杜鈺　竺向佳　盧奕

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·綜述·

DNA甲基化在常見(jiàn)眼科疾病中的研究進(jìn)展

杜鈺竺向佳盧奕

復(fù)旦大學(xué)附屬眼耳鼻喉科醫(yī)院眼科上海200031

【摘要】表觀遺傳學(xué)是近年新興起的有別于傳統(tǒng)遺傳學(xué)的一門(mén)學(xué)科。它通過(guò)DNA甲基化、組蛋白共價(jià)修飾、非編碼RNA調(diào)控等方式改變基因表達(dá)或細(xì)胞表型，這一改變能夠遺傳給子代，但DNA序列并未發(fā)生變化。DNA甲基化作為一種表觀遺傳學(xué)的重要機(jī)制，已被證實(shí)在大量復(fù)雜生命現(xiàn)象，比如衰老、氧化應(yīng)激中起到作用。以往DNA甲基化的研究主要著重于全身性疾病，而在眼科領(lǐng)域的應(yīng)用才剛剛興起。本文重點(diǎn)介紹DNA甲基化在眼科常見(jiàn)疾病中的研究進(jìn)展。(中國(guó)眼耳鼻喉科雜志，2016，16：60-64)

【關(guān)鍵詞】表觀遺傳學(xué)；DNA甲基化；眼科疾病

表觀遺傳學(xué)是近年發(fā)展起來(lái)的有別于傳統(tǒng)遺傳學(xué)的一門(mén)遺傳學(xué)分支學(xué)科，它是功能基因組學(xué)的重要組成部分，研究在不改變DNA序列的前提下，對(duì)基因表達(dá)所進(jìn)行的可遺傳修飾改變。其主要機(jī)制包括：①DNA甲基化；②組蛋白共價(jià)修飾；③非編碼RNA調(diào)控；④基因印跡等。其中DNA甲基化是研究較多的表觀遺傳現(xiàn)象。具體指在DNA甲基轉(zhuǎn)移酶(DNMT)的催化作用下，以S-腺苷甲硫氨酸為供體，將甲基添加到富含胞嘧啶、鳥(niǎo)嘌呤二核苷酸序列中胞嘧啶5號(hào)碳原子上，從而形成5-甲基胞嘧啶。甲基位于DNA雙螺旋的大溝內(nèi)，通過(guò)吸引或排斥各種DNA結(jié)合蛋白來(lái)發(fā)揮對(duì)基因表達(dá)的調(diào)控作用。通常DNA胞嘧啶甲基化與基因沉默有關(guān)，而去甲基化則與基因活化有關(guān)。已有大量研究證實(shí)DNA甲基化在衰老、氧化應(yīng)激、炎癥等復(fù)雜的生命事件中起了重要作用。常見(jiàn)眼科疾病中發(fā)病機(jī)制未完全明確者，常常是受到遺傳、表觀遺傳、環(huán)境等的多重影響。研究DNA甲基化這一主要表觀遺傳機(jī)制在眼科疾病中的作用，有助于進(jìn)一步了解復(fù)雜眼病的機(jī)制，并為尚無(wú)理想治療方法的眼病提供新的治療思路。

1DNA甲基化與白內(nèi)障

白內(nèi)障是全球范圍內(nèi)的首要致盲眼病，根據(jù)病因的不同可分為老年性白內(nèi)障、并發(fā)性白內(nèi)障、代謝性白內(nèi)障等，病理機(jī)制仍未完全闡明。近幾年的研究發(fā)現(xiàn)各類白內(nèi)障的發(fā)生、發(fā)展都與DNA甲基化有著密切的聯(lián)系。1.1年齡相關(guān)性白內(nèi)障年齡相關(guān)性白內(nèi)障(age-related cataract, ARC)是晶狀體受到環(huán)境、營(yíng)養(yǎng)、代謝和遺傳等多重因素長(zhǎng)期綜合作用后在中老年開(kāi)始發(fā)生的晶狀體渾濁，發(fā)病因素十分復(fù)雜。目前認(rèn)為是氧化應(yīng)激引起了白內(nèi)障的最早期變化[1-3]。

α-晶狀體蛋白是晶狀體的主要結(jié)構(gòu)蛋白之一，由A、B 2個(gè)亞基組成，是晶狀體內(nèi)抗氧化機(jī)制的重要組成，在維持晶狀體的透明中起著關(guān)鍵作用[4-5]。Zhou等[6]研究了年齡相關(guān)核性白內(nèi)障和年齡匹配的正常透明晶狀體上皮細(xì)胞中αA-晶狀體蛋白基因(CRYAA)的表達(dá)，發(fā)現(xiàn)在年齡相關(guān)核性白內(nèi)障晶狀體上皮細(xì)胞中CRYAA表達(dá)明顯下調(diào)，且CRYAA基因啟動(dòng)子上游-856～-640 bp序列中有6個(gè)CpG位點(diǎn)較對(duì)照組呈明顯的高甲基化。經(jīng)DNA甲基轉(zhuǎn)移酶抑制劑zebularine處理過(guò)的人晶狀體上皮細(xì)胞，其CRYAA mRNA和蛋白質(zhì)產(chǎn)物的量較對(duì)照組有所提高[6]。這項(xiàng)研究表明DNA甲基化對(duì)CRYAA表達(dá)的下調(diào)在年齡相關(guān)核性白內(nèi)障的形成中起了重要作用。

多數(shù)氧化應(yīng)激導(dǎo)致的DNA損傷可以被相關(guān)酶類修復(fù)，其中包括8-氧鳥(niǎo)苷酸DNA糖苷酶(OGG1)[7]。Wang等[8]對(duì)OGG1的表達(dá)在修復(fù)晶狀體細(xì)胞氧化損傷中的保護(hù)作用進(jìn)行了驗(yàn)證，并對(duì)年齡相關(guān)性皮質(zhì)性白內(nèi)障患者晶狀體皮質(zhì)中DNA甲基化和OGG1的表達(dá)情況進(jìn)行了研究。通過(guò)qRT-PCR、Western印跡及免疫熒光等方法，得到ARC患者晶狀體皮質(zhì)中提取出的DNA中OGG1基因第1個(gè)外顯子的CpG島呈現(xiàn)高甲基化，OGG1 mRNA與蛋白質(zhì)水平較對(duì)照組明顯減少，ARC皮質(zhì)中OGG1陽(yáng)性的細(xì)胞比例也明顯下降等結(jié)果。利用DNA甲基轉(zhuǎn)移酶抑制劑5-Aza-dC誘導(dǎo)體外培養(yǎng)的人晶狀體上皮DNA去甲基化后，發(fā)現(xiàn)OGG1表達(dá)上調(diào)[8]，說(shuō)明在ARC患者晶狀體皮質(zhì)中，OGG1表達(dá)會(huì)減少，且與OGG1基因啟動(dòng)子CpG島的高度甲基化相關(guān)。

為了減少隨著年齡增長(zhǎng)逐漸加重的氧化應(yīng)激損傷，機(jī)體會(huì)誘導(dǎo)生成一系列保護(hù)性蛋白。核因子E2相關(guān)因子 (Nrf2)是能夠激活多種抗氧化酶的中心物質(zhì)，而kelch樣環(huán)氧氯丙烷相關(guān)蛋白(Keap1)是Nrf2的抑制劑，促進(jìn)Nrf2的蛋白酶解[9]。Nrf2/Keap1依賴性抗氧化保護(hù)系統(tǒng)在維持晶狀體透明中起著重要作用。Gao等[10]對(duì)人晶狀體細(xì)胞進(jìn)行特定基因DNA甲基化分析發(fā)現(xiàn)隨著年齡的增大(60～88歲)，Keap1基因啟動(dòng)子區(qū)域甲基化水平逐漸下降，Keap1的基因表達(dá)產(chǎn)物增多，繼而晶狀體內(nèi)抗氧化能力下降，提示DNA甲基化對(duì)Keap1基因啟動(dòng)子的調(diào)控可能在ARC的發(fā)生中發(fā)揮了作用。

1.2代謝性白內(nèi)障隨著糖尿病在全球范圍內(nèi)患病率的日益增加，糖尿病性白內(nèi)障的發(fā)病率顯著上升，分為真性糖尿病性白內(nèi)障和假性糖尿病性白內(nèi)障，其中假性者與老年性白內(nèi)障很相似，只是發(fā)病率較高、發(fā)生較早、進(jìn)展較快。Palsamy等[11]研究了糖尿病患者白內(nèi)障晶狀體中CpG島甲基化與正常透明晶狀體之間的差別，發(fā)現(xiàn)較透明晶狀體而言，糖尿病患者的白內(nèi)障晶狀體中Keap1基因啟動(dòng)子亦呈明顯去甲基化；而用去甲基化藥物5-Aza處理人晶狀體上皮細(xì)胞株，得到Keap1mRNA增加9倍、蛋白質(zhì)增加2倍的結(jié)果。Keap1基因啟動(dòng)子低甲基化引起其表達(dá)的上調(diào)導(dǎo)致Nrf2所介導(dǎo)的抗氧化保護(hù)作用受抑制，晶狀體原本的氧化還原平衡被打破，處在更高水平的氧自由基環(huán)境，進(jìn)而促發(fā)晶狀體的渾濁[3, 10-12]。這一機(jī)制與糖尿病性白內(nèi)障的形成或許有著密切的聯(lián)系，然而高血糖是通過(guò)怎樣的途徑影響晶狀體上皮細(xì)胞基因DNA甲基化的程度進(jìn)而促使白內(nèi)障的早發(fā)有待進(jìn)一步研究探索。1.3高度近視性白內(nèi)障高度近視是屈光度>-6.00 D或眼軸>26 mm的近視類型，它與白內(nèi)障發(fā)生的關(guān)聯(lián)已被若干研究證實(shí)[13-15]。高度近視患者并發(fā)性白內(nèi)障多為核性白內(nèi)障，且多見(jiàn)棕黑色硬核。關(guān)于其中的DNA甲基化機(jī)制的研究有很多，但目前僅檢索出一篇文獻(xiàn)。Zhu等[16]對(duì)白內(nèi)障手術(shù)患者晶狀體上皮細(xì)胞中CRYAA啟動(dòng)子區(qū)域CpG島甲基化程度進(jìn)行分析發(fā)現(xiàn)，高度近視性白內(nèi)障LOCS Ⅲ核分級(jí)NC5-6者CRYAA啟動(dòng)子CpG島呈高度甲基化，且αA-晶狀體蛋白表達(dá)水平明顯低于相同核分級(jí)年齡相關(guān)性白內(nèi)障患者和高度近視無(wú)白內(nèi)障患者。該研究提示高度近視是黑色核性白內(nèi)障的危險(xiǎn)因素，CRYAA啟動(dòng)子CpG島的高度甲基化引起其表達(dá)的下調(diào)，可能在高度近視患者較普通人白內(nèi)障更早發(fā)，且在易發(fā)硬核性白內(nèi)障中起了作用。

2DNA甲基化與視網(wǎng)膜疾病

視網(wǎng)膜是眼球后部最內(nèi)層組織，結(jié)構(gòu)精細(xì)、功能復(fù)雜，極易受到內(nèi)外致病因素的影響而引發(fā)病變。隨著表觀遺傳學(xué)的發(fā)展，DNA甲基化在視網(wǎng)膜變性疾病中的研究正在逐步深入。

2.1年齡相關(guān)性黃斑變性年齡相關(guān)性黃斑變性(age-related macular degeneration, AMD)是60歲以上老人視力損害不可逆的首要原因，以黃斑區(qū)視網(wǎng)膜組織退行性病變?yōu)橹饕憩F(xiàn)。病理、生理特點(diǎn)包括視網(wǎng)膜玻璃膜蛋白質(zhì)、脂質(zhì)沉積——玻璃膜疣(drusen)的形成，視網(wǎng)膜色素上皮細(xì)胞營(yíng)養(yǎng)代謝障礙，黃斑區(qū)色素紊亂，最終導(dǎo)致中心視力減退，甚至喪失。

已有大量研究[17-21]證實(shí)氧化應(yīng)激參與了AMD的發(fā)生，且該過(guò)程應(yīng)該受到了表觀遺傳學(xué)調(diào)節(jié)。有研究[22-23]對(duì)同卵雙胞胎關(guān)于AMD的相關(guān)基因型與AMD表型進(jìn)行分析后都得到：基因在一定程度上決定了AMD的易感性，然而疾病真正的發(fā)生過(guò)程及最后的視力轉(zhuǎn)歸受到環(huán)境因素更大的影響，提示表觀遺傳機(jī)制參與了AMD的發(fā)生、發(fā)展。Hunter等[24]對(duì)AMD患者和年齡匹配正常人的視網(wǎng)膜色素上皮細(xì)胞和睫狀體進(jìn)行全基因甲基化圖譜分析，發(fā)現(xiàn)AMD患者2種谷胱甘肽S轉(zhuǎn)移酶同工酶Gstm1和Gstm5基因啟動(dòng)子區(qū)域高甲基化，且視網(wǎng)膜神經(jīng)感覺(jué)層中這2種抗氧化酶的表達(dá)明顯少于對(duì)照。證實(shí)在AMD患者的視網(wǎng)膜色素上皮和睫狀體中，Gstm1和Gstm5的表達(dá)被DNA甲基化下調(diào)，提高了黃斑對(duì)氧化應(yīng)激損傷的易感性，促發(fā)了AMD的形成[24]。

而氧化應(yīng)激對(duì)視網(wǎng)膜的損傷是由炎癥反應(yīng)來(lái)介導(dǎo)的，炎癥反應(yīng)加速drusen的形成，促使AMD的發(fā)生[25-26]，炎癥因子IL-17、IL-2等參與其中[26]。 Liu和Wei等[27]發(fā)現(xiàn)AMD患者血清中IL-17，IL-2等炎癥因子水平較非AMD人群高，并進(jìn)一步對(duì)AMD患者外周血單核細(xì)胞中231個(gè)基因啟動(dòng)子區(qū)域的CpG島進(jìn)行甲基化分析，發(fā)現(xiàn)AMD細(xì)胞內(nèi)IL-17RC啟動(dòng)子區(qū)域呈明顯低甲基化，對(duì)應(yīng)黃斑中IL17-RC基因的轉(zhuǎn)錄水平升高，IL-17RC陽(yáng)性的單核細(xì)胞數(shù)目增多使得AMD患者對(duì)IL-17所介導(dǎo)的炎癥反應(yīng)更為敏感[28]，進(jìn)而得到IL17RC基因啟動(dòng)子區(qū)域低甲基化和AMD發(fā)病的確切關(guān)系。

clusterin/apolipoprotein J是體內(nèi)各組織器官普遍存在的一種糖蛋白，是細(xì)胞遭受氧化應(yīng)激的一個(gè)生物標(biāo)記[29]，在氧化應(yīng)激中對(duì)細(xì)胞有保護(hù)作用[30-31]，同時(shí)也是drusen中的主要沉積物[32-34]。研究發(fā)現(xiàn)隨著年齡增長(zhǎng)，絲生蛋白(clusterin)在眼內(nèi)的表達(dá)增多，正如drusen在視網(wǎng)膜色素上皮下的逐漸形成。Suuronen等[35]使用脫氧氮雜胞苷(5-Aza)，一種DNA甲基化轉(zhuǎn)移酶抑制劑，作用于人視網(wǎng)膜色素上皮細(xì)胞誘導(dǎo)其DNA去甲基化，得到clusterin mRNA和蛋白質(zhì)的顯著增加，而且其分泌也明顯增加，提示clusterin基因中CpG島甲基化水平的下降或許參與了AMD的形成。

2.2糖尿病性視網(wǎng)膜病變糖尿病性視網(wǎng)膜病變(diabetic retinopathy, DR)是最常見(jiàn)的視網(wǎng)膜微血管病變。高血糖對(duì)視網(wǎng)膜內(nèi)皮細(xì)胞線粒體DNA,尤其是D-loop結(jié)構(gòu)造成損害，使得細(xì)胞受損死亡，并形成一個(gè)惡性循環(huán)，導(dǎo)致血糖恢復(fù)正常后DR的持續(xù)進(jìn)展[36-38]。受損DNA的堿基錯(cuò)配可被DNA聚合酶γ亞基1(POLG1)所修正，然而Tewari等[37, 39]對(duì)大鼠糖尿病模型進(jìn)行了一系列實(shí)驗(yàn)，發(fā)現(xiàn)其視網(wǎng)膜內(nèi)皮細(xì)胞POLG1基因調(diào)控序列CpG島在高血糖和血糖恢復(fù)正常后都呈現(xiàn)持續(xù)高甲基化狀態(tài)，POLG1表達(dá)持續(xù)下調(diào)，線粒體DNA復(fù)制體系功能障礙。提示DR的發(fā)生與持續(xù)進(jìn)展同POLG1基因啟動(dòng)子CpG島高甲基化有關(guān)，且通過(guò)藥物或分子手段對(duì)DNA甲基化進(jìn)行調(diào)適以維持線粒體穩(wěn)態(tài)也許可以成為一種新的DR治療思路。

2.3視網(wǎng)膜色素變性視網(wǎng)膜色素變性(retinitis pigmentosa, RP)是一組遺傳眼病，屬于光感受器細(xì)胞及視網(wǎng)膜色素上皮細(xì)胞營(yíng)養(yǎng)不良性退行性病變。目前尚無(wú)有效治療。最近的研究[40]結(jié)果發(fā)現(xiàn)，DNA甲基化參與了光感受器細(xì)胞的死亡和凋亡過(guò)程。Farinelli等[41]發(fā)現(xiàn)在嚙齒類動(dòng)物RP模型rd1,rd2,P23HS334ter中，光感受器細(xì)胞死亡時(shí)DNA中胞嘧啶甲基化水平較野生型非RP模型有所升高；對(duì)光感受器細(xì)胞進(jìn)行超微結(jié)構(gòu)觀察，發(fā)現(xiàn)在視網(wǎng)膜變性過(guò)程中染色質(zhì)構(gòu)型發(fā)生改變，且與此同時(shí)檢測(cè)到的細(xì)胞內(nèi)一種DNA甲基轉(zhuǎn)移酶DNMT3a的表達(dá)增加。進(jìn)一步實(shí)驗(yàn)后，發(fā)現(xiàn)rd1模型小鼠中幾個(gè)細(xì)胞死亡相關(guān)基因的轉(zhuǎn)錄因子結(jié)合位點(diǎn)較野生型小鼠甲基化水平明顯較高，且相對(duì)應(yīng)的基因轉(zhuǎn)錄活性有所下降。不過(guò)需要注意的是，這些基因的表達(dá)是否是光感受器細(xì)胞特異的或與RP相關(guān)仍需進(jìn)一步研究明確。用decitabine——一種DNA甲基轉(zhuǎn)移酶抑制劑作用于rd1小鼠后，其光感受器細(xì)胞的死亡明顯減少[41]，為RP提供了一種可能的表觀遺傳學(xué)治療方法。

3DNA甲基化與青光眼

青光眼是一組由眼壓病理性升高所導(dǎo)致的疾病，以視神經(jīng)萎縮和視野缺損為共同特征。一般分為原發(fā)性、繼發(fā)性和先天性三大類，根據(jù)眼壓升高時(shí)前房角的狀態(tài)又可分為閉角型青光眼和開(kāi)角型青光眼。繼發(fā)性青光眼的發(fā)病因素一般比較明確，原發(fā)性青光眼中以開(kāi)角型較為多見(jiàn)，且表觀遺傳學(xué)研究最多。

原發(fā)性開(kāi)角型青光眼病因尚不完全明了,遺傳、表觀遺傳和環(huán)境等因素在其中都起到了一定作用[42-45]。Jünemann等[46]提取原發(fā)性開(kāi)角型青光眼患者外周血單核細(xì)胞中DNA并進(jìn)行全基因DNA甲基化水平分析，發(fā)現(xiàn)較繼發(fā)性青光眼和非青光眼人群明顯升高，提示DNA甲基化可能參與了原發(fā)性開(kāi)角型青光眼的發(fā)生，但具體機(jī)制還需針對(duì)特定基因甲基化狀態(tài)進(jìn)行研究以明確。

目前認(rèn)為小梁網(wǎng)結(jié)構(gòu)的改變會(huì)引起房水引流系統(tǒng)的異常、眼壓增高，繼而導(dǎo)致青光眼一系列的病理改變[47-48]。促纖維化因子TGF-β促進(jìn)細(xì)胞外基質(zhì)(ECM)的生成[49-50]，而ECM在小梁網(wǎng)和視神經(jīng)乳頭篩板的過(guò)多沉積會(huì)阻礙房水回流并使視神經(jīng)受到壓迫而發(fā)生病變[51-52]?，F(xiàn)已明確原發(fā)性開(kāi)角型青光眼患者房水中TGF-β的含量高于正常對(duì)照人群[50,53]，且DNA甲基化在肺、卵巢等器官中提高了TGF-β的促纖維化作用[54-56]。DNA甲基化與TGF-β、ECM在原發(fā)性開(kāi)角型青光眼中增多的關(guān)系有待進(jìn)一步的研究證實(shí)。

4DNA甲基化與眼部腫瘤

眼科學(xué)中最常見(jiàn)的腫瘤包括視網(wǎng)膜母細(xì)胞瘤及葡萄膜黑色素瘤，其中視網(wǎng)膜母細(xì)胞瘤是嬰幼兒最常見(jiàn)的眼內(nèi)惡性腫瘤，而葡萄膜黑色素瘤則是成年人中最常見(jiàn)的眼內(nèi)惡性腫瘤。對(duì)于這2種疾病的發(fā)生與轉(zhuǎn)歸，已有大量圍繞DNA甲基化機(jī)制的研究，其中已發(fā)現(xiàn)許多抑癌基因啟動(dòng)子區(qū)域CpG島的高度甲基化與基因沉默的相關(guān)性，且該機(jī)制參與這2種腫瘤的發(fā)生。

Ras相關(guān)區(qū)域家族1A(RASSF1A)是一個(gè)常見(jiàn)的腫瘤抑制基因，在正常組織中的甲基化發(fā)生率非常低，而在視網(wǎng)膜母細(xì)胞瘤及葡萄膜黑色素瘤中被證明在啟動(dòng)子區(qū)域的甲基化率高達(dá)89%[57]和70%[58]。Choy等[59]在一系列實(shí)驗(yàn)中發(fā)現(xiàn)，視網(wǎng)膜母細(xì)胞瘤中，RASSF1A基因啟動(dòng)子區(qū)甲基化程度越高，其mRNA表達(dá)水平越低；而經(jīng)5-Aza處理后的細(xì)胞株該基因的表達(dá)有所恢復(fù)。Maat等[60]在實(shí)驗(yàn)中發(fā)現(xiàn)RASSF1A基因啟動(dòng)子的甲基化可能與葡萄膜黑色素瘤的轉(zhuǎn)移相關(guān)。

此外，O-6-甲基鳥(niǎo)嘌呤-DNA甲基轉(zhuǎn)移酶(MGMT)基因、視網(wǎng)膜母細(xì)胞瘤樣蛋白2(RBL2)基因等抑癌基因也被證明，其啟動(dòng)子的高度甲基化與視網(wǎng)膜母細(xì)胞瘤的發(fā)生、發(fā)展緊密相關(guān)[59, 61]。hTERT、TIMP3等抑癌基因啟動(dòng)子的高甲基化與葡萄膜黑色素瘤的發(fā)生與轉(zhuǎn)移相關(guān)[62-63]。

5總結(jié)與展望

許多眼部疾病的發(fā)生，包括老年性白內(nèi)障、年齡相關(guān)性黃斑變性、青光眼及眼部腫瘤等都受到環(huán)境因素的影響，而表觀遺傳模式的改變很可能就是聯(lián)系環(huán)境影響因素與基因表達(dá)之間的橋梁。盡管目前對(duì)DNA甲基化在眼科常見(jiàn)疾病中作用的認(rèn)識(shí)還處于很初步的階段，但毋庸置疑它在許多眼病的發(fā)生、發(fā)展過(guò)程中十分重要。如果能進(jìn)一步明確各病具體的甲基化位點(diǎn)，并解決給予DNA甲基轉(zhuǎn)移酶及其抑制劑治療時(shí)的非靶向作用的困擾，相信在將來(lái)，DNA甲基化會(huì)為臨床預(yù)防、診斷及治療眼病打開(kāi)新的思路并發(fā)揮重要作用。

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(本文編輯諸靜英)

The research progress of DNA methylation in common ocular diseases

DUYu,ZHUXiang-jia,LUYi.

DepartmentofOphthalmology,EyeEarNoseandThroatHospitalofFudanUniversity,Shanghai200031,ChinaCorresponding author： LU Yi, Email: luyieent@126.com

【Key words】Epigenetics; DNA methylation; Ocular diseases

【Abstract】Epigenetics is an emerging discipline studying the heritable regulation of gene function and celluar phenotype by means of DNA methylation, histone modification and non-coding RNA without changing DNA sequence, which is different from the traditional genetics. Being one of the most important mechanisms in epigenetics, DNA methylation is involved in a large number of complex biological phenomena, such as aging, oxidative stress, etc. Previously, the study of DNA methylation were mostly focused on systemic diseases, while in ophthalmology it just started. This article is an review of the research progress of DNA methylation in common ocular diseases. (Chin J Ophthalmol and Otorhinolaryngol,2016,16:60-64)

通訊作者：盧奕(Email: luyieent@126.com)

DOI:10.14166/j.issn.1671-2420.2016.01.022

(收稿日期2015-01-26)