曲卉，柳毅，陳雅文，汪暉,2

綜 述

環(huán)境因素所致印跡基因改變與子代器官發(fā)育

曲卉1，柳毅1，陳雅文1，汪暉1,2

1. 武漢大學(xué)基礎(chǔ)醫(yī)學(xué)院藥理學(xué)系，武漢 430071 2. 發(fā)育源性疾病湖北省重點實驗室，武漢 430071

印跡基因是由大約100個基因組成的一類特殊子集，主要以親本單等位基因的方式表達(dá)，對胚胎的生長發(fā)育具有重要作用。近年來發(fā)現(xiàn)，環(huán)境因素所引起的印跡基因表觀遺傳修飾改變可造成胎兒多臟器發(fā)育不良甚至成年后多疾病易感，且存在多代遺傳效應(yīng)。本文基于國內(nèi)外最新研究進(jìn)展，總結(jié)了印跡基因表達(dá)改變對個體發(fā)育階段以及生命后期器官功能的影響，提出環(huán)境有害因素所致印跡基因表觀遺傳修飾及表達(dá)異常是子代多器官發(fā)育不良的重要發(fā)生機制，這對于理解個體發(fā)育過程中印跡基因表達(dá)改變所引起的表型改變及探尋疾病早期防治策略具有重要意義。

印跡基因；環(huán)境因素；印跡基因的調(diào)控機制；表觀遺傳修飾；器官發(fā)育

印跡基因(imprinted gene)是一類主要以親本單等位基因方式表達(dá)的基因，其表達(dá)受到表觀遺傳的精密調(diào)控。由于印跡基因高度參與胎兒的生長發(fā)育，且在受精后發(fā)生的全基因組去甲基化過程中某些表觀遺傳修飾會保留并傳遞給子代，因此印跡基因的異常表觀遺傳修飾及表達(dá)改變可導(dǎo)致子代多疾病易感[1]。研究表明，在配子和胚胎發(fā)育過程中，多種環(huán)境因素如酒精、香煙、親代應(yīng)激等通過改變印跡基因表達(dá)來影響胚胎生長發(fā)育和能量平衡，導(dǎo)致其成年后代謝性疾病易感及發(fā)生[2]，并且該過程可能與表觀遺傳修飾異常有關(guān)[3]。本文結(jié)合近年來的國內(nèi)外研究進(jìn)展，對環(huán)境因素所致印跡基因改變與個體多器官發(fā)育及其調(diào)控機制進(jìn)行綜述，有助于理解表觀基因組、基因組和環(huán)境之間的相互作用，為發(fā)育早期采取新的干預(yù)治療提供思路。

1 印跡基因定義、功能及作用機制

1.1 印跡基因定義、分類及功能

印跡基因是一類以基因簇形式存在的特殊基因，每個簇內(nèi)通常包含1個印跡控制區(qū)域(imprinting control region, ICR)。該ICR的甲基化印跡狀態(tài)只在胚胎的一條親源染色體上維持，并且能夠調(diào)控整個結(jié)構(gòu)域內(nèi)多個印跡基因的表達(dá)。印跡基因分為父源性和母源性印跡基因。父源性印跡基因是指父源性等位基因位點帶有印跡，如胰島素樣生長因子2(insulin-like growth factor 2,)和等，其功能為促進(jìn)胎兒生長，最大化地利用母體資源。母源性印跡基因則相反，如和等，其功能為控制胎兒生長，以節(jié)省對母體資源的需求[4]。除直接調(diào)節(jié)胎兒生長發(fā)育外，印跡基因還可以通過調(diào)節(jié)胎盤的內(nèi)分泌和運輸功能，間接地促進(jìn)胎兒的生長[5,6]。

1.2 印跡基因發(fā)生、維持和消除

來源于不同親本的印跡基因在個體發(fā)育過程中承擔(dān)著不同的重要功能。印跡基因通過建立、維持和消除基因組印記，參與調(diào)控個體的發(fā)育過程。印跡基因的表達(dá)與親本等位基因的DNA甲基化印記有關(guān)。親本印記的建立需要生殖細(xì)胞首先刪除父母表觀基因組的DNA甲基化標(biāo)記，進(jìn)一步于子代配子形成期間以等位基因特異性方式重建DNA甲基化印記[7,8]。這個DNA甲基化的動態(tài)過程包括發(fā)生、維持和消除三個部分。在原始生殖細(xì)胞(primordial germ cells, PGCs)形成時期，細(xì)胞發(fā)生DNA去甲基化，以擦除親本表觀遺傳“記憶”[9]。進(jìn)一步，PGCs發(fā)育至成熟配子，重新建立起DNA甲基化印記。受精后，DNA甲基化印記會在整個胚胎發(fā)育時期和生命后期得以維持[10]。然而，在發(fā)育胚胎的PGCs中，先前建立的DNA甲基化印記再次被擦除，以在配子形成的階段重新建立新的印記，從而完成印跡周期(圖1)。這種循環(huán)的甲基化和去甲基化過程，將有助于細(xì)胞特性的建立、維持和動態(tài)變化，以保證所形成的印記在體細(xì)胞分裂過程中能穩(wěn)定遺傳，進(jìn)而使得胚胎可以正常發(fā)育。

2 影響印跡基因表達(dá)的環(huán)境因素

已知印跡的建立、維持和擦除發(fā)生在受精和胚胎發(fā)育早期[11]，在這一過程中表觀基因組易受到環(huán)境因素的影響，導(dǎo)致印跡基因的表達(dá)改變。環(huán)境因素主要包括外源性因素(如化學(xué)因素、物理因素、生物因素等)和親代因素(如應(yīng)激、疾病狀況等)。

圖1 印跡基因發(fā)生、維持和消除

隨著生活水平的日益提高，酒精、香煙、咖啡因等物質(zhì)已經(jīng)成為大多數(shù)男性和女性日常生活中不可或缺的一部分。然而，有證據(jù)表明，親代接觸酒精、香煙以及咖啡等環(huán)境有害因素會導(dǎo)致子代發(fā)育等遠(yuǎn)期危害[12,13]。臨床研究和動物模型顯示，親代暴露于多種外源性因素，如化學(xué)因素(如酒精、尼古丁等)、物理因素(如電離輻射等)、生物因素(如細(xì)菌、真菌等)，印跡基因的表觀遺傳調(diào)控方式會發(fā)生改變，使其表達(dá)持續(xù)改變。而這些改變往往可導(dǎo)致子代發(fā)育異常，如宮內(nèi)發(fā)育遲緩(intrauterine growth retardation, IUGR)、早期代謝缺陷、大腦神經(jīng)發(fā)育障礙等[14～16]。同時，隨著輔助生殖技術(shù)(assisted reproductive technology, ART)的快速發(fā)展，其安全性也成為社會關(guān)注的問題之一。由于ART發(fā)生在雌雄配子結(jié)合期間和受精后，在這一過程中胚胎冷凍解凍、體外培養(yǎng)、胚胎移植等因素可能會誘導(dǎo)胚胎DNA甲基化印記建立和維持的異常[17]，從而增加了不良妊娠結(jié)局和出生后成年疾病發(fā)生的風(fēng)險。既往研究表明，ART可導(dǎo)致早產(chǎn)、低出生體重等不良妊娠結(jié)局的發(fā)生[18,19]，并與成年后心血管疾病和代謝性疾病的發(fā)生密切相關(guān)[20,21]。

親代的疾病狀況也是影響胎兒發(fā)育的關(guān)鍵因素。生物體的代謝狀態(tài)可以直接影響表觀遺傳修飾[22]。例如，父體體重指數(shù)與其精子、胎兒臍帶血中DNA甲基化水平之間存在顯著的相關(guān)性。親代肥胖可能通過影響生殖細(xì)胞中印跡基因的表觀遺傳修飾，造成胎兒表觀基因組改變，從而影響胎兒的發(fā)育進(jìn)程[23]。應(yīng)激是指各種緊張性刺激物引起個體產(chǎn)生非特異性反應(yīng)，導(dǎo)致體內(nèi)生理或心理平衡失調(diào)的長期過程。親代應(yīng)激是改變胎兒表觀遺傳標(biāo)記從而造成胎兒發(fā)育不良的另一重要誘因[24]。研究表明，孕婦產(chǎn)前抑郁癥會導(dǎo)致胎盤印跡基因的表達(dá)改變，從而介導(dǎo)胎盤功能受損，最終導(dǎo)致胎兒生長受限和神經(jīng)發(fā)育不良[25]。在父體中也存在類似的現(xiàn)象[26]。其發(fā)生機制可能與親代下丘腦–垂體–腎上腺軸功能改變及血糖皮質(zhì)激素水平升高誘導(dǎo)的生殖細(xì)胞發(fā)生過程中甲基供體或甲基化酶、去甲基化酶表達(dá)改變，從而間接影響胎兒表觀基因組有關(guān)[27]。因此，親代因素也被認(rèn)為是調(diào)控印跡基因的表觀遺傳修飾，最終影響子代發(fā)育的重要因素之一(表1)。

3 環(huán)境因素所致印跡基因改變與器官發(fā)育

印跡基因在胎盤和胎兒多器官發(fā)育過程中扮演著重要的角色。越來越多的證據(jù)表明，在發(fā)育早期階段，環(huán)境因素易影響印跡基因的表觀遺傳修飾及表達(dá)，進(jìn)而編程子代多種器官發(fā)育及成年后多疾病易感。這種基因組印記對發(fā)育過程具有長期的、決定性的影響，因此探尋環(huán)境因素所致印跡基因改變及其調(diào)控機制對闡明機體發(fā)育編程改變及疾病發(fā)生至關(guān)重要。

表1 影響印跡基因表達(dá)的因素

TCDD：2,3,7,8-四氯苯并-對-二噁英；PCOS：多囊卵巢綜合征。

3.1 環(huán)境因素所致印跡基因改變與胎盤發(fā)育

胎盤是促進(jìn)母體和胎兒相互作用的器官。在發(fā)育早期階段，環(huán)境因素所致印跡基因的表觀遺傳修飾及表達(dá)改變可能通過編程胎盤發(fā)育，從而干擾子代的正常發(fā)育過程。大量印跡基因在人的胎盤中表達(dá)，并在調(diào)節(jié)胎盤發(fā)育和胎兒生長過程中發(fā)揮著重要的作用。例如，印跡基因生長因子受體結(jié)合蛋白10(growth factor receptor bound protein 10,) 可調(diào)控胎盤和胎兒的生長，并參與調(diào)控mTOR信號通路，進(jìn)而參與調(diào)節(jié)胎盤的轉(zhuǎn)運功能[38]，當(dāng)其在胎盤特異性敲除后可導(dǎo)致子代小鼠過度生長[39]。此外，印跡基因?qū)υ缙谔ケP形成以及對胎兒營養(yǎng)供應(yīng)方面起著不可或缺的作用[40]。研究顯示，主要通過IGFs信號通路促進(jìn)胎兒的生長發(fā)育，其過表達(dá)則導(dǎo)致胎盤肥大和胎兒過度生長[41]。Cao等[42]發(fā)現(xiàn)，孕期三氯生暴露通過抑制胎盤Akt-mTOR- P70S6K信號通路，影響胎盤發(fā)育和營養(yǎng)物質(zhì)運輸，導(dǎo)致胎兒低出生體重。一項隊列研究顯示，孕期接觸三氯生可引起胎盤等多個印跡基因DNA甲基化水平升高[43]。提示，環(huán)境因素可能通過誘導(dǎo)胎盤印跡基因DNA甲基化修飾，參與調(diào)控mTOR信號通路，引起胎盤中氧氣和營養(yǎng)物質(zhì)運輸障礙，導(dǎo)致不良妊娠結(jié)局發(fā)生。此外，ART可誘導(dǎo)人胎盤印跡基因和表達(dá)增加，子代表現(xiàn)為IUGR。其發(fā)生機制可能與ART引起的母體高雌激素水平通過降低ICR的DNA甲基化修飾，增加ICR的DNA甲基化水平有關(guān)[44]。近幾年的研究提示，ART可誘導(dǎo)人胎盤ICR DNA低甲基化，同時伴隨ICR組蛋白H3的第9位賴氨酸甲基化(tri-methylation at lysine 9 on histone H3, H3K9me3)、H3K9me2降低和H3K4me2升高，共同作用導(dǎo)致染色質(zhì)結(jié)構(gòu)疏松從而促進(jìn)轉(zhuǎn)錄[45]。提示，組蛋白修飾和DNA甲基化可能共同作用參與調(diào)控ART所致的胎盤中印跡基因表觀遺傳修飾異常。在出生時胎盤ICR的表觀遺傳修飾狀態(tài)可能對胎兒的發(fā)育產(chǎn)生顯著影響。然而，在這種機制作用下的具體影響尚不清楚。這些研究表明，環(huán)境因素可通過影響印跡基因表觀遺傳修飾及表達(dá)，導(dǎo)致胎盤轉(zhuǎn)運功能等異常，最終調(diào)控胎盤和胎兒的發(fā)育過程。

3.2 環(huán)境因素所致印跡基因改變與肝臟發(fā)育

肝臟是人體的重要代謝器官, 參與糖脂代謝、生物轉(zhuǎn)化等過程。印跡基因參與調(diào)控肝細(xì)胞增殖與分化，并影響與胎兒肝臟發(fā)育相關(guān)基因的表達(dá)，從而調(diào)控肝臟發(fā)育[46,47]。臨床研究顯示，在人類肝臟相關(guān)疾病(如肝纖維化、肝硬化、原發(fā)性硬化性膽管炎和原發(fā)性膽汁性肝硬化)的患者中，表達(dá)顯著升高[48]。此外，妊娠期使用二甲雙胍可致胎兒肝中表達(dá)增加，通過降低肝細(xì)胞核因子4α(hepatocyte nuclear factor 4α, Hnf4α)的甲基化水平而增加其表達(dá)[49]。而Hnf4α表達(dá)增加會阻礙肝臟分化、影響肝結(jié)構(gòu)，并且在上調(diào)糖異生相關(guān)基因的表達(dá)中具有不可或缺的作用[50]?；诖送茰y，胎兒發(fā)育過程中可能通過調(diào)控Hnf4α進(jìn)而影響肝臟的發(fā)育及功能。在胎兒肝臟中高度表達(dá)的模式提示，孕期二甲雙胍暴露引起的表達(dá)增加可能是成年代謝性疾病發(fā)生的潛在機制之一。Zhu等[51,52]發(fā)現(xiàn)，高脂飲食通過抑制組蛋白去乙酰化酶3(histone deacetylase 3, HDAC3)誘導(dǎo)小鼠肝臟表達(dá)升高，而作為miR-214競爭性內(nèi)源RNA，促進(jìn)叉頭狀轉(zhuǎn)錄因子O1(forkhead box transcription factor, FoxO1)表達(dá)，從而抑制糖異生相關(guān)基因表達(dá)，導(dǎo)致肝臟胰島素抵抗發(fā)生。還有研究顯示，在父體慢性應(yīng)激的小鼠模型中，F(xiàn)1代小鼠肝臟中印跡基因啟動子區(qū)DNA甲基化水平升高，使內(nèi)含子miR-466b-3p表達(dá)下調(diào)，其轉(zhuǎn)錄后抑制磷酸烯醇式丙酮酸羧激酶(phosphoenolpyruvate carboxykinase, PEPCK)表達(dá)，最終造成F1代小鼠出現(xiàn)高血糖[53]。提示，親代慢性應(yīng)激可調(diào)控子代肝臟中印跡基因的表觀遺傳修飾，從而引起子代肝臟發(fā)育異常及代謝性疾病易感。以上研究顯示，印跡基因主要參與調(diào)控胎兒的肝臟發(fā)育及出生后的代謝功能，生命早期遭受的環(huán)境刺激可對印跡基因產(chǎn)生顯著影響，并且可能和肝臟相關(guān)疾病的發(fā)生密切相關(guān)。

3.3 環(huán)境因素所致印跡基因改變與腦發(fā)育

基因組印記廣泛存在于大腦中，并參與調(diào)控神經(jīng)發(fā)育、突觸功能、社會行為、情緒和認(rèn)知等。是大腦中研究的較為成熟的母源性印跡基因，其存在于神經(jīng)突觸中，對于調(diào)控神經(jīng)可塑性非常重要。過表達(dá)是孤獨癥譜系障礙(autism spectrum disorder, ASD)發(fā)生的重要因素之一[54]。研究顯示，可通過影響結(jié)節(jié)性硬化癥復(fù)合物2(tuberous sclerosis complex 2, TSC2)表達(dá)，參與調(diào)控mTOR信號通路[55]。在ASD人腦中，mTOR信號傳導(dǎo)的中斷，導(dǎo)致正常發(fā)育樹突棘修剪所需的自噬水平下調(diào)，表現(xiàn)為突觸功能缺陷[56]。提示，發(fā)育過程中大腦的突觸功能障礙可能與介導(dǎo)神經(jīng)元mTOR信號傳導(dǎo)異常有關(guān)。近幾年，研究人員開始探索在人類大腦神經(jīng)元中表達(dá)異常與染色質(zhì)相關(guān)的全基因組效應(yīng)。研究發(fā)現(xiàn)，患有15q重復(fù)綜合征的人腦中表達(dá)升高，通過調(diào)節(jié)組蛋白H2A.Z單泛素化，引起大腦發(fā)育相關(guān)基因差異甲基化區(qū)域的DNA甲基化水平改變[57]。提示，疾病因素所致大腦發(fā)育相關(guān)基因的表達(dá)異?？赡芷鹗加谀X神經(jīng)元中表達(dá)改變，其潛在機制可能與組蛋白泛素化引起的DNA甲基化修飾異常有關(guān)，但其具體的信號通路還需進(jìn)一步探究。此外，印跡基因表達(dá)改變也會影響海馬的發(fā)育過程。例如，母體攝入甜菜堿可誘導(dǎo)F1代海馬中啟動子區(qū)出現(xiàn)高甲基化，進(jìn)而抑制表達(dá)及其下游AKT信號通路，并伴隨雌激素受體相關(guān)基因表達(dá)降低，最終導(dǎo)致子代海馬發(fā)育異常[58]。已知雌性大鼠海馬中雌激素參與調(diào)控和IGFBP2表達(dá)，因此甜菜堿所致胎兒海馬發(fā)育異常相關(guān)的編程機制可能與雌激素結(jié)合其核受體后，引起下游表觀遺傳修飾改變有關(guān)。以上研究表明，印跡基因通過參與調(diào)控神經(jīng)發(fā)育相關(guān)信號通路，影響全基因組DNA甲基化以及大腦發(fā)育相關(guān)基因的表達(dá)，在大腦發(fā)育多個過程中發(fā)揮著重要的作用，其異常表達(dá)可能引起神經(jīng)發(fā)育障礙，最終導(dǎo)致神經(jīng)相關(guān)疾病的發(fā)生。

3.4 環(huán)境因素所致印跡基因改變與性腺發(fā)育

性腺是下丘腦–垂體–性腺軸的重要組成部分。印跡基因是性腺發(fā)育中重要的調(diào)控因子。與女性顆粒細(xì)胞中促性腺激素受體的表達(dá)有關(guān)，能夠促進(jìn)卵泡的增殖、成熟以及雌二醇、孕酮的產(chǎn)生[59]。研究發(fā)現(xiàn)，宮內(nèi)暴露于TCDD的雌性大鼠卵巢中和表達(dá)降低，表現(xiàn)為血雌二醇水平升高、卵泡刺激素生成減少及原始卵泡數(shù)減少。然而，卵巢中ICR的甲基化水平并未發(fā)生改變，只有少數(shù)CpG位點甲基化水平升高[60]。這表明TCDD所致雌性子代卵巢發(fā)育毒性可能與和低表達(dá)有關(guān)，并且還存在其他調(diào)控機制。此外，印跡基因簇是調(diào)控促性腺激素重要的印跡區(qū)域。有文獻(xiàn)報道，妊娠期全氟辛酸暴露可通過降低睪丸中印跡基因簇的靶基因(等)表達(dá)水平，導(dǎo)致雄性子代血清睪酮水平降低及睪丸發(fā)育異常[61]。已知，印跡基因簇存在DMRDMR等多個差異甲基化區(qū)域(differentially methylated region, DMR)。這提示，全氟辛酸可能誘導(dǎo)印跡基因簇中DMR甲基化發(fā)生改變，進(jìn)而對睪酮的生成及生殖功能產(chǎn)生影響?？傊?，上述一系列證據(jù)提示，環(huán)境因素對印跡基因的調(diào)控具有長期的影響，不僅可以直接影響子代性腺的發(fā)育，還可以通過調(diào)節(jié)性腺激素的生成繼而影響其生殖功能。在這一過程中，表觀遺傳遺傳修飾扮演著重要的角色，可能是不良環(huán)境因素介導(dǎo)不育癥等疾病發(fā)生的關(guān)鍵機制。

3.5 環(huán)境因素所致印跡基因改變與其他器官發(fā)育

印跡基因還參與了其他器官的發(fā)育，如腎上腺、骨和垂體腺等。本實驗室前期研究發(fā)現(xiàn)，孕期咖啡因暴露可致子代大鼠腎上腺甾體合成功能抑制，其發(fā)生機制與宮內(nèi)母源性高濃度糖皮質(zhì)激素激活腎上腺受體(glucocorticoid receptor, GR)，降低CTCF表達(dá)并抑制其與結(jié)合，同時增加DNA甲基轉(zhuǎn)移酶3a(DNA methyltransferase 3a, Dnmt3a)表達(dá)并促進(jìn)其與結(jié)合，進(jìn)而導(dǎo)致高甲基化及低表達(dá)有關(guān)[62]。已知宮內(nèi)機體糖皮質(zhì)激素水平是決定胎組織成熟及其出生后命運的關(guān)鍵[63]。糖皮質(zhì)激素可能通過調(diào)控印跡基因的表達(dá)，參與調(diào)控環(huán)境因素所致的子代腎上腺發(fā)育不良。還有研究證實，環(huán)境因素所致印跡基因的表達(dá)改變會影響骨發(fā)育過程。例如，父體攝入低蛋白飲食，胎盤等印跡基因表達(dá)升高，并伴隨Dnmt1、Dnmt3a等表達(dá)升高，胚胎表現(xiàn)為骨礦物質(zhì)沉積[64]。此外，印跡基因可以調(diào)控垂體腺的發(fā)育及相關(guān)激素的分泌。敲除小鼠表現(xiàn)出生長發(fā)育遲緩、出生后追趕性生長和早期肥胖等表型[65,66]，而過表達(dá)小鼠在禁食期間垂體生長激素產(chǎn)生增加、脂質(zhì)代謝增強[67]。已有文獻(xiàn)指出，在個體早期發(fā)育過程中，環(huán)境因素可誘導(dǎo)表達(dá)發(fā)生改變[61]。提示，環(huán)境因素可能通過調(diào)控垂體生長激素的產(chǎn)生，進(jìn)而對機體的代謝功能產(chǎn)生影響。然而，關(guān)于環(huán)境因素相關(guān)的印跡基因改變對其它器官發(fā)育的影響報道較少，仍有待進(jìn)一步研究。

4 環(huán)境因素所致印跡基因改變的多代遺傳效應(yīng)及其機制

眾所周知，親代在備孕期間接觸不良環(huán)境因素可影響子代生長發(fā)育，導(dǎo)致其出生后成年疾病的發(fā)生，并可能持續(xù)多代。在過去幾年中，越來越多的證據(jù)顯示，不良環(huán)境暴露相關(guān)的印跡基因表觀遺傳修飾改變在經(jīng)歷兩次重編程事件后仍得以保留[68]。因此推測，父體和母體配子中印跡基因的表觀遺傳修飾改變，可能是解釋子代表型改變及多代遺傳效應(yīng)發(fā)生的重要依據(jù)。例如，暴露于苯并吡喃的雄性F0代大鼠精子中和等印跡基因甲基化水平發(fā)生改變，且F1、F2代精子中這兩個印跡基因的甲基化水平與F0代具有良好的一致性[69]。提示，環(huán)境因素引起生殖細(xì)胞中的印跡基因DNA甲基化改變并可能傳遞多代。還有研究顯示，在父體慢性應(yīng)激的小鼠模型中，F(xiàn)0代精子和F1代肝臟中印跡基因啟動子區(qū)DNA甲基化水平升高，F(xiàn)1代小鼠出現(xiàn)高血糖[53]。此外，當(dāng)給予親代慢性應(yīng)激和GR拮抗劑RU486后，可發(fā)現(xiàn)相關(guān)表觀遺傳修飾及子代高血糖現(xiàn)象被逆轉(zhuǎn)。提示，糖皮質(zhì)激素參與調(diào)控親代慢性應(yīng)激所致生殖細(xì)胞中印跡基因的表觀遺傳修飾異常及子代多疾病易感。此外，ZFP57是印跡基因重要的調(diào)控因子，環(huán)境因素還可能通過ZFP57調(diào)控印跡基因的表達(dá)，從而介導(dǎo)多代遺傳效應(yīng)的發(fā)生。Legoff等[70]發(fā)現(xiàn)，雄性F1代宮內(nèi)殺蟲劑暴露可引起其生殖細(xì)胞中ZFP57表達(dá)降低，并且ZFP57的靶基因在H3K27me3區(qū)域富集，這種甲基化改變在F2代和F3代中依舊存在。已知組蛋白修飾是配子形成和胚胎植入前的關(guān)鍵調(diào)控步驟[71]。因此推測，環(huán)境因素可能通過ZFP57影響印跡基因的H3K27me3水平，該修飾可通過生殖細(xì)胞傳遞給子代，從而干擾子代的發(fā)育過程。除了DNA甲基化和組蛋白修飾兩種表觀遺傳調(diào)控方式以外，非編碼RNA對印跡基因的調(diào)控也越來越受到學(xué)者們的廣泛關(guān)注。非編碼RNA是一類不編碼蛋白質(zhì)的RNA，它們可在RNA水平上行使各自的功能，并廣泛參與生命活動中重要的生物功能，如生物個體的發(fā)育、生殖、細(xì)胞重編程等，與人類疾病的發(fā)生密切相關(guān)。Short等[72]發(fā)現(xiàn)，接受皮質(zhì)酮治療的雄性小鼠精子中多種miRNA含量改變，并預(yù)測到其可與結(jié)合，導(dǎo)致子代海馬中表達(dá)增加。這一現(xiàn)象表明，環(huán)境因素可能通過影響精子中miRNA的含量，誘導(dǎo)精子中印跡基因的表達(dá)改變，從而實現(xiàn)印跡基因從親代到子代的傳遞。由于miRNA還可以調(diào)控其他表觀遺傳修飾[73]，因此另一種可能機制為：在環(huán)境因素的作用下，精子中發(fā)生變化的miRNA通過進(jìn)一步調(diào)控DNA甲基化或組蛋白修飾，該修飾如果在多代遺傳中得以保留，則可能對連續(xù)幾代胎兒的正常發(fā)育產(chǎn)生影響。綜上所述，環(huán)境因素可誘導(dǎo)生殖細(xì)胞中印跡基因的表觀遺傳修飾改變，這種表觀遺傳標(biāo)記可能逃逸生殖細(xì)胞重編程，通過減數(shù)分裂穩(wěn)定地遺傳至子代的生殖細(xì)胞和其他臟器，為發(fā)育源性疾病早期編程并實現(xiàn)多代遺傳提供了可行的道路。

5 結(jié)語與展望

在個體的生長發(fā)育過程中，印跡基因?qū)Τ錾?、后各器官的正常發(fā)育及功能調(diào)節(jié)具有重要作用。印跡基因的改變可引起多器官發(fā)育不良，并誘發(fā)多種疾病的發(fā)生?；蚪M印記是驅(qū)動胎兒生長的表觀遺傳決定因素，其可對環(huán)境中各種來源的暴露作出反應(yīng)，進(jìn)而通過表觀遺傳修飾影響基因的表達(dá)和子代發(fā)育(圖2)。然而，環(huán)境因素所致子代發(fā)育異常的多代遺傳效應(yīng)及其性別差異的分子機制仍有待進(jìn)一步完善。未來有望將印跡基因作為疾病的潛在生物標(biāo)志物，采用高靈敏度的甲基化檢測技術(shù)進(jìn)行疾病的早期診斷。由于表觀遺傳學(xué)的可逆性，有可能通過開發(fā)新的分子靶向藥物逆轉(zhuǎn)表觀遺傳修飾改變來治療相關(guān)疾病。此外，由于基因組印跡是在發(fā)育早期出現(xiàn)的，臍帶血和胎盤中的印跡基因可用作胚胎發(fā)育障礙預(yù)警和干預(yù)的靶標(biāo)，并輔以有效的干預(yù)方式，進(jìn)而為這些發(fā)育障礙相關(guān)疾病提供防治策略。

圖2 印跡基因在胚胎多臟器發(fā)育和疾病易感中的作用

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Alteration of imprinted genes and offspring organ development caused by environmental factors

Hui Qu1, Yi Liu1, Yawen Chen1, Hui Wang1,2

Imprinted genes are a special subset of about 100 genes, which are mainly expressed in the form of parental monoallelic genes, and play important roles in the growth and development of embryos. In recent years, it has been found that epigenetic modification of imprinted genes induced by environmental factors can cause fetal multi-organ dysplasia and even susceptibility to multiple diseases in adulthood, which also exhibit multi-generational inheritance. In this review, we summarize the effects of expression changes of imprinted genes on ontogenetic development and organ functions in late stage of life, and propose that abnormal epigenetic modification and expression of imprinted genes caused by environmental deleterious factors are important mechanisms for explaining the multi-organ dysplasia in offspring. Such mechanisms are greatly significant for understanding the phenotypic changes caused by alteration of imprinted gene expression during ontogeny and exploring early prevention and treatment strategies of diseases.

imprinted genes; environmental factors; regulatory mechanisms of imprinted genes; epigenetic modification; organ development

2021-10-01;

2021-12-21;

2021-12-22

國家重點研發(fā)計劃重點專項(編號: 2020YFA0803900)資助[Supported by the Key Project of National Key R&D Program of China (No. 2020YFA0803900)]

曲卉，在讀碩士研究生，專業(yè)方向：腎上腺發(fā)育毒理。E-mail: 1937211743@qq.com

汪暉，教授，博士生導(dǎo)師，研究方向：親代應(yīng)激與子代多代發(fā)育編程及疾病易感，藥物靶標(biāo)與新藥研究。E-mail: wanghui19@whu.edu.cn

10.16288/j.yczz.21-302

(責(zé)任編委: 杜茁)