組蛋白共價(jià)修飾在肝臟疾病發(fā)生與發(fā)展中作用的研究進(jìn)展

孔德松，張 峰，邱 萍，鄭仕中, 3

(1. 南京中醫(yī)藥大學(xué)第三附屬醫(yī)院科教科，江蘇 南京 210001；2. 南京中醫(yī)藥大學(xué)藥學(xué)院，江蘇 南京 210023；3. 江蘇省中藥藥效與安全性評(píng)價(jià)重點(diǎn)實(shí)驗(yàn)室，江蘇 南京 210023)

組蛋白共價(jià)修飾在肝臟疾病發(fā)生與發(fā)展中作用的研究進(jìn)展

孔德松1，張 峰2,3，邱 萍2，鄭仕中2, 3

(1. 南京中醫(yī)藥大學(xué)第三附屬醫(yī)院科教科，江蘇 南京 210001；2. 南京中醫(yī)藥大學(xué)藥學(xué)院，江蘇 南京 210023；3. 江蘇省中藥藥效與安全性評(píng)價(jià)重點(diǎn)實(shí)驗(yàn)室，江蘇 南京 210023)

組蛋白共價(jià)修飾通過乙酰化、甲基化、磷酸化等多種形式，影響基因的轉(zhuǎn)錄活性，參與疾病的發(fā)生與發(fā)展，是表觀遺傳學(xué)研究中的重要領(lǐng)域。越來越多的研究證實(shí)組蛋白共價(jià)修飾在肝臟疾病的發(fā)生與發(fā)展過程中扮演著重要角色。該文詳細(xì)闡述與分析了組蛋白共價(jià)修飾在各類肝臟疾病中的具體作用及近年來的研究進(jìn)展，以期能為各類肝病的治療與藥物的開發(fā)提供一定的理論支持。

組蛋白共價(jià)修飾;酒精性肝病;非酒精性脂肪肝;肝纖維化;病毒性肝炎;肝細(xì)胞癌

組蛋白共價(jià)修飾是表觀遺傳修飾的一種，組蛋白的修飾形式有很多種，包括組蛋白末端的乙?；⒓谆?、磷酸化、泛素化、ADP核糖基化等，這些修飾都能影響基因的轉(zhuǎn)錄活性[1]。目前研究較多的是組蛋白乙?；图谆?。乙?；饕芙M蛋白乙?；D(zhuǎn)移酶(histone acetyltransferase, HATs)和組蛋白去乙?；?histone deacetylase, HDACs)的共同調(diào)控，這兩種酶能夠調(diào)控基因的轉(zhuǎn)錄，一般而言，乙?；龠M(jìn)轉(zhuǎn)錄，而去乙酰化則抑制轉(zhuǎn)錄。甲基化由組蛋白甲基轉(zhuǎn)移酶(histone methyltransferase, HMTs)和組蛋白去甲基轉(zhuǎn)移酶調(diào)控，主要發(fā)生在組蛋白H3和H4殘基上。越來越多的研究報(bào)道顯示，組蛋白共價(jià)修飾在多種慢性肝臟疾病的發(fā)生與發(fā)展進(jìn)程中都具有重要作用，如酒精性肝病、非酒精性脂肪性肝病、肝纖維化、病毒性肝炎、肝癌等[2-4]。本文對(duì)組蛋白共價(jià)修飾在各種慢性肝臟疾病發(fā)生與發(fā)展中的作用及作用機(jī)制的最新研究進(jìn)展進(jìn)行綜述。

1 組蛋白共價(jià)修飾與酒精性肝病

研究證實(shí)，酒精能夠改變肝內(nèi)細(xì)胞中組蛋白的乙?；?、甲基化以及磷酸化狀態(tài)。Park等[5]觀察到酒精能夠通過增加HAT的活性，抑制HDAC的活性，選擇性地乙酰化組蛋白H3上的賴氨酸9(H3AcK9)位點(diǎn)。而HAT/HDAC比值的大小就決定了組蛋白的乙?；盎虻谋磉_(dá)水平[6-7]。暴露于酒精的肝細(xì)胞，其去乙?；?(sirtuin 1, SIRT1)表達(dá)減少，而SIRT1在調(diào)控肝臟脂質(zhì)代謝，進(jìn)而影響酒精性脂肪肝發(fā)病進(jìn)程中扮有重要角色，敲除SIRT1基因的小鼠肝臟，在暴露于酒精后其脂質(zhì)堆積、炎癥及纖維化程度更加嚴(yán)重[8-9]。同組蛋白乙酰化一樣，組蛋白磷酸化在酒精性肝病的發(fā)病進(jìn)程中也起著至關(guān)重要的作用。有研究顯示，急性酒精性肝損傷的肝細(xì)胞中，組蛋白絲氨酸10與28位點(diǎn)發(fā)生了磷酸化的改變，這種作用可能通過p38信號(hào)通路調(diào)控產(chǎn)生[10]。James等[11]則研究發(fā)現(xiàn)組蛋白10與28位點(diǎn)絲氨酸的磷酸化，以及K9S10的磷酸化-乙?；瘜?duì)酒精的敏感度是有區(qū)別的，同時(shí)所產(chǎn)生的效應(yīng)也是不同的。他們發(fā)現(xiàn)組蛋白28位點(diǎn)絲氨酸磷酸化的增加，與c-jun、纖溶酶原激活物抑制劑-1(plasminogen activator inhibitor-1)啟動(dòng)子的活性變化有關(guān)。同時(shí)，Pal-Bhadra等[12]研究發(fā)現(xiàn)，體外暴露于酒精的肝細(xì)胞出現(xiàn)組蛋白H3與H4甲基化的現(xiàn)象，并導(dǎo)致乙醇脫氫酶(alcohol dehydrogenase, ADH1)的表達(dá)上調(diào)，這表明組蛋白甲基化在ALD的發(fā)病進(jìn)程中也發(fā)揮著重要作用。另外，我們知道長(zhǎng)期的酒精刺激會(huì)導(dǎo)致肝臟代謝功能的異常，組蛋白共價(jià)修飾在這種代謝紊亂的發(fā)生發(fā)展及調(diào)控中也具有重要作用[13]。多條信號(hào)通路如p38、c-jun參與酒精調(diào)控組蛋白的乙?；?、磷酸化、甲基化進(jìn)程，其具體機(jī)制如何，各調(diào)控通路間的相互作用又是如何仍需我們進(jìn)一步的研究。

2 組蛋白共價(jià)修飾與非酒精性脂肪肝

組蛋白共價(jià)修飾在酒精性肝病中具有重要作用，研究發(fā)現(xiàn)它在非酒精性脂肪肝中也扮演著重要角色。Jun等[14]研究發(fā)現(xiàn)，在脂質(zhì)代謝異常的肝臟中，組蛋白H3K9 和H3K4 三甲基(H3K9me3、H3K4me3)狀態(tài)發(fā)生了異常改變。而H3K9me3與H3K4me3在過氧化物酶體增殖劑激活受體α(peroxisome proliferator-activated receptor alpha,PPARα)及肝臟脂質(zhì)代謝的基因調(diào)控網(wǎng)絡(luò)中，調(diào)控著它們的mRNA表達(dá)，進(jìn)而影響非酒精性脂肪肝的發(fā)病進(jìn)程。Pazienza等[15]研究發(fā)現(xiàn)組蛋白MacroH2A1.1的過表達(dá)能夠改善糖代謝，抑制脂質(zhì)形成相關(guān)基因的表達(dá)，及脂肪酸的含量。SIRT1/macroH2A1.1復(fù)合物通過調(diào)控脂代謝相關(guān)表觀遺傳狀態(tài)，參與非酒精性脂肪肝的發(fā)生發(fā)展。Cao等[16]研究發(fā)現(xiàn)多發(fā)性內(nèi)分泌腺瘤致病因子1(multiple endocrine neoplasia 1，Men1)基因敲除將會(huì)促進(jìn)小鼠脂肪變性的發(fā)展，Men1基因通過組蛋白磷酸化招募SIRT1，進(jìn)而調(diào)控CD36的表達(dá)及甘油三脂的聚積。有趣的是，脂代謝與生物節(jié)律調(diào)節(jié)之間也有著密切的關(guān)聯(lián)。生物節(jié)律轉(zhuǎn)錄因子CLOCK-BMAL1調(diào)控著數(shù)以百計(jì)的基因的表達(dá)，其中就包括PPARs[17]。因此，我們看到PPARs調(diào)控的代謝調(diào)控相關(guān)基因也是呈節(jié)律性的表達(dá)。生物節(jié)律基因表達(dá)缺失的小鼠會(huì)變得貪食、肥胖并逐步發(fā)展為NASH[18]。去乙?；窼IRT1可與CLOCK-BMAL1形成一種染色質(zhì)復(fù)合物。這種復(fù)合物則決定著組蛋白的乙?；脚c生物節(jié)律和代謝相關(guān)基因的轉(zhuǎn)錄水平。SIRT1穩(wěn)定高表達(dá)則能抑制給予高脂飼料導(dǎo)致的小鼠代謝性疾病的發(fā)生[19]。而流行病學(xué)顯示生活無規(guī)律的人，其患有代謝紊亂性疾病的風(fēng)險(xiǎn)明顯增高，與實(shí)驗(yàn)研究結(jié)果一致[20]。這提醒我們保持規(guī)律健康的生活狀態(tài)對(duì)于預(yù)防非酒精性脂肪肝等肝臟疾病的重要意義。

3 組蛋白共價(jià)修飾與病毒性肝炎

我國(guó)是肝病大國(guó)，病毒性肝炎是我國(guó)最主要的傳染病之一，每年大約有200萬新發(fā)病的肝炎患者。組蛋白共價(jià)修飾同樣調(diào)控著病毒性肝炎的發(fā)病進(jìn)程。肝炎病毒能夠形成cccDNA(covalently closed circular DNA)微型染色體，或整合宿主基因，通過對(duì)自身基因表觀遺傳學(xué)的調(diào)控，或改變宿主肝臟細(xì)胞的表觀遺傳學(xué)狀態(tài)，影響肝臟疾病的發(fā)展進(jìn)程[21]。組蛋白可直接與HBV的cccDNA結(jié)合，或通過蛋白間連接與微型染色體相結(jié)合。研究顯示，與cccDNA結(jié)合的組蛋白H3與H4的甲基化狀態(tài)對(duì)HBV的復(fù)制具有重要的調(diào)控作用[22]。另有研究發(fā)現(xiàn)，組蛋白的甲基化與磷酸化同樣也具有相應(yīng)的調(diào)控作用。Palumbo等[23]應(yīng)用小分子化合物抑制p300和PCAF(P300/CBP associated factor, P300/CBP相關(guān)因子)的活性，或者激活SIRT1/2和 EZH2(enhancer of zeste homolog 2)的活性，能夠改變cccDNA微型染色體的表觀遺傳學(xué)狀態(tài)，進(jìn)而抑制病毒基因的復(fù)制。更多調(diào)控機(jī)制的深入研究將對(duì)病毒性肝炎的防治具有重要意義。

4 組蛋白共價(jià)修飾與肝纖維化

肝纖維化是各類肝臟疾病發(fā)展的必由之路，我們不難想象組蛋白共價(jià)修飾在肝纖維化的發(fā)生發(fā)展中也必將有著重要作用。有研究發(fā)現(xiàn)，肝纖維化發(fā)生時(shí)，肝星狀細(xì)胞(hepatic stellate cell, HSC)中組蛋白的去乙?；饔靡种屏嘶|(zhì)金屬蛋白酶(matrix metalloproteinase, MMPs)基因啟動(dòng)子的活性，造成了細(xì)胞外基質(zhì)(extracellular matrix, ECM)的堆積。激活的大鼠HSC細(xì)胞染色質(zhì)免疫沉淀(ChIP)顯示，與MMP-9及MMP-13啟動(dòng)子相近的組蛋白H4乙?；矫黠@下降，導(dǎo)致該處染色質(zhì)構(gòu)象改變，阻止轉(zhuǎn)錄因子及RNA聚合酶與啟動(dòng)子結(jié)合，從而沉默兩者的基因[24]。EdU參入標(biāo)記和免疫細(xì)胞化學(xué)染色顯示，組蛋白去乙?；敢种苿┍焖?valproic acid, VPA)可抑制HSC的增殖和刺激核內(nèi)組蛋白H4的乙?；?；在mRNA水平，VPA可抑制HSC激活的標(biāo)志物，如α-SMA、賴氨酸氧化酶(Lox)、分泌磷蛋白1或Spp1、平滑肌肌球蛋白(Myh11)等的表達(dá)[25]。用1 mmol·L-1的VPA作用于人HSC細(xì)胞系L190可明顯抑制TGF-β1和Ⅰ型膠原mRNA及蛋白水平的表達(dá)[26]。使用不引起細(xì)胞凋亡的劑量(400 nmol·L-1)時(shí)，組蛋白去乙?；敢种苿┣乓志?TSA)可以抑制TGF-β1誘導(dǎo)的小鼠肝細(xì)胞AML12發(fā)生EMT，同時(shí)抑制該細(xì)胞Ⅰ型膠原基因的表達(dá)[27]。近年來，有越來越多的新型組蛋白去乙?；敢种苿┍谎邪l(fā)，并用于抗肝纖維化的研究，如N-羥基-7-(2-萘硫) heptanomide (HNHA)、拉格唑拉等[28-29]。研究顯示，甲基CpG結(jié)合蛋白2(methyl-CpG binding protein 2, MeCP2)能夠誘導(dǎo)增強(qiáng)子EZH2的產(chǎn)生與組蛋白3賴氨酸27(H3K27)的高度甲基化，高甲基化的H3K27能夠改變PPARγ的基因結(jié)構(gòu)進(jìn)而抑制其轉(zhuǎn)錄[30]。MeCP2還可促進(jìn)H3K9與轉(zhuǎn)錄抑制因子HP1α的結(jié)合，進(jìn)而抑制PPARγ的表達(dá)，促進(jìn)了HSC脂質(zhì)表型的消失[31]?？傊?，組蛋白共價(jià)修飾在肝纖維化的發(fā)生發(fā)展中具有重要作用，調(diào)控組蛋白共價(jià)修飾新型藥物的開發(fā)將為肝纖維化的防治提供一個(gè)新的視角。

5 組蛋白共價(jià)修飾與肝細(xì)胞癌

肝細(xì)胞癌是各類肝臟疾病發(fā)展的最終結(jié)局，而組蛋白共價(jià)修飾所表現(xiàn)的基因轉(zhuǎn)錄沉默，與多種腫瘤的發(fā)生、發(fā)展有密切的關(guān)聯(lián)，組蛋白共價(jià)修飾在肝細(xì)胞癌發(fā)生發(fā)展中的重要作用受到越來越多的學(xué)者關(guān)注[32-33]。Wang等[34]研究發(fā)現(xiàn)，與正常肝細(xì)胞相比，肝癌細(xì)胞組蛋白H3乙?；磉_(dá)下調(diào)，并且肝癌轉(zhuǎn)移細(xì)胞H3乙?；较抡{(diào)更明顯。有研究顯示SIRT1能夠通過對(duì)組蛋白的表觀遺傳修飾調(diào)控端粒酶(TERT)基因的表達(dá)，進(jìn)而影響肝細(xì)胞癌的發(fā)展進(jìn)程[35]。Zheng等[36]研究發(fā)現(xiàn)，在多數(shù)肝癌細(xì)胞中，組蛋白乙?；D(zhuǎn)移酶(PCAF)處于低水平表達(dá)，PCAF的過表達(dá)能夠通過乙?；M蛋白H4及抑制Akt信號(hào)通路的活性，進(jìn)而抑制肝癌細(xì)胞的增殖，促進(jìn)其凋亡。另外，高水平的組蛋白H3的賴氨酸 4 甲基化 (H3K4me3)與肝癌的生存率降低與較差的預(yù)后息息相關(guān)。高水平的賴氨酸 4 甲基化(H3K27me3)可增加肝癌細(xì)胞的惡性生物學(xué)程度，如血管生成能力的增加、增殖能力的增強(qiáng)、分化能力的降低等[37-38]。Park等[39]研究發(fā)現(xiàn)，組蛋白去甲基化酶JMJD1A在缺氧誘導(dǎo)的HepG2 和Hep3B增殖活化中具有關(guān)鍵調(diào)控作用，JMJD1A的高表達(dá)能夠減少其目的基因ADM啟動(dòng)子區(qū)域的甲基化狀態(tài)。另一種組蛋白去甲基化酶(lysine specific demethylase 1, LSD1)則在肝細(xì)胞癌病理組織中高表達(dá)。LSD1高表達(dá)的肝細(xì)胞癌患者其腫瘤分期處于更高等級(jí)，5年生存率更低[40]。目前，已有多種組蛋白去乙?；?、組蛋白甲基轉(zhuǎn)移酶等調(diào)控組蛋白共價(jià)修飾的酶類抑制劑正在進(jìn)行深入的基礎(chǔ)與臨床研究，如帕比司他、丁酸鈉、3-deazaneplanocin A (DZNep)等[41-43]。隨著研究的深入，相關(guān)抑制劑的不斷研發(fā)，我們相信組蛋白修飾酶相關(guān)抑制劑一定會(huì)為治療肝癌提供更廣闊的方法和途徑。

6 總結(jié)與展望

組蛋白共價(jià)修飾是表觀遺傳修飾中的重要部分，它與人類疾病的發(fā)生關(guān)系密切。大量研究證實(shí)，組蛋白共價(jià)修飾是信號(hào)通路網(wǎng)絡(luò)中的關(guān)鍵環(huán)節(jié)，它可以某種信號(hào)來激活或者沉默基因。在肝臟疾病中，組蛋白可通過乙酰化、甲基化、磷酸化等途徑調(diào)控目的基因的表達(dá)，進(jìn)而影響疾病的發(fā)生與發(fā)展。這其中也存在眾多信號(hào)通路的傳導(dǎo)，如p38、c-jun、Akt、PPAR等。組蛋白修飾的調(diào)控機(jī)制的研究不僅對(duì)闡明各類肝臟疾病的發(fā)病機(jī)制，而且對(duì)肝臟疾病的診斷、防治及預(yù)后判斷都具有重要意義。

在對(duì)組蛋白修飾調(diào)控機(jī)制研究的同時(shí)，學(xué)者們發(fā)現(xiàn)了多種組蛋白修飾酶的抑制劑。組蛋白修飾酶相關(guān)抑制劑可以抑制相關(guān)修飾酶的活性，改變相關(guān)細(xì)胞異常組蛋白修飾模式，達(dá)到治療肝臟疾病甚至肝癌的目的，已然成為國(guó)內(nèi)外靶向治療的研究熱點(diǎn)。開展組蛋白修飾酶抑制劑的研發(fā)，將成為肝臟疾病治療的新的突破口。隨著人們對(duì)組蛋白共價(jià)修飾的不斷深入研究，必將對(duì)各種肝病的診斷、治療提供有益的幫助。

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Role of histone modification in occurrence and progress of liver diseases

KONG De-song1, ZHANG Feng2,3, QIU-Ping2, ZHENG Shi-zhong2,3

(1.theThirdAffiliatedHospitalofNanjingUniversityofChineseMedicine,Nanjing210001,China;2.CollegeofPharmacy,NanjingUniversityofChineseMedicine,Nanjing210023,China;3.JiangsuKeyLaboratoryforPharmacologyandSafetyEvaluationofChineseMateriaMedica,NanjingUniversityofChineseMedicine,Nanjing210023,China)

Histone modification participates in the occurrence and development of the diseases though affecting gene transcription activity by acetylation, methylation, phosphorylation, and other forms. It is an important field in the study of epigenetics. Numerous studies have demonstrated that histone modification plays an important role in the occurrence and development of liver diseases. This paper reviews the recent progress in understanding the role and mechanisms of histone modification in alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, liver fibrosis and hepatocellular carcinoma, with an aim to provide a theoretical basis for the treatment of liver diseases and drug development.

histone modification; alcoholic liver disease; non-alcoholic fatty liver disease; liver fibrosis; viral hepatitis; hepatocellular carcinoma

時(shí)間：2015-4-15 15:44 網(wǎng)絡(luò)出版地址：http://www.cnki.net/kcms/detail/34.1086.R.20150415.1545.006.html

2015-01-08,

2015-01-31

國(guó)家自然科學(xué)基金資助項(xiàng)目(No 81270514,31401210)；江蘇高校優(yōu)勢(shì)學(xué)科建設(shè)工程資助項(xiàng)目(No ysxk-2010)；江蘇省自然科學(xué)基金青年基金資助項(xiàng)目(No BK20140955)；江蘇省高校自然科學(xué)研究面上項(xiàng)目(No 14KJB310011)；南京市醫(yī)學(xué)科技發(fā)展項(xiàng)目(No YKK14143)

孔德松(1989-)，男，碩士，研究方向：天然藥物預(yù)防和治療肝纖維化與腫瘤，Tel：025-52276506，E-mail：kongds0675@126.com; 鄭仕中(1962-)，男，博士，教授，博士生導(dǎo)師，研究方向：天然藥物預(yù)防和治療肝纖維化與腫瘤,通訊作者,Tel:025-85811246，E-mail:nytws@163.com

10.3969/j.issn.1001-1978.2015.05.006

A

1001-1978(2015)05-0615-04

R-05;R 341.27;R 394;R 575;R 512.6;R 735.7;R 977.6