AtSCC2功能存在特異性。最近研究發(fā)現(xiàn)，玉米中DEK15是SCC4的同源蛋白。在突變體中，姐妹染色單體形態(tài)異常，非整倍數(shù)細胞增多，且種子胚乳發(fā)育異常，胚胎早期死亡率增加。玉米DEK15對于染色體精確的分離非常重要，且可以協(xié)同染色質(zhì)重塑因子促進cohesin在染色質(zhì)上的結(jié)合[65]。

2.2 Cohesin在染色質(zhì)上的維持

在有絲分裂S期前，cohesin在SCC2和SCC4的招募下與DNA結(jié)合。從S期到分裂中期，cohesin一直結(jié)合在染色體臂及著絲粒上，維持姐妹染色單體連接在一起，直至后期cohesin從染色體上解離下來。在這個過程中，cohesin復合體在染色質(zhì)上的維持依賴幾個關鍵蛋白：ECO1 (establishment of cohe-sion 1)又稱為CTF7 (chromosome transmission fide-lity 7)，以及sororin因子。

酵母中CTF7/ECO1是乙酰轉(zhuǎn)移酶，在S期可以對SMC3的head結(jié)構(gòu)域的兩個賴氨酸殘基進行乙?；揎梉66~69]。SMC3的ATPase位點K112和K113位被乙?；?，ATPase結(jié)構(gòu)域關閉，使kleisin亞基與SMC亞基結(jié)合緊密，進而使cohesin環(huán)狀結(jié)構(gòu)穩(wěn)定[68~70]。SMC3的這兩個賴氨酸殘基位點在多種生物中都是非常保守的，在人體細胞中，ESCO1 (es-tablishment of sister chromatid cohesion N-acetyltran-sferase 1)和ESCO2兩個乙?；竿瑯涌梢砸阴；疭MC3[69,70]。酵母CTF7缺失會造成染色質(zhì)狀態(tài)混亂，導致cohesin在染色體臂及著絲粒上分布異常，以及細胞周期異常[71,72]。酵母CTF7/ECO1與增值細胞核抗原(proliferating cell nuclear antigen, PCNA)和復制因子C (replication factor C, RFC)復合體直接相互作用，這表明在姐妹染色單體形成過程中，DNA的復制和cohesin作用下的姐妹染色單體粘連是同時進行的[73,74]。

在脊椎動物中，還存在另外一個對cohesin與染色質(zhì)的穩(wěn)定結(jié)合起到重要作用的sororin因子。由于一些解離因子的存在，僅僅乙?；腟MC3不足以讓cohesin在復制過程中穩(wěn)定地結(jié)合在染色質(zhì)上，還需要乙酰化結(jié)合蛋白sororin來維持整個復合體的穩(wěn)定。Sororin含有FGF結(jié)合序列，可以結(jié)合在PDS5 (precocious dissociation of sisters 5)蛋白上，進而起到穩(wěn)定cohesin-DNA的作用[75~77]。在裂殖酵母()中，PDS5可以加強SMC3的乙?；痆78]。PDS5在間期與sororin相互作用，有協(xié)助cohesin結(jié)合DNA，并有維持cohesin與DNA穩(wěn)定結(jié)合的功能。在后期，PDS5與解離因子相互作用，促進cohesin從DNA上解離下來，可見PDS5與不同因子相互作用發(fā)揮的功能也不同[79~81]。

擬南芥可以互補酵母突變體表型[82~84]，這表明cohesin在細胞分裂過程中的功能在擬南芥和酵母中是非常保守的。AtCTF7包含PIP-BOX (PCNA-interacting protein BOX)、一個C2H2鋅指蛋白結(jié)構(gòu)域和一個乙酰轉(zhuǎn)移酶結(jié)構(gòu)域[82]。與其他生物相同，AtCTF7功能也有劑量效應，atctf7雜合體雄配子異常，小孢子母細胞發(fā)育正常，植物營養(yǎng)生長無明顯異常，但育性降低。完全缺失的突變體擬南芥表現(xiàn)出嚴重的生長缺陷表型：胚胎在發(fā)育到球形胚階段就嚴重畸形，僅能獲得少數(shù)純合植株，表現(xiàn)出極矮小、不育的表型，同時cohesin在染色質(zhì)上的結(jié)合明顯減少[82,83]。過表達CTF7也會導致擬南芥胚珠在發(fā)育早期死亡[85]。

2.3 Cohesin從染色質(zhì)上解離

WAPL是調(diào)控cohesin從染色質(zhì)上的解離下來的關鍵因子。有絲分裂中后期，cohesin開始逐漸從 染色體臂上解離下來，僅保留在著絲粒區(qū)域。起始cohesin從染色體臂上解離下來的過程與SCC3亞基的磷酸化相關，這個磷酸化過程依賴于WAPL解離因子[86]。有絲分裂后期，SCC3與sororin被磷酸化，磷酸化后的sororin不再與PDS5相互作用，PDS5與解離因子WAPL相互作用，PDS5-WAPL復合體促進cohesin從染色體壁上解離下來。Cohesin從著絲粒上解離下來的過程依賴蛋白酶對kleisin亞基的水解，整個過程WAPL-PDS5-SCC3協(xié)同發(fā)揮作用[79,87,88]。

擬南芥中有5個同源基因，在不同器官中檢測表達量，發(fā)現(xiàn)在種子成熟過程中其表達量明顯下降。當植株被γ射線照射后，表達上升。敲除后，減數(shù)分裂只輕微受到影響，但是DNA的同源重組修復能力明顯減弱[89]。擬南芥中有兩個同源基因和[90]，而僅有一個拷貝[82]，分子及遺傳學實驗證明AtWAPL和AtCTF7二者功能拮抗[91]。和T-DNA插入突變體在植物生長發(fā)育以及育性方面都沒有異常[90]，純合雙突變體在營養(yǎng)生長階段與野生型相比沒有差異，但雌配子雄配子活性下降，植株育性降低。在減數(shù)分裂方面，雙突變體的同源染色體配對異常，紡錘體形成異常，且cohesin在染色體臂上滯留，出現(xiàn)黏連在一起的姐妹染色單體，在后期不能正常分離[90]。WAPL在許多生物有絲分裂過程中發(fā)揮重要功能，減數(shù)分裂中的研究較少。對擬南芥AtWAPL的研究發(fā)現(xiàn)，其在植物減數(shù)分裂中同樣發(fā)揮重要功能。擬南芥atctf7雜合子突變體植株育性降低，純合突變體植株生長發(fā)育嚴重缺陷，并且不育[83]。Kuntal De等[91]在研究AtCTF7和AtWAPL功能時發(fā)現(xiàn)，將純合突變體與atctf7突變體雜交，獲得三突純合突變體，其生長發(fā)育與野生型無明顯差異，但育性比和atctf7低，可見AtWAPL蛋白缺失可以抵消突變體在有絲分裂過程中cohesin不能結(jié)合到染色體上的缺陷。同時表明作為調(diào)控cohesin動態(tài)變化的因子，AtWAPL和AtCTF7在功能上相互拮抗。

3 Cohesin功能

早期關于cohesin的研究大多集中在細胞分裂過程中，其中在有絲分裂和減數(shù)分裂過程中cohesin對于姐妹染色單體間有序的凝聚在一起發(fā)揮著重要功能。近期研究表明cohesin還可以在分子間起到連接的作用，在長距離范圍內(nèi)影響DNA的交互，進而調(diào)控轉(zhuǎn)錄。另外，cohesin在DNA損傷修復方面也發(fā)揮重要功能，Scc1亞基就是在酵母中篩選易發(fā)生DNA損傷突變體時發(fā)現(xiàn)的[92,93]。對非洲爪蟾()和雞()的細胞進行持續(xù)γ射線照射會導致染色體的斷裂，此過程伴隨著cohesin在DNA上的結(jié)合增多，以及cohesin動態(tài)變化會更加活躍[94]。

3.1 Cohesin在細胞分裂中的功能

一個細胞在分裂成兩個不同細胞的過程中需要很多蛋白協(xié)同發(fā)揮作用，并要經(jīng)歷幾個重要時期以確保正常的細胞能繼續(xù)完成整個細胞周期，阻止異常的細胞進行分裂。有絲分裂過程中，G1期需要完成細胞健康與否的分揀，正常的細胞進入S期，異常的細胞不再進行分裂。G2期確保細胞完成了正確的DNA復制過程，才能進入分裂期。在S期染色體經(jīng)歷了復制過程，產(chǎn)生兩個一樣的姐妹染色單體。從S期DNA開始復制起cohesin就將兩個姐妹染色單體有序地黏連在一起，直到分裂后期才完全從染色體上解離下來。這個機制在所有真核生物中都是非常保守的[95~99]。

體細胞進行有絲分裂的過程中，G1期SCC2和SCC4招募cohesin與DNA結(jié)合，這個過程也依賴SMC蛋白ATP水解酶活性。SMC1和SMC3形成的hinge結(jié)構(gòu)是DNA鏈進入cohesin環(huán)的“入口”[60]。Cohesin與DNA結(jié)合后，從間期到中期，在染色體上的維持依賴于ECO1/CTF7這個乙酰轉(zhuǎn)移酶對SMC3亞基的乙?；饔?，以及sororin-PDS5蛋白的結(jié)合抑制了WAPL蛋白打開cohesin環(huán)的作用[77,100,101]。在S期，cohesin在DNA上的加載與DNA的復制過程協(xié)同進行[102]。在前期–中期轉(zhuǎn)換的階段，染色體臂上的cohesin開始解離下來，這個過程依賴一些有絲分裂激酶的作用。以哺乳動物為例，cohesin的SA (SCC3)亞基被Plk1磷酸化以及sororin蛋白被Cdk1和Aurora B磷酸化都與cohesin從染色體臂上的解離相關，其中WAPL也發(fā)揮重要作用[103,104]。但在有絲分裂后期姐妹染色單體分離之前，cohesin會一直結(jié)合在著絲粒上，此時SGO1以及PP2A會保護SA及sororin不被磷酸化，從而使cohesin維持在著絲粒上[103,105]。中后期紡錘體上的微管向細胞兩極牽引，此時著絲粒上的cohesin產(chǎn)生的內(nèi)聚力可以抵消掉部分紡錘體的牽引力。在中期赤道板上的姐妹染色單體有了分別向兩極移動的重新定向，確保染色體可以正常移動到兩極后，才進行后期著絲粒解凝聚。這時cohesin的kleisin亞基在蛋白水解酶作用下水解，致使cohesin從著絲粒上解離下來，姐妹染色單體向兩極移動[12,106]。

在減數(shù)分裂過程中cohesin同樣發(fā)揮著重要作用。在哺乳動物生殖細胞中，與體細胞相比cohesin的SMC1α亞基及SA1和SA2亞基絕大多數(shù)被SMCβ及STAG3/SA3代替，SMCβ及STAG3/SA3是減數(shù)分裂特異的cohesin亞基[107~109]。生殖細胞中的kleisin亞基為REC8和RAD21L,這也是哺乳動物中減數(shù)分裂特異的亞基(表2)。減數(shù)分裂過程中cohesin在DNA上的結(jié)合和維持過程同樣是依賴SCC2和SCC4、PDS5以及sororin，且這些調(diào)控因子在減數(shù)分裂和有絲分裂中的功能保守[110~112]。在減數(shù)分裂過程中，kleisin亞基與cohesin在染色質(zhì)上的時空分布相關。在哺乳動物減數(shù)分裂前期，REC8類cohesin在DNA復制前結(jié)合到染色質(zhì)上，大量REC8類cohesin與DNA的結(jié)合會貫穿整個減數(shù)分裂過程，直到第二次減數(shù)分裂中期。而RAD21L類cohesin大多是在DNA復制完成之后與染色體結(jié)合，且在第一次減數(shù)分裂的粗線期后期就從染色體上解離下來[113~115]。減數(shù)分裂過程中cohesin從染色體上的解離過程同樣依賴WAPL[116]，其機制也與有絲分裂相同。在釀酒酵母中，減數(shù)分裂SMC亞基與有絲分裂亞基相同，都為PSM1和PSM2。Klesin亞基與有絲分裂不同，為減數(shù)分裂特異的REC8，有絲分裂中的PSC3亞基在減數(shù)分裂中為REC11。目前已知擬南芥cohesin亞基中只有SYN1是減數(shù)分裂特有的(表2)。

無論是有絲分裂還是減數(shù)分裂，cohesin對維持姐妹染色單體凝聚在一起發(fā)揮著重要功能，這種凝聚力從間期DNA復制開始一直持續(xù)到中后期姐妹染色單體分開。如果缺少了分子間的凝聚力，會導致基因組不穩(wěn)定、非整倍體細胞增多、DNA修復力下降、染色體異位等異常[117~119]。

表2 Cohesin亞基在有絲分裂及減數(shù)分裂中的比較

3.2 Cohesin在維持染色質(zhì)構(gòu)像及基因表達調(diào)控中的功能

最早是在果蠅（）中發(fā)現(xiàn)cohesin具有轉(zhuǎn)錄調(diào)控的功能。Cohesin的加載因子 Nipped-B(SCC2)發(fā)生突變后，基因的表達受到抑制，Nipped-B可以介導基因區(qū)域增強子–啟動子的相互作用。如果cohesin不能結(jié)合到基因上，啟動子不能與增強子互作，基因轉(zhuǎn)錄水平降低[120]。同樣，當人缺失了cohesin 加載因子CdLS(SCC2)會造成科妮莉亞·德·蘭格發(fā)育綜合征(Cornelia de Lange syndrome)，這是一種引起上肢發(fā)育畸形、智力缺陷的疾病，其致病原因是由于CdLS的缺失導致下游基因轉(zhuǎn)錄調(diào)控異常[121,122]。

CTCF(CCCTC-binding factor)是協(xié)同cohesin維持染色質(zhì)三維結(jié)構(gòu)及調(diào)控轉(zhuǎn)錄的關鍵因子。染色質(zhì)在細胞核內(nèi)相互作用形成拓撲異構(gòu)相關結(jié)構(gòu)域(topologically associating domain, TAD)，TADs是與染色質(zhì)三維結(jié)構(gòu)功能相關的重要區(qū)域，TADs內(nèi)部染色質(zhì)交互密集，TADs之間染色質(zhì)交互頻率低[123]。有研究提出TAD的主要作用是限制啟動子和增強子間的相互作用[124,125]。不同TAD之間被邊界區(qū)域(boundary)隔開，邊界區(qū)域富集CTCF和cohesin(圖2)[126]，且多富集轉(zhuǎn)錄相對活躍的管家基因[127~130]。邊界區(qū)域基因表達相對活躍，與染色質(zhì)結(jié)構(gòu)相對松散，以及富集著一些與活躍染色質(zhì)相關的組蛋白修飾標記(H3K4me3和H3K36me3)相關。

擬南芥中，染色體組織形態(tài)上沒有明顯的TAD。同時，擬南芥中也缺少動物中經(jīng)典的CTCF絕緣蛋白，這與擬南芥中缺少典型的TAD存在相關性。僅有很少的可信證據(jù)表明在擬南芥中存在類似于絕緣元件的DNA (insulator-like DNA)序列。然而，在對擬南芥進行高分辨率的全基因組染色質(zhì)構(gòu)象捕獲(Hi-C)后發(fā)現(xiàn)超過1000個類似TAD(TAD-like)的區(qū)域[131]。擬南芥中這些區(qū)域和動物中的TAD有著相似的特性：在TAD內(nèi)部，染色質(zhì)交互密集；在TAD之間，染色質(zhì)的交互受到限制。同樣它們在染色體松散的地方以及基因表達活躍的地方富集[131,132]。但植物中還沒有關于cohesin與三維基因組的相關報道。

研究發(fā)現(xiàn)cohesin加載因子、SMC和kleisin不同亞基在全基因組上的結(jié)合位點與CTCF有顯著重疊，并且cohesin與CTCF共同對這些基因轉(zhuǎn)錄起到抑制的作用。盡管CTCF和cohesin在很多環(huán)狀DNA結(jié)構(gòu)處共同結(jié)合，但是它們在維持染色質(zhì)構(gòu)象上的功能不盡相同。CTCF與轉(zhuǎn)錄抑制相關，而cohesin除了與CTCF共同作用的位點外，還在很多基因位點與轉(zhuǎn)錄激活相關[127]。根據(jù)染色質(zhì)包裝緊密程度可以將cohesin的結(jié)合位點分類：在包裝緊密的DNA結(jié)合位點，通常是cohesin與CTCF共同結(jié)合的位點；染色質(zhì)包裝松散的DNA結(jié)合位點，通常沒有CTCF結(jié)合，這些區(qū)域大多為啟動子或增強子區(qū)[133~139]。Cohesin還和一些其它的調(diào)控因子如調(diào)控蛋白復合體(mediator complex)相互作用發(fā)揮轉(zhuǎn)錄激活作用[133~137]。可見cohesin作為分子間橋梁，通過影響長距離范圍內(nèi)DNA上調(diào)控元件如：絕緣子/增強子-啟動子(insulator/enhancer-promoter)之間的染色質(zhì)交互來調(diào)控轉(zhuǎn)錄。Cohesin將增強子-啟動子拉近在一起時，可以起到轉(zhuǎn)錄激活作用，此時cohesin多與轉(zhuǎn)錄因子或mediator共同起作用；當cohesin將絕緣子–啟動子拉近在一起時，可以起到轉(zhuǎn)錄抑制功能(圖3)[18,140]，此時cohesin多與CTCF共同發(fā)揮作用。

圖2 拓撲異構(gòu)結(jié)構(gòu)域的二維結(jié)構(gòu)示意圖

根據(jù)參考文獻[126]繪制。

在復制過程中關于cohesin在染色質(zhì)上結(jié)合機制的研究相對較多，最近Murayama等[141]人用詳盡巧妙的體外實驗探索了cohesin在DNA復制過程中動態(tài)結(jié)合DNA的機制：cohesin在加載因子及ATP的存在下可以結(jié)合在雙鏈DNA上，當cohesin先結(jié)合一分子DNA雙鏈上后，僅能再結(jié)合一分子單鏈DNA，這個過程也是依賴加載因子和ATP的作用。Cohesin結(jié)合了單鏈DNA后，體外再給予單鏈DNA、DNA聚合酶和dNTP等條件會穩(wěn)定整個DNA-cohesin結(jié)構(gòu)。這個過程成功模擬了復制叉形成及推進過程中cohesin動態(tài)結(jié)合DNA的過程[142,143]。而在轉(zhuǎn)錄過程中，是否會形成DNA-cohesin-RNA復合體，目前還不是很清楚，還沒有直接的證據(jù)表明cohesin能在轉(zhuǎn)錄過程中可以沿著DNA移動。最近Peters和他的同事利用遺傳學結(jié)合基因組學方法研究發(fā)現(xiàn)在轉(zhuǎn)錄過程中cohesin在轉(zhuǎn)錄復合體的作用下可以隨轉(zhuǎn)錄進程移動。在突變體中，cohesin在轉(zhuǎn)錄起始位點結(jié)合增加30%。在雙突變體中，cohesin在轉(zhuǎn)錄終止位點下游滯留?；虻霓D(zhuǎn)錄程度不同，cohesin的分布也隨之不均一，轉(zhuǎn)錄活躍區(qū)域的基因上的cohesin會被推到轉(zhuǎn)錄不活躍區(qū)域[144]。這些結(jié)果暗示轉(zhuǎn)錄過程中cohesin可能在PolII-TFs的推動下從轉(zhuǎn)錄起始位點向轉(zhuǎn)錄終止位點移動。全基因組范圍內(nèi)PolII-ChIP-seq，RAD21-ChIP-seq也表明cohesin不僅可以通過控制長距離范圍內(nèi)DNA上轉(zhuǎn)錄元件的結(jié)合調(diào)控轉(zhuǎn)錄，也可以直接與轉(zhuǎn)錄復合體等相關因子在轉(zhuǎn)錄起始位點發(fā)揮作用[144]。

圖3 Cohesin在基因表達調(diào)控中的功能

根據(jù)參考文獻[18]繪制。

4 結(jié)語與展望

對cohesin復合體研究至今已有30多年的時間，除了其主要組成亞基SMC1、SMC3、kleisin和SCC3以外，許多與其功能相關的因子也被發(fā)現(xiàn)，包括cohesin加載因子SCC2、SCC4和解離因子WAPL等。這些研究使得cohesin在細胞分裂過程中的功能及機制逐漸清晰。在細胞周期中，cohesin對于維持染色體的正常形態(tài)和有序排布是至關重要的。在擬南芥和水稻中，cohesin在有絲分裂及減數(shù)分裂中的功能與酵母，哺乳動物高度保守。此外，cohesin在植物中對于胚胎發(fā)育、育性及DNA損傷修復也發(fā)揮重要作用。

在cohesin的作用下，兩條姐妹染色單體靠凝聚力聯(lián)系在一起，這對于染色體在整個細胞周期中正確的動態(tài)變化和正確的分布是至關重要的。在真核生物有絲分裂過程中，DNA復制同時cohesin就已經(jīng)開始發(fā)揮作用。在S期DNA成功復制后就形成了聯(lián)系在一起的姐妹染色單體，直到末期cohesin從染色體上解離下來，新的子細胞形成。在第一次減數(shù)分裂中期，cohesin確保聯(lián)會合復合體形成，保證第一次減數(shù)分裂后期同源染色體間可以正常交換和分離。當植物缺失cohesin的SMC亞基后在胚胎發(fā)育早期就死亡；一些敲低cohesin表達的植物有絲分裂，減數(shù)分裂染色體形態(tài)分布嚴重異常，育性明顯降低。這都表明，cohesin對于一個物種的生存和繁衍有著重要的影響。

近些年，ChIP-seq技術及Hi-C技術的應用，為cohesin調(diào)控染色質(zhì)間相互作用、影響基因表達提供了很多證據(jù)。在動物中，cohesin是一個研究染色質(zhì)長距離交互、三維基因組與轉(zhuǎn)錄調(diào)控關系的重要蛋白復合體，在植物中卻缺少相關研究。在哺乳動物中發(fā)現(xiàn)cohesin與染色質(zhì)構(gòu)像及轉(zhuǎn)錄調(diào)控相關功能與CTCF這個關鍵因子緊密聯(lián)系，但在擬南芥中并不存在CTCF的同源蛋白。另外，擬南芥染色體組織形態(tài)上沒有明顯的TADs，但有超過1000個類似TAD的區(qū)域，并且這些TAD-like的區(qū)域性質(zhì)與動物中TAD的特性相類似。擬南芥基因組中沒有典型的TAD結(jié)構(gòu)域，這可能與缺少CTCF相關，但TAD-like區(qū)域與TAD性質(zhì)相似，推測擬南芥cohesin在維持三維基因組結(jié)構(gòu)及轉(zhuǎn)錄調(diào)控中可能同樣會發(fā)揮功能。動物細胞中發(fā)現(xiàn)cohesin與一些中介因子（mediator）、轉(zhuǎn)錄因子及轉(zhuǎn)錄復合體相互作用，并且它們在基因組上有顯著共同結(jié)合位點。在植物缺少CTCF的情況下，cohesin是否能與一些其他類型轉(zhuǎn)錄因子相互作用來調(diào)控基因表達及是否參與植物三維基因組產(chǎn)生和維持是值得進一步研究的。擬南芥中有研究發(fā)現(xiàn)在RNAi植株中，與同源染色體聯(lián)合及染色體同源重組相關基因表達水平發(fā)生變化[145]，以及在突變體中等基因的轉(zhuǎn)錄水平也發(fā)生了變化[83,85]。這些基因轉(zhuǎn)錄水平的變化是否直接由cohesin引起的并不清楚，其中的機制也沒有研究，有待進一步探索。

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Progresses on the structure and function of cohesin

Yu Zhang, Yuda Fang

Cohesin is an evolutionarily conserved protein complex in eukaryotes. The four subunits of cohesin form a ring structure that plays an important role in maintaining the orderly arrangement of chromatin during cell division. In addition, metazoan cohesin was found to act as an intermolecular linker, which regulates insulator/enhancer–promoter interactions, leading to either enhancement or inhibition of gene expressions. However, little is known about the role of cohesin in the transcriptional regulation in plants. In the review, we introduce the structure and core subunits of cohesin, and summarize the factors that regulate its dynamic changes on chromatin. Based on the functional study of plant cohesin in recent years and researches in animals about the roles of cohesin in the three-dimensional genome organization and transcriptional regulation, we prospect the potential functions of plant cohesin in regulating transcription.

SMC; cohesin; cell cycle; three-dimensional genome; transcriptional regulation

2019-11-07;

2019-12-10

國家自然科學基金項目(編號：31871230)資助[Supported by the National Natural Science Foundation of China (No. 31871230)]

張雨，博士后，研究方向：染色質(zhì)結(jié)構(gòu)與功能。E-mail: zhangyu2065@sjtu.edu.cn

方玉達，博士，特聘教授，博士生導師，研究方向：植物細胞核與染色質(zhì)的結(jié)構(gòu)和功能。E-mail: yuda.fang@sjtu.edu.cn

10.16288/j.yczz.19-288

2019/12/19 14:30:58

URI: http://kns.cnki.net/kcms/detail/11.1913.R.20191218.1615.005.html

(責任編委: 史慶華)