轉(zhuǎn)錄中介體復(fù)合物在心血管發(fā)育和疾病中的轉(zhuǎn)錄調(diào)控作用

張?jiān)w語(yǔ)婷，莊樂南,2,，賀津

綜 述

轉(zhuǎn)錄中介體復(fù)合物在心血管發(fā)育和疾病中的轉(zhuǎn)錄調(diào)控作用

張?jiān)?，趙語(yǔ)婷1，莊樂南1,2,3，賀津3

1. 浙江大學(xué)動(dòng)物科學(xué)學(xué)院動(dòng)物醫(yī)學(xué)系，杭州 310058 2. 浙江大學(xué)醫(yī)學(xué)院附屬邵逸夫醫(yī)院心內(nèi)科，浙江省心血管介入與再生修復(fù)研究重點(diǎn)實(shí)驗(yàn)室，杭州 310016 3. 浙江大學(xué)動(dòng)物科學(xué)學(xué)院動(dòng)物遺傳育種與繁殖研究所，杭州 310058

哺乳動(dòng)物心血管系統(tǒng)發(fā)育過程中，各分子、細(xì)胞和組織器官形態(tài)發(fā)生過程的精細(xì)協(xié)調(diào)對(duì)于形成成熟且功能齊全的心血管系統(tǒng)是不可或缺的，這些過程出現(xiàn)異常通常會(huì)導(dǎo)致嚴(yán)重的先天性心血管發(fā)育缺陷。多細(xì)胞生物中細(xì)胞命運(yùn)的決定和維持在很大程度上依賴于對(duì)RNA聚合酶II (Pol II)轉(zhuǎn)錄活性的時(shí)空精確調(diào)控，而轉(zhuǎn)錄中介體(Mediator)在Pol II轉(zhuǎn)錄過程中起著重要的協(xié)同作用。Mediator是一種進(jìn)化上保守的多亞基蛋白質(zhì)復(fù)合體，包括頭部、中部、尾部和激酶部四個(gè)部分，是轉(zhuǎn)錄因子和基礎(chǔ)轉(zhuǎn)錄機(jī)器之間的功能聯(lián)系的橋梁。近年來，鑒于Mediator在基因表達(dá)中的關(guān)鍵作用，越來越多的人類心血管疾病被證實(shí)與特定的Mediator基因突變相關(guān)，如心臟瓣膜缺陷、大動(dòng)脈轉(zhuǎn)位、DiGeorge綜合征及一些與能量穩(wěn)態(tài)失衡相關(guān)的心血管疾病。本文就Mediator在心血管系統(tǒng)發(fā)育和疾病中的作用進(jìn)行綜述，重點(diǎn)討論Mediator對(duì)轉(zhuǎn)錄調(diào)控的影響在心血管疾病發(fā)生發(fā)展中的作用，旨在為與Mediator相關(guān)的心血管系統(tǒng)發(fā)育和疾病的研究提供廣闊的研究思路。

轉(zhuǎn)錄中介體復(fù)合物；轉(zhuǎn)錄調(diào)控；心血管系統(tǒng)發(fā)育；心血管系統(tǒng)疾病

轉(zhuǎn)錄中介體(Mediator)是從芽殖酵母()中提純出來的一個(gè)大的多亞基復(fù)合體，通過與DNA結(jié)合的轉(zhuǎn)錄因子(transcription factor, TF)的相互作用介導(dǎo)基因的轉(zhuǎn)錄激活。目前，研究發(fā)現(xiàn)Mediator幾乎涉及到真核生物基因轉(zhuǎn)錄的所有方面[1]。除此之外，Mediator還調(diào)節(jié)染色質(zhì)循環(huán)[2]和染色質(zhì)高階折疊[3]，以及mRNA加工[4]和出核[5]、轉(zhuǎn)錄記憶[6]和再啟動(dòng)[7]。Mediator除調(diào)控基因表達(dá)之外還有其他作用，如DNA修復(fù)[8]和類開關(guān)重組(class switch recombination, CSR)[9]等。近年來，在多種發(fā)育障礙和癌癥等疾病中發(fā)現(xiàn)Mediator某個(gè)亞基發(fā)生了突變或異常表達(dá)[10]，進(jìn)一步引起大家的廣泛關(guān)注。雖然已經(jīng)有很多文章闡明了Mediator的組成、結(jié)構(gòu)及其在轉(zhuǎn)錄方面的作用，但是關(guān)于Mediator的生物學(xué)意義及涉及其突變引發(fā)疾病的分子機(jī)制仍存在許多有待探究的地方。本文主要綜述了Mediator近年來相關(guān)的研究進(jìn)展，重點(diǎn)介紹了其在調(diào)控心血管發(fā)育和疾病發(fā)生發(fā)展中的重要作用。

1 Mediator的發(fā)現(xiàn)與相關(guān)研究

1.1 Mediator的組成與結(jié)構(gòu)

在2000年，酵母[11]和哺乳動(dòng)物細(xì)胞[12,13]中的Mediator被通過遺傳學(xué)和生物化學(xué)方法鑒定為轉(zhuǎn)錄的共同調(diào)節(jié)因子，同時(shí)其結(jié)構(gòu)也被解析。研究發(fā)現(xiàn)酵母和人類()間Mediator的結(jié)構(gòu)和亞基組織是保守的(在芽殖酵母中含有25個(gè)亞基，在高等生物中含有30個(gè)以上的亞基)。對(duì)酵母Mediator結(jié)構(gòu)的研究表明，其各亞單位穩(wěn)定組合成復(fù)合物，整個(gè)復(fù)合物的結(jié)構(gòu)可以分成明顯不同的模塊，包括頭部、中部、尾部和激酶。正常情況下，Mediator的頭部、中部和尾部是關(guān)聯(lián)在一起的，但與激酶模塊的結(jié)合不太穩(wěn)定[14]。Mediator的這種模塊化的組成方式也同時(shí)反映了Mediator組件的不同功能。在酵母和人類中，Mediator頭部和中部模塊構(gòu)成了轉(zhuǎn)錄調(diào)控所必需的核心，而尾部和CDK8激酶模塊則起著調(diào)節(jié)功能[15,16]。

盡管Mediator的許多亞單位呈現(xiàn)相對(duì)較高的序列多樣性，但研究表明Mediator具有較為保守的組織結(jié)構(gòu)[17]，且在人類中得到了驗(yàn)證[18,19]。一項(xiàng)利用冷凍電鏡對(duì)小鼠CH12細(xì)胞中Mediator結(jié)構(gòu)解析的研究詳細(xì)地闡述了小鼠Mediator的分子模型[20]。首先是頭部模塊，小鼠Mediator頭部模塊的結(jié)構(gòu)與酵母非常相似，MED17充當(dāng)頭部模塊的中心；中部模塊可以分為由長(zhǎng)螺旋束形成的頂部和底部，頂部由MED7和MED21組成，底部由MED4和MED9組成，其中MED14充當(dāng)了連接其他模塊的樞紐[15]。圖1顯示了人類Mediator的亞單位結(jié)構(gòu)組成，各個(gè)亞基模塊在復(fù)合體中的相對(duì)位置基于已發(fā)表的蛋白質(zhì)相互作用研究和部分結(jié)構(gòu)生物學(xué)研究數(shù)據(jù)[21]。

圖1 人類Mediator的模塊化結(jié)構(gòu)示意圖

箭頭表示對(duì)應(yīng)亞基突變或缺失導(dǎo)致的心臟發(fā)育異?；蛐呐K疾病。

1.2 Mediator與轉(zhuǎn)錄調(diào)控

1.2.1 轉(zhuǎn)錄調(diào)控

所有真核細(xì)胞中與DNA相關(guān)的過程，包括轉(zhuǎn)錄和DNA修復(fù)，都發(fā)生在染色質(zhì)擁擠的環(huán)境中，而基因表達(dá)啟始于轉(zhuǎn)錄。真核生物中編碼蛋白質(zhì)的基因大多是由RNA聚合酶II(Pol II)轉(zhuǎn)錄的。由Pol II調(diào)控的轉(zhuǎn)錄需要各種轉(zhuǎn)錄激活因子和抑制因子的協(xié)同作用，包括轉(zhuǎn)錄激活因子、一組通用轉(zhuǎn)錄因子(gen-eral transcription factors, GTFs)和轉(zhuǎn)錄輔助因子[22]。它們與轉(zhuǎn)錄調(diào)節(jié)區(qū)的靶序列相結(jié)合，通過直接的蛋白質(zhì)-蛋白質(zhì)相互作用或通過影響染色質(zhì)(進(jìn)行染色質(zhì)結(jié)構(gòu)重塑、組蛋白修飾等)來調(diào)節(jié)轉(zhuǎn)錄機(jī)器的組裝和活性。TF的這些功能進(jìn)一步受到轉(zhuǎn)錄協(xié)同調(diào)節(jié)因子的調(diào)節(jié)。而Mediator復(fù)合物是真核生物中Pol II轉(zhuǎn)錄的關(guān)鍵調(diào)節(jié)因子，是轉(zhuǎn)錄所必需的。這一基本、保守且極其復(fù)雜的生物過程受到嚴(yán)格監(jiān)管以確保遺傳程序適應(yīng)細(xì)胞的要求。轉(zhuǎn)錄調(diào)控的失衡會(huì)導(dǎo)致嚴(yán)重的疾病，包括癌癥和心臟疾病[23]。

1.2.2 Mediator在轉(zhuǎn)錄過程中的協(xié)同作用

Mediator的發(fā)現(xiàn)徹底改變了人們之前對(duì)轉(zhuǎn)錄調(diào)控的研究。在經(jīng)典的Mediator功能模型中，Mediator充當(dāng)適配器，將轉(zhuǎn)錄信號(hào)從激活子傳遞到一般的轉(zhuǎn)錄機(jī)器，以幫助Pol II啟動(dòng)轉(zhuǎn)錄。在酵母和哺乳動(dòng)物中，一些Mediator亞單位被證明與各種激活物相互作用[21,24,25]，頭部模塊的特定亞基也被證實(shí)與Pol II和其他GTF相互作用[26,27]。除了作為TF和預(yù)起始復(fù)合物(包括Pol II和GTF)之間橋梁的經(jīng)典功能外，Mediator還參與轉(zhuǎn)錄的許多其他方面，包括轉(zhuǎn)錄延伸[28～30]、終止[31]、RNA加工[32]、染色質(zhì)在啟動(dòng)子中的重塑[33～35]以及表觀遺傳調(diào)控[36]等。25個(gè)酵母Mediator亞基中的10個(gè)亞基(MED4、MED6、MED7、MED8、MED10、MED11、MED14、MED17、MED21和MED22)的單獨(dú)缺失是致死的；并且各種哺乳動(dòng)物Mediator亞基的敲除也是胚胎致死的[37～41]。以上這些研究證實(shí)了Mediator在轉(zhuǎn)錄過程中的重要協(xié)同作用。

1.2.3 Mediator在預(yù)起始復(fù)合體(preinitiation com-plex, PIC)上游招募的功能

在轉(zhuǎn)錄過程中，Mediator被招募到酵母的上游激活序列(upstream activation sequence, UAS)區(qū)域或哺乳動(dòng)物中增強(qiáng)子的調(diào)節(jié)區(qū)域，作為結(jié)合到這些區(qū)域的特定TF和核心啟動(dòng)子等基礎(chǔ)轉(zhuǎn)錄機(jī)器之間的功能紐帶。因此，Mediator是TF和基礎(chǔ)轉(zhuǎn)錄機(jī)器之間的功能聯(lián)系的橋梁[42]。真核轉(zhuǎn)錄需要組裝多亞基PIC，PIC由Pol II、Mediator和TFIIA、TFIIB、TFIID、TFIIE、TFIIF和TFIIH組成。在轉(zhuǎn)錄調(diào)控中，Mediator主要的“中介橋梁”功能是刺激PIC的形成。為了促進(jìn)PIC在體內(nèi)的組裝，Mediator與PIC的各組分通過特定的蛋白-蛋白相互作用連接[29,43]。根據(jù)這些不同的相互作用，Mediator在體內(nèi)的不同階段協(xié)調(diào)PIC組裝，并且Mediator的頭部和中間模塊都參與了這些功能[44]。Mediator足夠大，足以作為PIC的支架，支撐PIC在核心啟動(dòng)子上的組裝[26,45]。

1.2.4 Mediator與TREX-2在轉(zhuǎn)錄啟動(dòng)和mRNA輸出中的作用

目前有研究證實(shí)TREX-2與Pol II的重要調(diào)節(jié)因子Mediator相互作用[46,47]。核孔復(fù)合物(nuclear pore complex, NPC)是細(xì)胞質(zhì)與細(xì)胞核內(nèi)物質(zhì)輸送活動(dòng)相關(guān)的一種大型超級(jí)分子復(fù)合物，既是分子轉(zhuǎn)運(yùn)的門戶，又是染色體的附著位點(diǎn)。除了在核運(yùn)輸中的既定功能外，NPC還會(huì)影響基因表達(dá)[48]。而酵母TREX-2定位于NPC，由Sac3、Thp1、Sem1、Sus1和Cdc31組成，可分為PCI結(jié)構(gòu)域部分和NPC錨定元件，TREX-2可影響基因與NPC的相互作用[49]、轉(zhuǎn)錄和mRNA輸出[50]。

而MED31/MED7N亞基不僅位于Mediator頭部的Pol II C端結(jié)構(gòu)域(C-terminal domain, CTD)結(jié)合位點(diǎn)處，同時(shí)也在Mediator中間模塊上的CKM結(jié)合位點(diǎn)處，所以Mediator中間模塊和頭部模塊之間的接口由MED31通過MED7中的非結(jié)構(gòu)化接頭連接而成。因此，MED31缺失會(huì)導(dǎo)致Mediator架構(gòu)的重排[18]。在這種情況下，Sac3 PCI域與MED31/MED7N亞基復(fù)合體的對(duì)接可以局部改變介體構(gòu)象，從而調(diào)節(jié)與Pol II的相互作用，因?yàn)镾ac3、MED31和CDK8都是正常Ser5-P水平所必需的[51,52]。同樣的原理可能延伸到CDK8激酶模塊(CDK8 kinase module, CKM)[53]，主要通過與中間模塊MED19亞基之間的接觸和Mediator頭部的區(qū)域與核心Mediator相互作用。酵母MED19位于靈活的MED7/MED21亞基復(fù)合體的末端，該亞基復(fù)合體反過來錨定MED31。因此，相關(guān)結(jié)合位點(diǎn)的緊密連接可以解釋TREX-2對(duì)Pol II和CKM的雙重作用。同時(shí)，TREX-2還利用其與Mediator相互作用表面來調(diào)節(jié)mRNA輸出，提示了一種將轉(zhuǎn)錄啟動(dòng)和mRNA處理的早期步驟相耦合的機(jī)制[46]。根據(jù)現(xiàn)有的轉(zhuǎn)錄啟動(dòng)模型，Mediator和染色質(zhì)重塑復(fù)合物SAGA共同占據(jù)了許多酵母啟動(dòng)子[54]。酵母TREX-2主要定位于NPC，考慮到SAGA調(diào)節(jié)TREX-2的C端結(jié)構(gòu)域和Mediator與PCI的相互作用，TREX-2可能可以與SAGA和Mediator聯(lián)系[55]。綜上所述，TREX-2的小部分可以在核孔穿梭，從而擴(kuò)大其工作范圍。而TREX-2通過與Mediator相結(jié)合，利用Mediator的已知整合外部信號(hào)能力(如結(jié)合TF和共激活因子并將它們直接與Pol II相連)。對(duì)于NPC靶向的高誘導(dǎo)性基因，Mediator可以通過TREX-2與NPC優(yōu)化轉(zhuǎn)錄輸出，以此作為對(duì)基因位置做出反應(yīng)的一種方式。

2 Mediator與心血管發(fā)育和疾病

心血管疾病(cardiovascular disease, CVD)是中國(guó)人死亡和過早死亡的主要原因[56]，心血管病死亡約占城鄉(xiāng)居民總死亡原因的40%[57]。研究表明，先天性心臟病是最常見的先天性疾病，影響約0.8%的活產(chǎn)兒[58]。Mediator作為TF和基礎(chǔ)轉(zhuǎn)錄機(jī)器之間的結(jié)構(gòu)和功能聯(lián)系的橋梁，其突變已被證實(shí)與許多人類疾病，包括心血管疾病(表1)。下面主要介紹與Mediator相關(guān)的心血管系統(tǒng)發(fā)育異常及心血管系統(tǒng)疾病。

2.1 Mediator與心血管發(fā)育

在心血管系統(tǒng)發(fā)育過程中，各分子、細(xì)胞和組織器官形態(tài)發(fā)生過程的精細(xì)協(xié)調(diào)對(duì)于形成成熟且功能齊全的心血管系統(tǒng)是不可或缺的，這些過程的異常通常會(huì)導(dǎo)致嚴(yán)重的先天性心血管發(fā)育缺陷。但驅(qū)動(dòng)心血管系統(tǒng)發(fā)育的確切分子和細(xì)胞機(jī)制以及在發(fā)育過程中導(dǎo)致心血管系統(tǒng)缺陷的相關(guān)病理機(jī)制仍未完全理解。目前已有多項(xiàng)研究證實(shí)，Mediator的改變會(huì)影響心血管系統(tǒng)發(fā)育。

心臟瓣膜的缺陷是較為常見的先天性和獲得性心臟病，但目前只有少數(shù)心臟瓣膜病變相關(guān)的遺傳和分子機(jī)制被探究。已有研究證實(shí)，MED12功能缺陷與人類先天性心臟病有關(guān)，并對(duì)小鼠和斑馬魚心臟發(fā)育產(chǎn)生影響。對(duì)小鼠的早期發(fā)育和正確的Wnt和Wnt/PCP信號(hào)轉(zhuǎn)導(dǎo)是必不可少的，表達(dá)異常的小鼠在神經(jīng)管閉合、體細(xì)胞發(fā)育和心臟形成方面存在嚴(yán)重缺陷，且缺陷胚胎的凋亡細(xì)胞主要存在于心臟中，表現(xiàn)為心臟增大及心功能不全[60]。有研究證實(shí)，的心臟特異性缺失小鼠表現(xiàn)為進(jìn)行性擴(kuò)張型心肌病[70]。一項(xiàng)有關(guān)缺陷的斑馬魚突變體的研究發(fā)現(xiàn)在斑馬魚心臟房室管發(fā)育、心內(nèi)膜墊發(fā)育和心臟瓣膜形成過程中發(fā)揮重要作用，并且首次證明了可能在調(diào)節(jié)和的表達(dá)和心臟的發(fā)育中發(fā)揮重要作用，從而使斑馬魚胚胎心臟內(nèi)膜墊的形成不依賴于[71]。

表1 與Mediator相關(guān)的心血管疾病

大動(dòng)脈轉(zhuǎn)位(transposition of the great arterie, TGA)是新生兒中最常見的紫紺型心臟缺陷，占所有先天性心臟病的5%～7%。TGA患者心臟主動(dòng)脈和肺動(dòng)脈與正常心臟流出相反，導(dǎo)致缺氧血液返回身體而不是肺部。研究表明，(也被稱為或)在胎兒和成人組織中廣泛表達(dá)，在心臟及主動(dòng)脈中高度表達(dá)[72]。對(duì)97名TGA患者的篩選分析顯示(p.E251G、p.R1872H、p.D2023G)中有3個(gè)錯(cuò)義突變[72]。這些發(fā)現(xiàn)表明突變會(huì)導(dǎo)致先天性心臟病TGA[62,63]，并表明該Mediator亞基在心臟正常發(fā)育中發(fā)揮重要作用。

染色體22q11.2缺失綜合征又稱為DiGeorge綜合征(digeorge syndrome, DGS)或velocardiofacial綜合征(velocardiofacial syndrome, VCFS)，是人類最常見的多發(fā)性先天性異常綜合征之一，在兒童中的發(fā)病率約為1/3900。DGS常見的臨床表現(xiàn)包括心臟缺陷、腭異常、特征性面部畸形、免疫功能障礙、胸腺和甲狀旁腺發(fā)育不全引起的低鈣血癥[64,65]。22q11.2缺失綜合征相關(guān)的復(fù)雜臨床癥狀表明其涉及多個(gè)基因，而就是其中之一。人類是甾醇調(diào)節(jié)元件結(jié)合蛋白1α ()和激活的的物理靶標(biāo)和功能傳感器，它們分別控制脂質(zhì)代謝和發(fā)育程序[73,74]。作為多種生物學(xué)上重要的信號(hào)轉(zhuǎn)導(dǎo)途徑中的關(guān)鍵樞紐，其表達(dá)降低將會(huì)導(dǎo)致與22q11.2缺失綜合征相關(guān)的臨床異質(zhì)表型[75]。

有研究證實(shí)，過氧化物酶體增殖物激活受體γ輔激活因子1α ()通過與過氧化物酶體增殖物激活受體γ ()相互作用的Mediator亞基MED1，直接與Mediator相互作用[76]，并在DNA模板上刺激Mediator依賴的功能。是氧化磷酸化基因表達(dá)的關(guān)鍵轉(zhuǎn)錄調(diào)節(jié)因子，可以刺激p300依賴的組蛋白乙?；娃D(zhuǎn)錄，以響應(yīng)[77]。根據(jù)研究報(bào)道，條件性缺失小鼠會(huì)出現(xiàn)類似于薄心肌壁綜合征的心臟表型，心肌壁發(fā)育不良，小梁發(fā)育異常，并且心肌致密層變薄，在E11.5左右開始出現(xiàn)死亡[38,78]，30%發(fā)育不全的小鼠可存活到E13.5，但胚胎心臟發(fā)育遲緩，最終死于E14.0[59]。

2.2 Mediator與心血管疾病

眾所周知，能量平衡失調(diào)是心血管病的一個(gè)危險(xiǎn)因素[62]。另外，心臟和骨骼肌等在傳統(tǒng)意義上不被認(rèn)為是新陳代謝調(diào)節(jié)器的多個(gè)器官被證實(shí)可調(diào)控全身能量消耗[79～81]。例如，心臟的傳統(tǒng)功能是為身體其他部位運(yùn)送血液。維持心肌收縮力需要很高的ATP生成能力，據(jù)估計(jì)，心臟自己儲(chǔ)存的ATP僅能維持其功能搏動(dòng)幾次。因此，心肌必須高度調(diào)節(jié)其自身代謝以應(yīng)對(duì)生理、病理和發(fā)育條件的變化[82]。心臟主要是以脂肪酸氧化的形式高速消耗能量，并通過微調(diào)心臟新陳代謝和改變基因表達(dá)來適應(yīng)能量供應(yīng)的變化，以最大限度地提高能量效率[82,83]。一旦發(fā)生心血管疾病，線粒體功能減弱，心臟能量代謝就會(huì)從β-氧化轉(zhuǎn)變?yōu)樘墙徒鈁84]。例如通過介導(dǎo)核激素受體依賴的轉(zhuǎn)錄來調(diào)節(jié)脂肪酸代謝等。Mediator在新陳代謝中的作用也在關(guān)于秀麗隱桿線蟲的研究中得到證實(shí)[85]。

心臟收縮力由鈣信號(hào)在分子水平上調(diào)控，細(xì)胞內(nèi)鈣的釋放和再攝取驅(qū)動(dòng)收縮和放松，并且這一過程在心肌細(xì)胞中受到嚴(yán)格調(diào)節(jié)。鈣離子(Ca2+)調(diào)控基因的破壞將會(huì)導(dǎo)致心臟收縮功能改變。例如，肌質(zhì)網(wǎng)(sarcoplasmic reticulum, SR)中Ca2+攝取減少或衰竭心臟發(fā)生SR鈣滲漏[86,87]，鈣離子調(diào)控基因的突變會(huì)導(dǎo)致心律失常和擴(kuò)張型心肌病(dilated cardiomyo-pathy, DCM)[88]。已有研究證實(shí)定位于心臟中鈣離子調(diào)控基因的TF結(jié)合序列，與心肌細(xì)胞中的TF共同結(jié)合鈣離子調(diào)控基因的啟動(dòng)子[70]。在心臟中的缺失會(huì)改變鈣離子調(diào)控基因的表達(dá)，從而改變心肌細(xì)胞中的鈣循環(huán)并中斷心肌細(xì)胞電活動(dòng)，影響心臟收縮，導(dǎo)致成年小鼠擴(kuò)張型心肌病，但的缺失不影響-DNA結(jié)合或Pol II的募集[70]。

在心臟中抑制許多甲狀腺激素受體(thyroid hormone receptor, TR)反應(yīng)基因，及心臟相關(guān)的研究已證實(shí)心臟調(diào)節(jié)全身能量穩(wěn)態(tài)的能力[79]。甲狀腺激素(thyroid hormone, TH)是心臟轉(zhuǎn)錄穩(wěn)態(tài)的關(guān)鍵調(diào)節(jié)因子，主要調(diào)控與維持心臟正常結(jié)構(gòu)和功能相關(guān)的基因轉(zhuǎn)錄。已知低TH水平與加速心力衰竭進(jìn)程和預(yù)后不良有關(guān)[89,90]，而高水平的TH會(huì)導(dǎo)致快速性心律失常和心室功能障礙[91,92]。心臟過表達(dá)小鼠由于能量消耗增加，表現(xiàn)出對(duì)高脂飲食誘導(dǎo)肥胖的抵抗力，而心臟特異性缺失的小鼠在高脂飲食刺激下出現(xiàn)肥胖的現(xiàn)象。同時(shí)，在甲狀腺功能減退癥小鼠的心臟中過表達(dá)維持了心臟中的表達(dá)，可以在一定程度上緩解心臟損傷[61]。此研究揭示了心臟轉(zhuǎn)錄通路在甲狀腺功能減退中的調(diào)節(jié)作用，并確定了由調(diào)節(jié)的響應(yīng)TH信號(hào)的分子通路在心臟疾病中發(fā)揮的作用。

與線粒體氧化磷酸化(oxidative phosp-horylation, OXPHOS)和脂肪酸氧化(fatty acid oxida-tion, FAO)代謝程序相關(guān)，進(jìn)而對(duì)心臟功能產(chǎn)生特定影響[10]。心肌的高能量需求需要充足的三磷酸腺苷(adenosine triphosphate, ATP)供應(yīng)，其主要可從線粒體OXYPHOS中獲得。因此，心臟線粒體功能障礙會(huì)導(dǎo)致ATP生成減少，進(jìn)而影響心臟收縮功能，嚴(yán)重時(shí)會(huì)導(dǎo)致心力衰竭和死亡[68]。已有研究證實(shí)，連接Mediator頭部和尾部模塊的MED30亞基缺失潛在地影響Mediator核心的穩(wěn)定性。(p.I44F)上的異亮氨酸到苯丙氨酸的純合突變小鼠斷奶后患致命的擴(kuò)張性心肌病，線粒體氧化磷酸化能力急劇下降、呼吸鏈功能下降且氧化磷酸化基因mRNA表達(dá)水平降低，但可以通過生酮飲食在一定程度上挽救，延長(zhǎng)一定的存活時(shí)間。

此外，其他Mediator也被證實(shí)影響代謝。如可通過介導(dǎo)核激素受體依賴的轉(zhuǎn)錄來調(diào)節(jié)脂肪酸代謝[85]；在脂肪形成和平滑肌細(xì)胞分化過程中都參與了胰島素信號(hào)的調(diào)節(jié)和細(xì)胞命運(yùn)的決定[32,93]；作為Mediator復(fù)合體的核心蛋白，MED1可直接與核激素受體結(jié)合以維持骨骼肌能量穩(wěn)態(tài)[94]。也有研究表明，在心肌肥厚時(shí)被激活[95]，的激活抑制的表達(dá)，導(dǎo)致線粒體功能障礙，從而導(dǎo)致凋亡性心肌病[96]。

目前，雖然一些研究發(fā)現(xiàn)了Mediator的部分亞基與特定的基因啟動(dòng)子共定位，進(jìn)而在心血管系統(tǒng)與心臟代謝過程中的發(fā)揮作用。但關(guān)于Mediator在心臟特異性發(fā)育和功能中的具體機(jī)制尚未見報(bào)道。

2.3 Mediator與人類其他疾病

多細(xì)胞生物中細(xì)胞命運(yùn)的決定和維持在很大程度上依賴于對(duì)Pol II轉(zhuǎn)錄活性的時(shí)空精確調(diào)控，以此影響細(xì)胞命運(yùn)決定信號(hào)。因此，擾亂生理轉(zhuǎn)錄控制的遺傳或環(huán)境因素可以改變細(xì)胞命運(yùn)決定，導(dǎo)致各種病理狀況，包括發(fā)育缺陷和癌癥[10]。鑒于Mediator在基因表達(dá)中的關(guān)鍵作用，除心血管疾病外，越來越多的人類其他疾病被證實(shí)與特定的Mediator基因突變相關(guān)，如行為障礙、神經(jīng)發(fā)育異常、多種形式的癌癥等。例如人類多種神經(jīng)發(fā)育疾病與[66]、[97]、[98]、[99]、[100]、[101]、[102]和[103]的突變或改變有關(guān)。MED20通過橋接C/EBPβ和Pol II來組織早期脂肪形成復(fù)合物，以促進(jìn)中央脂肪形成因子的轉(zhuǎn)錄，在促進(jìn)脂肪生成、脂肪組織發(fā)育和飲食誘導(dǎo)的肥胖中的關(guān)鍵作用[104]。此外，[78,105]突變導(dǎo)致乳腺癌及肝臟腫瘤、[4]通過調(diào)節(jié)TGF-β受體信號(hào)來控制對(duì)多種抗癌藥物的反應(yīng)、[106]在甲狀腺乳頭狀癌中表達(dá)下調(diào)、[107]在膀胱癌組織中的表達(dá)上調(diào)、[108]缺陷的自然殺傷細(xì)胞表現(xiàn)出抗腫瘤活性受損、[109]表達(dá)升高預(yù)示乳腺癌女性預(yù)后不佳、[110]在胰腺癌發(fā)展過程中具有致癌特性、的治療干預(yù)有益于結(jié)腸癌的臨床治療[111]。

3 Mediator的潛在治療作用

在臨床上轉(zhuǎn)錄激活因子的異常激活是導(dǎo)致很多疾病發(fā)生發(fā)展的重要原因，編碼Mediator亞基的基因表達(dá)水平變化與許多人類疾病有關(guān)[23,112]，因此，Mediator亞基可能被用作疾病治療靶點(diǎn)。由于Mediator的活性受含有CDK8、CycC、MED12和MED13的四亞單位激酶模塊的調(diào)節(jié)[2,113]，目前與Mediator相關(guān)的大部分疾病治療研究與激酶模塊相關(guān)[114]。

3.1 CDK8亞基與癌癥治療

Mediator的CDK8亞基位于激酶模塊，也代表了Mediator的唯一特征酶活性，顯示出與癌癥的強(qiáng)烈相關(guān)性，并且突變也被證實(shí)是重要的致癌基因[111,112]。目前大部分關(guān)于Mediator的治療作用的研究集中在通過對(duì)癌癥的治療。

CDK8亞基抑制劑：癌癥治療可以通過抑制Mediator中的完成。FDA批準(zhǔn)的索拉非尼(Sorafenib)是一種比較成熟的ATP競(jìng)爭(zhēng)性的II型抑制劑。高親和力結(jié)合CycC-CDK8，延長(zhǎng)了停留時(shí)間是體外化合物優(yōu)化和體內(nèi)藥效提高的關(guān)鍵成功因素[115]。除此之外，如選擇性ATP結(jié)合位點(diǎn)抑制劑Senexin A[116]、奶薊草的活性成分水飛薊素、漢黃芩、麥芽酮、TX522和TX527等化合物正在進(jìn)行開發(fā)或測(cè)試[117～120]。

干擾RNA (RNA interference, RNAi)療法：RNAi也被證實(shí)為癌癥的新治療方法提供了方案[121]。已有研究確定了一些對(duì)具有特異性的內(nèi)源性microRNAs，如和可靶向降解CDK8，與依賴的腫瘤發(fā)生有關(guān)[122,123]。因此，開發(fā)基于RNAi的針對(duì)異?；钚缘闹委熕幬锟赡芫哂信R床價(jià)值。

Mediator亞基間的連接阻斷：Mediator中激酶模塊各個(gè)亞基相互作用發(fā)揮功能，因此依賴于活性的亞基為抑制提供了替代靶點(diǎn)[114]。例如能夠特異性破壞依賴于CDK8活性的CycC-CDK8和MED12-CycC間的相互作用的化合物能提供較強(qiáng)的特異性抑制作用[124～126]。

3.2 Mediator與超級(jí)增強(qiáng)子

增強(qiáng)子結(jié)構(gòu)域由主要TF占據(jù)，并與編碼細(xì)胞特性關(guān)鍵調(diào)節(jié)因子的基因相關(guān)，包括許多致癌基因在內(nèi)的細(xì)胞身份關(guān)鍵決定基因的表達(dá)均受超級(jí)增強(qiáng)子的調(diào)控。超級(jí)增強(qiáng)子是緊密排列的增強(qiáng)子的集合，可以共同促進(jìn)相鄰基因的高水平轉(zhuǎn)錄。有研究表明，在多發(fā)性骨髓瘤細(xì)胞中有3%的增強(qiáng)子非常大，并且被大量的BRD4和Mediator占據(jù)。這些超級(jí)增強(qiáng)子通常比普通的增強(qiáng)子大一個(gè)數(shù)量級(jí)，并且含有的與增強(qiáng)子(H3K27Ac)相關(guān)的BRD4、Mediator和組蛋白標(biāo)記也比普通的增強(qiáng)子多一個(gè)數(shù)量級(jí)[127]。另外，在小細(xì)胞肺癌和多形性膠質(zhì)母細(xì)胞瘤中也同樣發(fā)現(xiàn)了具有相似特征的超級(jí)增強(qiáng)子，它們跨越大的基因組區(qū)域并包含大量的Mediator和BRD4[127]。

事實(shí)上，超級(jí)增強(qiáng)子并不局限于腫瘤細(xì)胞，并且已經(jīng)在其他幾種細(xì)胞類型中被鑒定出來，它們同樣與關(guān)鍵細(xì)胞識(shí)別基因相關(guān)[128]。腫瘤細(xì)胞依賴于致癌基因的高水平表達(dá)[129～131]，所以優(yōu)先破壞超增強(qiáng)子功能可能是選擇性抑制許多腫瘤細(xì)胞的致癌驅(qū)動(dòng)因素的方法。因此，有研究人員提出，通過破壞超級(jí)增強(qiáng)子來選擇性的抑制致病基因表達(dá)可能作為開發(fā)疾病治療藥物的一種策略[128,132]。

3.3 Mediator與心血管疾病治療可行性

在Mediator與心血管疾病治療方面，有研究證實(shí)甲狀腺功能減退小鼠的心臟中過表達(dá)可以在一定程度上緩解心臟損傷[61]。除過表達(dá)導(dǎo)致的小鼠進(jìn)行性擴(kuò)張型心肌病、心力衰竭外，目前已報(bào)道的大多數(shù)與Mediator相關(guān)的心臟疾病均與Mediator亞基缺失或突變相關(guān)，并不適應(yīng)于上述降低Mediator亞基表達(dá)或抑制其活性的治療方法。針對(duì)這種基因缺失或突變的心臟疾病，已有研究者提出CRISPR/Cas9介導(dǎo)的替換或矯正突變基因的基因治療方案，利用同源重組(homologous recombination, HDR)修復(fù)突變基因[133,134]，研究者使用腺相關(guān)病毒等工具將CRISPR/Cas9系統(tǒng)和功能性DNA模板(例如基因)遞送到組織細(xì)胞中。當(dāng)CRISPR/Cas9切割特定的基因組序列時(shí)，細(xì)胞會(huì)以導(dǎo)入的DNA序列為模板修復(fù)斷裂基因組DNA，同時(shí)將功能性DNA模板插入靶向基因組，用于替換或矯正突變基因。然而基于HDR的基因編輯效率非常低，尤其是HDR很可能只發(fā)生在分裂的細(xì)胞中[135]。因此，HDR的基因治療方法用于治療Mediator亞基缺失或突變相關(guān)的心臟疾病具有一定的局限性。鑒于Mediator是一個(gè)多亞基共同發(fā)揮作用的復(fù)合物，且與其靶基因的轉(zhuǎn)錄及其下游信號(hào)通路高度相關(guān)，有關(guān)Mediator亞基間的相互連接或協(xié)調(diào)作用也可能成為心血管疾病治療的重要研究方向。

4 結(jié)語(yǔ)與展望

本文主要闡述了Mediator及其部分亞基在基因轉(zhuǎn)錄調(diào)控中的關(guān)鍵作用，以及Mediator作為介導(dǎo)TF和基礎(chǔ)轉(zhuǎn)錄機(jī)器之間功能聯(lián)系的橋梁對(duì)心血管系統(tǒng)發(fā)育和疾病的影響。鑒于Mediator部分亞基的突變或缺失會(huì)影響Mediator核心的穩(wěn)定性[68]，且與Mediator亞基相關(guān)的基因表達(dá)水平變化與許多人類疾病密切相關(guān)[23,112]，Mediator部分亞基可作為一些疾病的治療靶點(diǎn)。但由于Mediator不具有組織特異性，且其調(diào)控基因轉(zhuǎn)錄表達(dá)的作用方式與傳統(tǒng)的藥物靶標(biāo)不同[136]，導(dǎo)致化學(xué)藥物等直接干預(yù)Mediator的手段相對(duì)有限[137]。因此，進(jìn)一步關(guān)于Mediator在轉(zhuǎn)錄調(diào)控相關(guān)的心血管發(fā)育和疾病中的研究還應(yīng)致力于探索針對(duì)Mediator參與轉(zhuǎn)錄調(diào)控具體機(jī)制的研究，包括TF與Mediator不同亞基的結(jié)合和下游基因啟動(dòng)子、增強(qiáng)子上表觀遺傳學(xué)修飾的改變等。

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Transcriptional regulation of transcriptional Mediator complexes in cardiovascular development and disease

Yuan Zhang1, Yuting Zhao1, Lenan Zhuang1,2,3, Jin He3

During the development of the mammalian cardiovascular system, the formation of a mature and fully functional cardiovascular system needs the fine coordination of the morphogenesis of various molecules, cells, tissues, and organs. Abnormalities in these processes usually lead to serious congenital heart defects. The determination and maintenance of cell fate in multicellular organisms depend to a large extent on the precise timing and control of RNA polymerase II (Pol II) transcription, and the transcription Mediator complex plays an irreplaceable role in the Pol II transcription process. Mediator is an evolutionarily conserved multi-subunit protein complex, including four parts: head, middle, tail, and kinase. It is a functional bridge between transcription factors and basic transcription machines. In recent years, due to the key role of Mediator in the transcriptional regulation of gene expression, many of human heart diseases have been confirmed to be related to specific Mediator gene mutations, such as heart valve defects, translocation of the great arteries, DiGeorge syndrome and some cardiovascular diseases related to energy homeostasis. In this review, we summarize the role of Mediator in cardiovascular development and disease, focusing on the role of Mediator in the development of cardiovascular disease, and provides a broad idea for the research on Mediator-related cardiovascular system development and diseases.

Mediator complex; transcriptional regulation; cardiovascular development; cardiovascular disease

2022-01-18;

2022-03-03;

2022-03-28

國(guó)家重點(diǎn)研發(fā)計(jì)劃(編號(hào)：2019YFE0117400, 2021YFA0805902)，國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：81941003)和中央高校基本科研業(yè)務(wù)費(fèi)專項(xiàng)基金(編號(hào)：2020XZZX002-20)資助[Supported by the National Key Research and Development Program (Nos. 2019YFE0117400, 2021YFA0805902), the National Natural Science Foundation of China (No. 81941003), and the Fundamental Research Funds for the Central Universities (No. 2020XZZX002-20)]

張?jiān)?，博士研究生，研究方向：轉(zhuǎn)錄調(diào)控。E-mail: zhangyuan2020@zju.edu.cn

莊樂南，博士，研究員，研究方向：表觀遺傳。E-mail: zhuangln@zju.edu.cn

賀津，博士，副教授，研究方向：家畜遺傳育種。E-mail: hejin@zju.edu.cn

10.16288/j.yczz.21-411

(責(zé)任編委: 劉峰)