張傲，岑山，李曉宇

綜 述

N-腺苷甲基化修飾及其對(duì)LINE-1的調(diào)控機(jī)制

張傲，岑山，李曉宇

中國醫(yī)學(xué)科學(xué)院&北京協(xié)和醫(yī)學(xué)院，醫(yī)藥生物技術(shù)研究所免疫生物學(xué)室，北京 100050

長(zhǎng)散布元件-1 (long interspersed elements-1，LINE-1)是現(xiàn)今在人類基因組中唯一具有自主轉(zhuǎn)座能力的轉(zhuǎn)座子，其轉(zhuǎn)座會(huì)引起細(xì)胞基因組結(jié)構(gòu)和功能的改變，是導(dǎo)致多種嚴(yán)重疾病的重要因素。在轉(zhuǎn)座過程中，LINE-1 mRNA是轉(zhuǎn)座中間體的核心，宿主細(xì)胞對(duì)其進(jìn)行相關(guān)修飾直接影響轉(zhuǎn)座。N-腺苷甲基化修飾(m6A)是真核細(xì)胞RNA上最豐富且動(dòng)態(tài)可逆的表觀遺傳修飾。目前發(fā)現(xiàn)m6A修飾也存在于LINE-1 mRNA上，參與LINE-1整個(gè)生命周期的調(diào)控，影響其轉(zhuǎn)座和基因組中LINE-1相鄰基因的表達(dá)，進(jìn)而影響基因組穩(wěn)定性、細(xì)胞自我更新與分化潛能，在人類發(fā)育和疾病中具有重要作用。本文介紹了LINE-1 m6A修飾的位置、功能以及相關(guān)機(jī)制，并總結(jié)了LINE-1的m6A修飾對(duì)其轉(zhuǎn)座調(diào)控的研究進(jìn)展，以期為相關(guān)疾病發(fā)生發(fā)展的機(jī)制研究和治療提供新的思路。

m6A修飾；逆轉(zhuǎn)錄轉(zhuǎn)座子；LINE-1；基因組；基因組穩(wěn)定性

長(zhǎng)散布元件(long interspersed elements，LINE-1)是一種非長(zhǎng)末端重復(fù)序列(non-long terminal repeats，non-LTR)逆轉(zhuǎn)錄轉(zhuǎn)座子。據(jù)統(tǒng)計(jì)大約45%的人類基因組衍生自轉(zhuǎn)座子(transposable elements，TEs)，其中LINE-1約占人基因組的17%，是目前人類基因組中唯一證實(shí)具有自主轉(zhuǎn)座活性的轉(zhuǎn)座子[1,2]。LINE-1以RNA為媒介進(jìn)行轉(zhuǎn)座，是一種RNA轉(zhuǎn)座子[3]，全長(zhǎng)約6 kb，其編碼的兩個(gè)蛋白ORF1蛋白(ORF1p)和ORF2蛋白(ORF2p)，在細(xì)胞質(zhì)中與LINE-1 mRNA形成核糖核蛋白復(fù)合物(ribonu-cleoprotein complexes，RNPs)，后利用ORF2p核酸內(nèi)切酶及逆轉(zhuǎn)錄酶活性，以LINE-1 mRNA為模板逆轉(zhuǎn)錄產(chǎn)生cDNA，形成RNA:DNA雜交體,該過程被稱為“靶點(diǎn)引導(dǎo)逆轉(zhuǎn)錄過程”(target-site primed reverse transcription，TPRT)[4,5]，是LINE-1復(fù)制的關(guān)鍵步驟。基因組中大多數(shù)LINE-1 5′ UTR區(qū)缺失或倒置，喪失轉(zhuǎn)座活性,僅80～100個(gè)LINE-1拷貝結(jié)構(gòu)完整，是具有逆轉(zhuǎn)座活性的LINE-1 (retrotransposition-competent LINE-1s，RC-L1s)。從物種進(jìn)化上來看，活躍的逆轉(zhuǎn)錄轉(zhuǎn)座子在生物進(jìn)化、物種形成和胚胎發(fā)育、記憶形成等方面發(fā)揮生理學(xué)作用[6,7]，但對(duì)個(gè)體而言，轉(zhuǎn)座的發(fā)生會(huì)對(duì)宿主細(xì)胞基因組的結(jié)構(gòu)和功能產(chǎn)生嚴(yán)重影響，LINE-1在基因組DNA中的插入、缺失和重組，會(huì)改變宿主基因的表達(dá)，導(dǎo)致衰老、癌癥、基因疾病、代謝性疾病、神經(jīng)退行性疾病和自身免疫性疾病等多種疾病的發(fā)生[8～11]。此外，LINE-1還可以協(xié)助不具有自主轉(zhuǎn)座能力的非LTR轉(zhuǎn)座子短散布元件(short interspersed elements，SINEs) Alu和加工后的假基因進(jìn)行轉(zhuǎn)座，進(jìn)而誘發(fā)疾病[12]。因此宿主對(duì)正常體細(xì)胞中LINE-1的表達(dá)與轉(zhuǎn)座活性是嚴(yán)格控制的，而且這種調(diào)控是多層次、多方面的，包括表觀遺傳修飾[13,14]、非編碼小RNA[15,16]以及多種宿主限制因子[17～19]等調(diào)控。

除研究較多的DNA、組蛋白甲基化外，N-甲基化腺嘌呤(N-methylated adenine，m6A)陸續(xù)在細(xì)菌DNA、細(xì)菌和酵母的RNA和哺乳動(dòng)物mRNA中被發(fā)現(xiàn)，m6A甲基化對(duì)RNA代謝和功能調(diào)控具有多樣性[20～23]。隨著對(duì)LINE-1轉(zhuǎn)座調(diào)控機(jī)制的深入研究，研究者們發(fā)現(xiàn)在LINE-1上存在的m6A修飾對(duì)其轉(zhuǎn)座調(diào)控也發(fā)揮著重要的作用。本文主要介紹m6A修飾的生物學(xué)功能，以及該修飾對(duì)LINE-1各階段的調(diào)控機(jī)制和LINE-1周圍染色質(zhì)狀態(tài)、基因表達(dá)的影響，以期對(duì)m6A修飾的生物學(xué)功能研究擴(kuò)展及宿主對(duì)LINE-1調(diào)控網(wǎng)絡(luò)的探究提供新的思路。

1 m6A修飾的生物學(xué)功能

m6A一般發(fā)生在RNA中腺苷酸的N位置上，是通過特定的甲基轉(zhuǎn)移酶進(jìn)行的甲基化修飾(圖1)，在mRNA和其他類型核內(nèi)RNA，如轉(zhuǎn)運(yùn)RNA (transfer RNA，tRNA)、核糖體RNA(ribosomal RNA，rRNA)、小核RNA(small nuclear RNA，snRNA)均有分布。m6A甲基化具有RRACH共同識(shí)別序列(其中R表示A或G，H表示A、C或U)，受多種調(diào)控因子調(diào)控，通過“編碼器”m6A甲基轉(zhuǎn)移酶裝配，并可被“讀碼器”m6A結(jié)合蛋白識(shí)別或被“消碼器”去甲基化酶移除[24,25]。m6A主要在終止密碼子和3′非翻譯區(qū)(3′UTR)附近富集，在內(nèi)含子和5′非翻譯區(qū)(5′UTR)也有低豐度的m6A。

m6A甲基化對(duì)RNA代謝過程的多個(gè)環(huán)節(jié)均具有重要的影響，包括RNA剪接[26,27]、核輸出[28]、降解[29,30]和翻譯[31,32]。在RNA剪接過程中，m6A被相應(yīng)蛋白識(shí)別并結(jié)合，通過招募YTHDC1蛋白、抑制剪接因子或改變RNA局部構(gòu)象來調(diào)節(jié)mRNA前體(pre-mRNA)選擇性剪接[26,27]。在核輸出過程中，m6A被YTHDC1蛋白識(shí)別，促進(jìn)RNA與核輸出組分的相互作用，調(diào)控mRNA的亞細(xì)胞定位[28]。m6A還可以被YTHDF2蛋白識(shí)別進(jìn)而降解m6A修飾的靶轉(zhuǎn)錄本[29,30]。此外，m6A對(duì)mRNA轉(zhuǎn)錄后調(diào)控也具有一定的作用，mRNA的翻譯方式與m6A在轉(zhuǎn)錄本的位置有關(guān)。正常生理?xiàng)l件下，m6A修飾主要位于RNA 的3′UTR區(qū)，被YTHDF1蛋白或YTHDF3蛋白識(shí)別，招募真核細(xì)胞翻譯起始因子eIF3，促進(jìn)帽依賴性翻譯[31,32]。而在應(yīng)激條件下，5′UTR區(qū)的m6A作為m6A誘導(dǎo)的核糖體進(jìn)入位點(diǎn)(m6A-induced ribosome engagement site，MIRES)，促進(jìn)mRNA進(jìn)行帽非依賴性翻譯，這種m6A介導(dǎo)的帽非依賴性翻譯同樣需要m6A“讀碼器”eIF3的識(shí)別[33]。另有研究表明，mRNA上的m6A可影響轉(zhuǎn)錄本與tRNAs的相互作用進(jìn)而抑制翻譯[34]。

圖1 腺苷酸甲基化修飾結(jié)構(gòu)示意圖

RNA腺苷酸N位置的甲基化修飾通過m6A甲基轉(zhuǎn)移酶裝配，被m6A結(jié)合蛋白識(shí)別或被去甲基化酶移除。

m6A還參與哺乳動(dòng)物多種病理生理學(xué)過程，包括胚胎發(fā)育[35]、神經(jīng)發(fā)生[36]、晝夜節(jié)律[37]、應(yīng)激反應(yīng)[38]、腫瘤發(fā)生[24,39]和病毒感染[40]等。隨著m6A甲基化組學(xué)分析的發(fā)展，m6A在腫瘤發(fā)生發(fā)展的相關(guān)機(jī)制研究取得了主要突破。RNA m6A甲基化水平改變影響細(xì)胞的增殖、分化與自我更新[41]。m6A是腫瘤代謝的重要調(diào)節(jié)因子，腫瘤代謝應(yīng)激反應(yīng)可導(dǎo)致異常的m6A甲基化，調(diào)節(jié)代謝重組相關(guān)的信號(hào)通路、轉(zhuǎn)錄因子和代謝酶[42]。目前已有多項(xiàng)研究發(fā)現(xiàn)，m6A修飾異常與多種癌癥的發(fā)生發(fā)展相關(guān)，不同底物的m6A修飾會(huì)促進(jìn)或抑制腫瘤的發(fā)展，具有促癌和抑癌的雙重作用，是一把雙刃劍[24]。機(jī)體對(duì)LINE-1的調(diào)控影響基因組穩(wěn)定性，含有m6A修飾的LINE-1 mRNA具有宿主逃逸機(jī)制，被正向選擇并表達(dá)，從而促進(jìn)疾病的發(fā)生發(fā)展。研究發(fā)現(xiàn)，是口腔鱗狀細(xì)胞癌(oral squamous cell carcinoma，OSCC)的原癌基因，其編碼的HNRNPA2B1蛋白可能作為m6A“讀碼器”促進(jìn)LINE-1 mRNA翻譯，進(jìn)而通過LINE-1/TGF-β1/Smad2/Slug信號(hào)通路靶向上皮細(xì)胞-間充質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition，EMT)，促進(jìn)腫瘤細(xì)胞增殖、遷移和侵襲[43]。這提示m6A修飾的LINE-1可能與多種癌癥致病機(jī)制均相關(guān)，為癌癥預(yù)防及治療提供了新的思路。根據(jù)m6A修飾的不同位置，將其分為4個(gè)部分：具有轉(zhuǎn)座活性的LINE-1 5′ UTR、位于宿主基因內(nèi)含子區(qū)域和形成R-環(huán)的LINE-1的m6A修飾，以及LINE-1 DNA的6mA修飾(圖2A)。近年來，研究人員發(fā)現(xiàn)m6A對(duì)LINE-1的整個(gè)復(fù)制周期均有調(diào)控作用，“編碼器”對(duì)各階段LINE-1進(jìn)行m6A修飾，該修飾被“讀碼器”識(shí)別，或被“消碼器”移除，影響LINE-1的轉(zhuǎn)座活性及轉(zhuǎn)錄與翻譯水平(圖2B)。

2 m6A修飾在LINE-1復(fù)制周期不同階段的調(diào)控機(jī)制

2.1 具有轉(zhuǎn)座活性的LINE-1 5′ UTR的m6A修飾

最新的一項(xiàng)研究表明，LINE-1轉(zhuǎn)錄本是人類細(xì)胞中主要的m6A修飾RNA。與DNA和一些組蛋白甲基化的抑制作用相反，如組蛋白H3K9me3，RC-L1s的RNA m6A修飾可促進(jìn)其表達(dá)與轉(zhuǎn)座。m6A偏向于修飾年輕的LINE-1，這些LINE-1結(jié)構(gòu)完整，并具有豐富的RRACH序列。除了帽依賴性翻譯外，m6A還啟動(dòng)LINE-1 RNA帽非依賴性翻譯。該研究發(fā)現(xiàn)，在LINE-1 5′ UTR第333位發(fā)生m6A獲得性突變后，形成m6A共識(shí)別序列，使得第332位腺苷上發(fā)生m6A修飾，eIF3識(shí)別該修飾位點(diǎn)后，提高ORF1的翻譯速率，刺激ORF2p合成，產(chǎn)生具有逆轉(zhuǎn)錄活性的LINE-1 核糖核蛋白R(shí)NP，促進(jìn)LINE-1逆轉(zhuǎn)錄轉(zhuǎn)座[44,45]。LINE-1的5′ UTR m6A修飾是其產(chǎn)生逆轉(zhuǎn)錄轉(zhuǎn)座功能所必需的，只有具有完整5′ UTR，m6A修飾相關(guān)酶才可調(diào)控LINE-1的表達(dá)[46]。此外，m6A修飾可以改變RNA-蛋白相互作用或RNA二級(jí)結(jié)構(gòu)，這可能影響LINE-1 ORF2p的酶活性[45]。目前已發(fā)現(xiàn)，m6A甲基化酶METTL3使LINE-1 m6A水平升高，促進(jìn)其逆轉(zhuǎn)座[45]。相反，m6A去甲基化酶ALKBH5使LINE-1 m6A水平降低，抑制其逆轉(zhuǎn)座[45]。m6A甲基化酶METTL14和ZC3H13或其識(shí)別蛋白YTHDC1缺失將降低宿主中m6A標(biāo)記的年輕LINE-1的水平[46]。雖然m6A修飾提高LINE-1 RNA的翻譯效率，但不改變LINE-1 RNA在細(xì)胞內(nèi)定位[45]。此外，m6A僅對(duì)年輕LINE-1的表達(dá)和逆轉(zhuǎn)座活性有促進(jìn)作用，在較老或低甲基化的LINE-1中有抑制作用，當(dāng)m6A識(shí)別蛋白缺陷時(shí)，古老的LINE-1轉(zhuǎn)座活性反而增加[46]。

2.2 基因內(nèi)含子中無轉(zhuǎn)座活性的 LINE-1 的m6A修飾

基因組中多數(shù)LINE-1 5′ UTR區(qū)域缺失或突變，失去逆轉(zhuǎn)座活性。研究發(fā)現(xiàn)，基因內(nèi)含子中經(jīng)m6A修飾后的無逆轉(zhuǎn)座活性的LINE-1 (m6A-marked intronic LINE-1s，MILs)是一種新的調(diào)控元件，優(yōu)先駐留在長(zhǎng)基因中，作為轉(zhuǎn)錄“障礙”阻礙宿主基因的表達(dá)，但具體機(jī)制尚不清楚[46]。這些長(zhǎng)基因在DNA損傷修復(fù)(DNA damage repair，DDR)等生理過程中發(fā)揮關(guān)鍵作用。研究發(fā)現(xiàn)，m6A識(shí)別蛋白SAFB/SAFB2復(fù)合體以m6A增強(qiáng)的方式結(jié)合RC-L1s和MILs RNA來抑制其表達(dá)[46]。此外，SAFB/SAFB2還可糾正MILs對(duì)重要宿主基因的轉(zhuǎn)錄阻斷作用，以保護(hù)宿主基因的轉(zhuǎn)錄，但SAFB并不與m6A發(fā)生特異性結(jié)合，可能通過m6A改變局部RNA結(jié)構(gòu)以實(shí)現(xiàn)RNA-RBP (RNA結(jié)合蛋白)相互作用(即“m6A開關(guān)”)，形成的LINE-1 RNA高級(jí)結(jié)構(gòu)允許更強(qiáng)的L1-SAFB結(jié)合[46]。MILs通過影響長(zhǎng)基因轉(zhuǎn)錄，使m6A調(diào)節(jié)的L1-宿主相互作用在基因調(diào)控、基因組完整性、人類發(fā)育和疾病中發(fā)揮廣泛作用[46,47]。

圖2 m6A修飾對(duì)LINE-1的影響

A：LINE-1的結(jié)構(gòu)。LINE-1由開放閱讀框ORF0、ORF1、ORF2和非編碼區(qū)5′UTR、3′UTR構(gòu)成，5′UTR 有兩個(gè)啟動(dòng)子，是雙向的：正義啟動(dòng)子活性可轉(zhuǎn)錄 ORF1、ORF2，反義啟動(dòng)子(ASP)能夠啟動(dòng)與LINE-1方向相反的轉(zhuǎn)錄物轉(zhuǎn)錄。B：m6A修飾酶影響LINE-1復(fù)制周期模式圖。①LINE-1 DNA可能富集6mA甲基化修飾，抑制mRNA轉(zhuǎn)錄；②LINE-1 mRNA與ORF1p、ORF2p結(jié)合生成LINE-1 RNP復(fù)合物，入核后進(jìn)行“TPRT”生成cDNA，插入宿主基因組；③在細(xì)胞質(zhì)中，翻譯起始因子eIF3與m6A特異性相互作用，提高翻譯水平；④METTL3、YTHDC1促進(jìn)LINE-1逆轉(zhuǎn)座，ALKBH5、SAFB/SAFB2抑制LINE-1逆轉(zhuǎn)座；⑤SAFB/SAFB2可糾正MILs對(duì)重要宿主基因的轉(zhuǎn)錄阻斷。

2.3 LINE-1 RNA:DNA雜交分子(R-環(huán))的m6A修飾

R-環(huán)普遍存在于高轉(zhuǎn)錄基因中，并在重復(fù)序列中積累，其中包括逆轉(zhuǎn)錄轉(zhuǎn)座子LINE-1[48]。LINE-1逆轉(zhuǎn)錄轉(zhuǎn)座過程中，RNP剪切基因組DNA雙鏈，形成由LINE-1 RNA:DNA雜交分子和未配對(duì)單鏈DNA組成的R-環(huán)，R環(huán)在細(xì)胞分裂S期達(dá)到頂峰，參與了從轉(zhuǎn)錄調(diào)控到DNA修復(fù)等諸多重要生物學(xué)過程[49]。Abakir等[50]發(fā)現(xiàn)，在人多能性干細(xì)胞(human pluripotent stem cells，hPSCs)RNA:DNA雜交體中有大量m6A修飾，m6A修飾存在于RNA:DNA雜交體的RNA鏈上，含有m6A的R環(huán)在細(xì)胞周期G2/M期積累，在G0/G1期耗盡。在正常生理?xiàng)l件下，R-環(huán)在基因啟動(dòng)子區(qū)和終止區(qū)富集，參與mRNA轉(zhuǎn)錄起始和終止，調(diào)控基因表達(dá)。當(dāng)R-環(huán)沒有被正常分解時(shí)，其積累會(huì)導(dǎo)致DNA損傷和/或復(fù)制叉停滯，破壞基因組的穩(wěn)定性[51～53]。m6A修飾可調(diào)控R環(huán)的積累，不同的m6A結(jié)合蛋白識(shí)別R環(huán)，維持基因組的穩(wěn)定性。目前已發(fā)現(xiàn)甲基轉(zhuǎn)移酶METTL3、識(shí)別蛋白HNRNPA2B1、促進(jìn)mRNA翻譯的YTHDF1以及促進(jìn)mRNA降解的YTHDF2均與富集R環(huán)的位點(diǎn)相互作用[50]。已有研究表明，YTHDF2可阻止含有m6A的LINE-1 RNA:DNA雜交體積累，有助于修復(fù)哺乳動(dòng)物中R-環(huán)依賴性DNA損傷，維護(hù)基因組穩(wěn)定性[50]。

2.4 LINE-1 DNA的6mA修飾

DNAN-甲基化腺嘌呤(6mA)修飾在原核生物中廣泛分布，而在哺乳動(dòng)物細(xì)胞中豐度極低[54,55]。早期研究人員利用SMRT-ChIP在小鼠胚胎干細(xì)胞(mouse embryonic stem cells，mESCs)中發(fā)現(xiàn)6mA修飾，證明6mA修飾與LINE-1轉(zhuǎn)座子的進(jìn)化年齡呈負(fù)相關(guān)，在年輕、完整的LINE-1元件中強(qiáng)烈富集。與LINE-1 RNA的m6A甲基化沉積位置相似，6mA大多數(shù)富集在年輕全長(zhǎng)LINE-1的5′ UTR和ORF1上。在6mA去甲基化酶ALKBH1缺陷的細(xì)胞中，DNA 6mA水平增加導(dǎo)致轉(zhuǎn)錄沉默。6mA修飾與LINE-1轉(zhuǎn)座子及其鄰近增強(qiáng)子和基因的表觀遺傳沉默相關(guān)，在胚胎干細(xì)胞分化過程中抵抗基因激活信號(hào)[56]。與其他常染色體相比，較年輕的全長(zhǎng)LINE-1在X染色體上強(qiáng)烈富集，經(jīng)6mA修飾后沉默位于X染色體上的基因[56,57]。不同于6mA在其他生物基因中的激活作用，它在哺乳動(dòng)物進(jìn)化中表現(xiàn)出表觀遺傳沉默的新作用。然而，該研究結(jié)果存在很大爭(zhēng)議，其他研究者對(duì)真核生物中DNA 6mA的存在表示懷疑，認(rèn)為已有方法受污染源的影響容易產(chǎn)生假陽性結(jié)果。故作者使用6mASCOPE方法對(duì)6mA定量去卷積，結(jié)果排除非特異性偏倚后，不支持HEK293中年輕LINE-1具有6mA富集特點(diǎn)[54]。但這項(xiàng)研究仍存在局限性，需要進(jìn)一步優(yōu)化檢測(cè)方法。

3 LINE-1的m6A修飾對(duì)染色質(zhì)狀態(tài)和基因表達(dá)的調(diào)控

LINE-1上修飾的m6A不僅調(diào)控其自身的復(fù)制過程，對(duì)其相鄰基因的表觀遺傳調(diào)控、塑造基因組結(jié)構(gòu)和維持基因組穩(wěn)定性方面也具有廣泛的作用。染色體相關(guān)調(diào)控RNA (chromat-in-associated regulatory RNAs，carRNAs)上的m6A修飾可以全局調(diào)控染色質(zhì)狀態(tài)和轉(zhuǎn)錄，依賴于METTL3甲基化的carRNAs包括啟動(dòng)子相關(guān)RNA、增強(qiáng)子RNA和重復(fù)序列RNA(如LINE-1)。carRNAs m6A修飾可以維持基因間區(qū)域染色質(zhì)濃縮，而YTHDC1識(shí)別m6A后，通過核外泌體靶向(nuclear exosome targeting，NEXT)復(fù)合物促進(jìn)carRNAs降解。m6A甲基化缺失導(dǎo)致染色質(zhì)開放和轉(zhuǎn)錄本富集，這與活性組蛋白H3K4me3和H3K27ac修飾增加相關(guān)，后續(xù)招募表觀遺傳因子如組蛋白乙酰轉(zhuǎn)移酶(EP-300)來維持開放的染色質(zhì)構(gòu)象和下游轉(zhuǎn)錄。此外，carRNAs中“重復(fù)序列RNA”在m6A高甲基化和轉(zhuǎn)錄下調(diào)之間表現(xiàn)出強(qiáng)相關(guān)性，其中LINE-1受影響最大，影響細(xì)胞自我更新和分化潛能[58～60]。

另有研究發(fā)現(xiàn)，識(shí)別蛋白YTHDC1通過多種機(jī)制參與逆轉(zhuǎn)錄轉(zhuǎn)座子的調(diào)控和染色質(zhì)修飾。在mESCs中，YTHDC1與m6A修飾的LINE-1轉(zhuǎn)錄本結(jié)合，募集組蛋白甲基轉(zhuǎn)移酶SETDB1、TRIM28和核仁素(nucleolin，NCL)，共同形成沉默復(fù)合物，促進(jìn)H3K9me3的富集，沉默逆轉(zhuǎn)錄轉(zhuǎn)座子[59,60]。此外，YTHDC1識(shí)別細(xì)胞核中LINE-1 RNA上的m6A，招募轉(zhuǎn)錄調(diào)控因子KAP1，并調(diào)控LINE1-NCL復(fù)合物的形成和KAP1在染色質(zhì)上的募集，形成LINE1-NCL-KAP1復(fù)合物，抑制2細(xì)胞期(two-cell stage，2C)胚胎特異性轉(zhuǎn)錄的主要激活因子Dux，關(guān)閉2C基因表達(dá)程序。同時(shí)，LINE1-NCL-KAP1復(fù)合物可與核糖體DNA(rDNA)結(jié)合，促進(jìn)rRNA合成和mESCs自我更新[59,61]。KAP1在LINE-1上的富集同樣也促進(jìn)H3K9me3沉積，導(dǎo)致在mESCs和內(nèi)細(xì)胞團(tuán)(ICM)細(xì)胞中組蛋白修飾位點(diǎn)的轉(zhuǎn)錄沉默，降低染色質(zhì)開放狀態(tài)，有助于識(shí)別mESCs并促進(jìn)胚胎發(fā)育，調(diào)節(jié)mESCs從2C樣狀態(tài)退出[62]。另一項(xiàng)研究發(fā)現(xiàn)，在mESCs中發(fā)現(xiàn)肥胖蛋白FTO是LINE-1 m6A去甲基化酶，促進(jìn)LINE-1相鄰基因位點(diǎn)的染色質(zhì)開放。FTO與LINE-1 RNA和LINE-1 RNA-DNA相互作用的消失導(dǎo)致染色質(zhì)濃縮、抑制性組蛋白標(biāo)記富集，順式調(diào)控相鄰基因，降低相鄰基因表達(dá)。有趣的是，與YTHDC1作用相反，F(xiàn)TO敲除后，LINE-1 RNA反式調(diào)節(jié)不相鄰的2C基因，使2C基因去抑制，導(dǎo)致類似2C狀態(tài)發(fā)生和mESCs狀態(tài)丟失，使得多功能性基因的表達(dá)減少，細(xì)胞分化和自我更新受損，因此FTO-LINE-1軸對(duì)于胚胎發(fā)育是必不可少的[63,64]。

4 結(jié)語與展望

m6A修飾對(duì)LINE-1的調(diào)控機(jī)制目前正在深入研究中，一些問題仍需要進(jìn)一步探究闡述，如LINE-1 RNA上的m6A被YTHDC1識(shí)別后促進(jìn)抑制性組蛋白富集，抑制基因表達(dá)。但另有研究發(fā)現(xiàn)，m6A“讀碼器”YTHDC1協(xié)同轉(zhuǎn)錄使組蛋白H3K9me2去甲基化，促進(jìn)基因表達(dá)[65]。多種表觀遺傳信號(hào)共同調(diào)節(jié)基因的表達(dá)，故仍需進(jìn)一步探究LINE-1不同表觀轉(zhuǎn)錄組修飾間的相互影響，以及與染色質(zhì)修飾的相互作用關(guān)系。此外，LINE-1 DNA 6mA是否具有顯著性富集特點(diǎn)也有待進(jìn)一步探討。若LINE-1 DNA 上6mA修飾富集且抑制其活性，而LINE-1 RNA m6A修飾促進(jìn)其轉(zhuǎn)座，那么兩者是否在發(fā)育或疾病中相互干擾，以及如何介導(dǎo)LINE-1活性或宿主基因表達(dá)，是未來研究的重要內(nèi)容。此外，LINE-1 m6A修飾調(diào)控組蛋白修飾，阻止染色質(zhì)開放狀態(tài)及相鄰基因的表達(dá)。但由不同m6A相關(guān)酶介導(dǎo)調(diào)控的2C基因表達(dá)作用相反，出現(xiàn)這種差異是由于m6A調(diào)控相關(guān)蛋白具有特異性還是其他調(diào)控系統(tǒng)參與其中仍不可知。另外，值得注意的是，m6A對(duì)不同的逆轉(zhuǎn)錄轉(zhuǎn)座子家族具有截然相反的影響：YTHDC1識(shí)別某些TEs上m6A修飾后破壞其穩(wěn)定性，如IAPs[60]；m6A通過招募YTHDF家族縮短IAP mRNA半衰期[66]。這表明在TEs可能發(fā)生了額外的依賴于m6A的調(diào)控，如依賴于其他m6A甲基轉(zhuǎn)移酶(METTL5、METTL16和ZCCHC4)或識(shí)別結(jié)合蛋白的活性，這些蛋白可以通過翻譯后修飾或與其他分子相互作用進(jìn)行調(diào)控[60]。隨著高通量測(cè)序等新技術(shù)的發(fā)展，研究人員對(duì)m6A的研究有望發(fā)現(xiàn)新的生物調(diào)節(jié)系統(tǒng)，LINE-1的m6A修飾也有望成為未來疾病治療與診斷的新靶點(diǎn)。

在腫瘤疾病研究方面，LINE-1可作為診斷癌癥的生物標(biāo)志物和潛在的治療靶點(diǎn)[67]。其中，LINE-1 DNA或組蛋白的大量低甲基化，被認(rèn)為是大多數(shù)惡性轉(zhuǎn)化的標(biāo)志，是一種很有前途的癌癥發(fā)展的候選生物標(biāo)志物[8]。而LINE-1雖通常被認(rèn)為具有促癌功能，但在急性髓系粒細(xì)胞白血病(AML)中發(fā)揮抑癌作用[68]。這是宿主不同調(diào)控機(jī)制的作用結(jié)果。LINE-1 m6A甲基化修飾研究的突破性進(jìn)展或許將有助于解開LINE-1相關(guān)疾病研究的許多未解之謎。

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N-adenosine methylation and the regulatory mechanism on LINE-1

Ao Zhang, Shan Cen, Xiaoyu Li

Long interspersed elements-1(LINE-1) is the only autonomous transposon in human genome，and its retrotransposition results in change of cellular genome structure and function, leading occurrence of various severe diseases. As a central key intermediated component during life cycle of LINE-1 retrotransposition, the host modification of LINE-1 mRNA affects the LINE-1 transposition directly.N-adenosine methylation(m6A), the most abundant epigenetic modification on eukaryotic RNA, is dynamically reversible. m6A modification is also found on LINE-1 mRNA, and it participants regulation of the whole LINE-1 replication cycle, with affecting LINE-1 retrotransposition as well as its adjacent genes expression, followed by influencing genomic stability, cellular self-renewal, and differentiation potential, which plays important roles in human development and diseases. In this review, we summarize the research progress in LINE-1 m6A modification, including its modification positions, patterns and related mechanisms, hoping to provide a new sight on the mechanism research and treatment of related diseases.

m6A modification; retrotransposon; LINE-1; genome; genome stability

2023-11-10;

2023-12-28;

2024-01-19

國家自然科學(xué)基金面上項(xiàng)目(編號(hào)：31870164)資助[Supported by the National Natural Science Foundation of China (No.31870164)]

張傲，碩士研究生，專業(yè)方向：LINE-1與腫瘤維持機(jī)制的研究。E-mail: za1632649341@163.com

岑山，博士，研究員，研究方向：病毒學(xué)。E-mail: shancen@hotmail.com

李曉宇，博士，研究員，研究方向：病毒學(xué)。E-mail: xiaoyulik@hotmail.com

10.16288/j.yczz.23-248

(責(zé)任編委: 宋旭)