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  微生物与感染  2019, Vol. 14 Issue (4): 238-482      DOI: 10.3969/j.issn.1673-6184.2019.04.007
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乙型肝炎病毒共价键闭环DNA的表观遗传调控研究进展
叶菲 , 张欣欣 , 于德敏     
上海交通大学医学院附属瑞金医院, 上海 200025
摘要:乙型肝炎病毒(hepatitis B virus, HBV)感染仍然是威胁全球人类生命与健康的重要危险因素。虽然目前的抗病毒治疗药物在控制乙型肝炎进展有显著疗效, 但却始终无法达到根治HBV感染的目标。HBV共价闭合环状DNA(HBV cccDNA)是HBV转录复制的原始模板, 也是HBV持续感染的关键因素。但由于缺少有效的完全清除HBV cccDNA的治疗方法, 慢性乙型肝炎患者需长期服药以防治疗后停药复发。研究证实HBV cccDNA的转录受表观遗传机制调控, 其中cccDNA甲基化、组蛋白修饰、miRNA、染色质重塑等均影响HBV cccDNA的功能。本文就HBV表观遗传调控的最新研究进展进行综述。
关键词乙型肝炎病毒    共价闭合环状DNA    表观遗传学    
Epigenetic regulation of hepatitis B virus covalently closed circular DNA: current progress
YE Fei , ZHANG Xinxin , YU Demin     
Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 200025, China
Abstract: Hepatitis B virus (HBV) infection remains a significant public health problem worldwide. Current therapies have made great progress for the controlling of liver disease progression and its detrimental clinical sequelae. However, the lack of curativeness of current antiviral therapies is attributed to their inability to eliminate HBV covalently closed circular DNA (cccDNA), which serves as a key factor in maintaining the persistent form of the viral genome and transcription template for virus reproduction, leading to chronic hepatitis B patients requiring long-term medication or relapse after treatment. Previous studies have confirmed that the transcription from HBV cccDNA is regulated by epigenetic mechanism, including cccDNA methylation, histone modification, microRNAs, chromatin remodeling and other aspects. In this review, we summarize the latest progress on epigenetic regulation of HBV from the related aspects.
Keywords: Hepatitis B virus    covalently closed circular DNA    Epigenetics    

乙型肝炎病毒(hepatitis B virus,HBV)感染仍然是威胁全球人类生命健康的重要危险因素[1]。慢性乙型肝炎(chronic hepatitis B,CHB)患者人数超过2.5亿,因HBV感染造成的CHB患者发展成为纤维化、肝硬化、肝功能衰竭和肝细胞癌等终末期肝病或者其他严重并发症而死亡的人数每年高达100万[2]。目前,治疗CHB的抗病毒药物主要有干扰素和核苷(酸)类似物两大类,它们能抑制HBV的复制,有效控制CHB患者病情的进一步发展[3-4]。但是上述两类药物对HBV共价闭合环状DNA(HBV cccDNA)却无直接清除作用,故患者需要长期服药以抑制病毒复制,防止出现治疗后停药复发[5]。作为DNA病毒,HBV具有独特的反转录病毒复制模式。既往的研究已证明HBV cccDNA可与组蛋白及非组蛋白(如HBc、HBx宿主转录因子)等相结合,以微染色体(minichromosome)形式存在于肝细胞核中[6-7],其半衰期较长,为HBV的转录和复制提供原始模板,可以转录出病毒所有mRNA,其中3.5 kb产物为HBV前基因组RNA(pgRNA),能翻译出HBV衣壳蛋白及P蛋白。pgRNA 5′端具有ε茎-环结构,P蛋白与该茎-环结构结合后衣壳蛋白开始包绕pgRNA使其衣壳化,同时P蛋白的反转录酶结构域以pgRNA为模板合成全长的基因组负链DNA,随后以负链DNA为模板合成正链DNA,新形成的松弛环状DNA(rcDNA)与病毒表面蛋白组装成完整的HBV颗粒后释放至细胞外,完成复制周期[8]

近年来的研究表明,表观遗传(epigenetic)调控基因表达机制在HBV cccDNA的持续存在和转录调控及HBV的持续感染等方面发挥着重要作用。表观遗传学不涉及任何可遗传DNA序列的直接改变, 但会发生基因功能的可遗传改变,其调控机制有多种,包括DNA甲基化、组蛋白修饰、非编码RNA干扰(non-coding RNA)和染色质重塑[9]。目前认为宿主因素和HBV自身抗原均可以参加cccDNA的表观遗传调控过程。本文就当前相关研究的最新进展进行综述。

1 HBV cccDNA甲基化

DNA甲基化是指由DNA甲基转移酶(DNA methyltransferases, DNMTs)催化,把一个甲基转移到胞嘧啶的第5位碳原子上,形成5-甲基胞嘧啶(5mC)。CpG岛长度大约为1 000个碱基对(bp), 比基因组其余区域有更多CpG序列的一段DNA,启动子区域附近的CpG岛DNA甲基化形成的5mC可以干扰转录因子对DNA的识别和结合,进而影响pgRNA的转录和减少病毒DNA的复制[10]

有研究证明,HBV基因组中至少存在6个CpG岛[11],研究较为详细的包括3个重要区域:CpG岛1与S基因的起始位点重叠,CpG岛2包含增强子Ⅰ和Ⅹ基因启动子,CpG岛3与Sp1启动子和P基因的起始密码子重叠。其中CpG岛2位于增强子Ⅱ/核心基因启动子的上游,是HBV cccDNA转录的关键调控区域[12]。另有实验报道从55例HBeAg阳性CHB患者的肝脏活检组织中提取HBV cccDNA,并对其CpG岛2甲基化状态和数量进行分析,结果表明HBeAg阳性患者肝细胞中cccDNA甲基化水平明显低于HBeAg阴性患者,HBeAg阳性患者cccDNA甲基化阳性标本中rcDNA与cccDNA的比值也显著低于cccDNA甲基化阴性标本,提示cccDNA的甲基化对HBV的转录和复制具有负向调控作用[13]。HBc与HBV DNA结合可减小核蛋白复合物的核小体间距,从而有利于HBV cccDNA转录调控[6]。HBc与HBV cccDNA结合发生在调控HBV转录的重要区域CpG岛2,HBc与CpG岛2的相对比例和HBV DNA水平及rcDNA/cccDNA的比值都呈正相关,同时HBc与乙酰转移酶CREB结合蛋白(CBP)正相关而与组蛋白去乙酰化酶1(HDAC1)负相关,CBP和HDAC1是组蛋白H3/H4乙酰化的关键调控因子。上述结果说明HBc Ag与CpG岛2的结合抑制了DNA甲基化。研究者进一步推测是HBc与CBP或HDAC1的相互作用,诱导组蛋白乙酰化,进而抑制CpG岛的甲基化,表明HBc对HBV cccDNA的转录发挥了正向调控作用[14]

在HBV感染的人肝细胞中,DNMTs表达活性上调,导致HBV cccDNA甲基化[12-13]。另有实验证明,野生型HBx可上调DNMTs酶活性和水平,而在HBx缺失的HBV突变稳定细胞株中未有此效果,表明HBx有可能作为HBV cccDNA复制的正向调控因子,诱导HBV cccDNA甲基化[15-16]。已证实cccDNA负调控元件(negative regulatory element,NRE)可以调控核心启动子的转录,一种NRE结合蛋白(NREBP)的抑制因子可与NRE的特定位点结合,抑制pgRNA的合成[17]。近期的实验发现HBx通过使HBV NRE结合位点的C-1619的甲基化,阻断NREBP作用,核心启动子激活,病毒基因组转录和复制增加,进一步阐述了HBx在HBV cccDNA复制中详细机制[18]

2 组蛋白修饰对HBV cccDNA的表观调控

组蛋白的翻译后修饰(post-translational modification, PTM)包括甲基化、乙酰化、磷酸化、泛素化等,这些修饰参与调控基因的表达。细胞采用一系列复杂而精确的酶,包括组蛋白乙酰转移酶(HATs)和去乙酰化酶(HDAC)、赖氨酸甲基转移酶(KMTs)和去甲基化酶(KDMs)、激酶和磷酸酶、泛素连接酶和去泛素化酶等,增加和去除这些修饰,从而介导对HBV cccDNA的表观遗传调控。

既往研究证实,HBV cccDNA结合的组蛋白H3上第4、36或79位赖氨酸的三甲基化(H3K4me3、H3K36me3、H3K79me3),H3K9、H3K7和H3K122的乙酰化(H3K9ac、H3K27ac、H3K122ac)以及H4上第3位精氨酸不对称的二甲基化(H4R3me2a)都能促进基因转录;而H3K9的二甲基化(H3K9me2)或三甲基化(H3K9me3)、H3K27的三甲基化(H3K27me3)与H4R3对称二甲基化(4R3me2a)能抑制基因转录[19-20]。同时发现乙酰转移酶p300和CBP以及Ⅰ类组蛋白去乙酰化酶HDAC1被招募到HBV cccDNA微染色体上[20]

在HBV的生命周期中,HBx的表达会介导细胞信号转导、转录、增殖和DNA的修复、表观调控、凋亡等多重细胞功能的改变。有报道证实HBx与HBV cccDNA招募上述与组蛋白乙酰化有关的酶(如p300、PCAF/GCN5及HDAC1、hSirt1等)密切相关[7, 21],而cccDNA结合H3/H4组蛋白乙酰化的状态对HBV的复制和转录产生影响[7]。研究人员观察到,当HBx缺失时,组蛋白3(H3)结合的cccDNA乙酰化明显减少,H3第4位赖氨酸三甲基化(H3K4me3)减少,H3第9位赖氨酸二甲基化和三甲基化(H3K9me2、H3K9me3)增加[22]。而H3第9位赖氨酸上的甲基化(H3K9me)可能与基因沉默相关,由含SETDB1在内的组蛋白赖氨酸甲基转移酶(histone lysine methyltransferases, HKMT)所介导[23-24]。HBV感染后,SETDB1能通过H3K9me3和HP1所介导调控染色质结构的细胞机制导致HBV cccDNA转录沉默,而HBx恢复存在时,HBV则正常转录[22, 25]。SETDB1酶有利于维持cccDNA微染色质被抑制的状态。近期研究者通过shRNA敲低SETDB1 mRNA(shSETDB1),特异性减少SETDB1蛋白的表达水平;在转染48h前用shSETDB1处理后的细胞中,病毒颗粒DNA水平明显增加,结果表明SETDB1能负向调控HBV的转录,这种负向调控是由组蛋白赖氨酸去甲基化酶-1(LSD1)和组蛋白甲基转移酶SET1A所介导,进一步试验发现,当HBx缺失时细胞中LSD未能激活cccDNA的H3K9去甲基化,SET1A也未能激活H3K4的甲基化,形成被抑制的cccDNA染色质状态。上述结果再次证明HBx对HBV cccDNA转录活性的重要性[25]。最新的研究利用HBV感染系统模型证明SIRT3可以介导HBV cccDNA的转录。SIRT3是组蛋白去乙酰化酶Sirtuin家族一员,SIRT3被招募到HBV cccDNA上,使cccDNA结合的组蛋白3第9位赖氨酸(H3K9)去乙酰化,增加组蛋白甲基化转移酶SUV39H1的募集,减少SETD1A的募集。同时SIRT3也通过降低RNA酶聚合酶Ⅱ和转录因子YY1与cccDNA的结合调控HBV的复制。而HBX可以通过抑制SIRT3的表达,减轻SIRT3介导的cccDNA转录抑制作用[26]。此外,在组蛋白泛素化方面,HBx与损伤特异性DNA结合蛋白1(damage-specific DNA-binding protein1,DDB1)、Cullin4-ROC1环E3泛素连接酶(CRL4)的相互作用对HBV cccDNA基因组的转录有调控作用[27]。研究人员利用蛋白组学实验鉴定染色体(SMC)复杂蛋白SMC5和SMC6能作为HBx的靶点,使CRL4-HBx-E3连接酶进行泛素化,从而抑制HBV cccDNA的转录[28]

有研究证实HBc是HBV cccDNA微染色体的组成成分之一,且参与HBV转录的表观调控。HBc通过与cccDNA的结合,减少cccDNA-组蛋白复合物的核糖体间距来调节HBV转录[6, 20]。近期研究确定了HBc可以调控cccDNA转录的特定区域,研究人员在HBc C端(CTD)的4个富含精氨酸区域进行多种突变,然后检测HBc突变株对HBV DNA、RNA、HBsAg水平的变化,最终确定HBc-CTD突变株区域Ⅲ、Ⅳ可能通过减少HBc与cccDNA间的相互作用,同时减少与cccDNA相结合组蛋白的乙酰化作用,调控HBV的转录[29]。PRMT5是蛋白精氨酸甲基转移酶, 研究者通过siRNA干扰方法将PRMT5敲低,检测到胞内pgRNA和核心颗粒DNA增加,而在细胞上清液中HBeAg、HBeAg表达水平降低;将PRMT5过表达后胞内pgRNA和核心颗粒DNA降低,而在细胞上清液中HBsAg、HBeAg表达水平增加。进一步研究发现PRMT5能优先结合cccDNA,并引发微染色体结合的组蛋白H4上第3位精氨酸对称二甲基化(H4R3me2s),抑制cccDNA的转录,但在组蛋白H3上却没有检测到类似结果。另外PRMT5还可能与反转录酶的H区域相结合,阻碍其与病毒聚合酶蛋白的相互作用,干扰pgRNA的核衣壳包装。以上研究提示PRMT5通过表观遗传抑制HBV cccDNA转录和干扰pgRNA包装[30]

3 非编码RNA对HBV cccDNA的表观调控

非编码RNA是指不编码蛋白质的RNA,其中包括rRNA、tRNA、snRNA、snoRNA、microRNA等多种已知功能的RNA。miRNA是其中一种小型、高度保守的小分子,长度一般为22个核苷酸左右,能在转录后水平调控相关基因的表达,通过与靶序列特异性配对结合,形成基因沉默复合物,促进该基因的降解或直接抑制该基因复制[31]。研究表明,miRNA在表观调控网络中对HBV cccDNA转录发挥着关键作用[32],可通过调控宿主免疫或非免疫基因的表达,对HBV复制起到间接调控作用,或者结合于HBV各种转录产物进行直接调控。一方面,在基因表达的不同水平,表观遗传修饰酶和ncRNAs都能进行多功能调控,并且两者能够相互作用,体现基因表达调控的复杂性和精准性。许多重要的表观遗传调控因子能被miRNA转录后调控,比如miRNA-152和miRNA-148的下调导致DNA(胞嘧啶-5)甲基转移酶1(DNMT1)的上调[33]。此外,组蛋白修饰酶的改变也参与miRNA调控过程。有报道miRNA-125b和miRNA-29能分别靶向调控组蛋白赖氨酸N-甲基转移酶SUV39H1和SETDB1,以此调控细胞基因的表达[34]。另一方面,ncRNA也属于表观遗传修饰的调控因子,有许多ncRNA被证明能招募表观遗传因子来介导基因组特定位点的表观遗传修饰。例如,H19、HOTTIP、lncBRM和lncTCF7都已被证明能够招募WDR5/MLL、CBP/P300、核小体重构复合物SWI-SNF等基因激活因子,激活特定基因的表达[35-37]

HBx是调控HBV复制的必需蛋白,有研究者通过染色质免疫沉淀测序(ChIP-Seq)发现了HBx调控cccDNA转录和HBV复制的机制与miRNA有关,HBx通过抑制miRNA-138、miRNA-224和miRNA-596的表达,缓解了miRNA对HBV pgRNA转录的抑制作用[38]。另有研究表明,miRNA-101能被HBx下调,且靶向定位于DNA甲基转移酶3A,使其DNA甲基化异常,可能与HBx介导的表观遗传调控所致肝癌发生的机制相关[39]。血清HBV水平与miRNA-192-3p呈负相关,HBx显著降低了miRNA-192-3p启动子活性和内源性miRNA-192-3p水平,但HBx缺失突变株未能抑制miRNA-192-3p的表达,而miRNA-192-3p能通过抑制HBV诱导的自噬信号通路,最终调节HBV在宿主细胞中的复制[40]

HBV自身蛋白HBc通过与HBV cccDNA结合或刺激HBV增强子活性正向调控HBV转录。有研究表明,miRNA-548家族成员可能在调节免疫应答,尤其在一些干扰素应答方面起关键作用[41]。在最近的一项研究中,研究人员通过生物信息学分析显示组蛋白乙酰化酶4(histone deacetylase 4,HDAC4)可能是miRNA-548ab的候选基因靶点之一。将miRNA-548ab过表达和敲低后,分别在3种肝癌细胞系和注射腺病毒HBV载体的小鼠模型中进行实验,结果表明miRNA-548ab的表达与HDAC4的表达呈负相关。进一步通过荧光qPCR检测cccDNA的表达水平,发现miRNA-548ab可以靶向HDAC4,抑制cccDNA结合的组蛋白H3的去乙酰化,从而正向调控HBV cccDNA的复制。HBc能增强miRNA-548ab在肝细胞中的表达,miRNA-548ab对HBV详细作用机制还有待进一步探究[42]。HBV编码的miRNA(HBV-miRNA-3)位于HBV基因组核苷酸373~393位,能通过外泌体和成熟病毒颗粒释放至细胞外,抑制HBsAg、HBeAg的表达和HBV的复制。为深入探究HBV-miRNA-3抑制HBV复制机制,通过生物信息学技术预测HBV-miRNA-3的作用靶点,实验证明HBV-miRNA-3靶向作用于HBV 3.5 kb mRNA(核苷酸1815~2452),从而特异性降低pgRNA的水平[43]

4 染色质重塑

染色质结构的高度动态变化在基因转录沉默和激活过程中起重要作用。一方面,核小体折叠形成结构紧密的高级结构——30nm染色质纤维,导致基因沉默;另一方面,基因激活过程中的关键是30nm染色质纤维的解聚和重塑,从而使各种转录因子接近DNA[44]。染色质重塑是指通过对染色质中核小体的定位动态改变染色质结构并以此调控基因表达的分子机制[45]。越来越多的证据表明,组成染色体重塑复合物的重塑因子功能变异,特别是氨基酸突变或缺失引起的变异与许多疾病的发生、发展密切相关。

表 1 主要表观遗传修饰调控因子及其机制 Tab. 1 Major epigenetic modification regulators and regulatory mechanisms
Category Factor Mechanism Reference
HBV DNA methylation DNMT1,DNMT3A,DNMT3B DNA methyltransferase catalyzes the transfer of a methyl group to the 5th carbon atom of cytosine to form 5-methylcytosine (5mC), resulting in changes in DNA conformation, stability, or DNA and protein interactions, thereby regulating gene expression. (9111-12)
APOBEC,TET1,TET2,TET3,TDG The conformation and stability of specific genes silenced by DNA methylation can be restored, reactivated and expressed by DNA demethylase action. (1416-17)
Histone modifications H3K4me,H3K36me3,H3K79me3,H3K9ac,H3K27ac,H3K122ac,H4R3me2a Histone acetylation introduces extra negative charge in histones, which reduces the interaction between positively charged histones and negatively charged DNA, making DNA relaxation for transcription. (18-19)
H3K9me2,H3K9me3,H3K27me,H4R3me2s Histone methylation, while not altering the electrical properties of histones by itself, recruits multiple protein factors to inhibit or activate gene expression. (18-19)
Non-coding RNA interference miRNA-138,miRNA-224,miRNA-596,miRNA-101,miRNA-548ab,miRNA-3,miRNA-192-3p 1, miRNAs can interact with epigenetic modified enzymes to exert gene expression regulation. 2, miRNAs are regulators of epigenetic modifications that recruit relevant epigenetic factors to mediate the modification of specific sites in the genome (38-4042)
Chromation remodeling SUZ12,ZNF198,SWI/SNF Gene expression was regulated by remodeling factors that alter the position and structure of tightly structured 30 nm chromatin fibers, known as nucleosomes. (45-50)

染色质重塑与HBV在HepG2细胞中的病毒复制和转录相关[46]。研究者通过一个全基因组短发夹RNA(shRNA)文库筛选出zeste12同源基因(果蝇)抑制因子(SUZ12)和锌指基因mym-2(ZNF198),它们可作为染色质重塑复合物的组成部分。通过siRNA敲低SUZ12和ZNF198后,发现HBV核心颗粒和mRNA水平均增加,且SUZ12/PRC2作为重要的染色质重构复合物组成部分,可通过H3K27me3修饰来抑制HBV的转录[47-48],其调控HBV转录的详细机制有待于进一步深入研究。SWI/SNF复合物(又称BAF复合物)是目前研究比较深入的染色质重塑蛋白复合物,由10~15个蛋白质亚基组成[45]。作为影响染色质重塑的主要突变靶点,其亚基中有多个常见基因突变均可能会改变蛋白质的表达水平或蛋白质的结构[49-50]。在前述的PRMT5进展研究中,PRMT5除了可以使组蛋白H4R3和H3R8甲基化而参与HBV转录的表观调控外,Brg1和hbrm作为SWI/SNF染色质重塑复合物的一部分,将PRMT5过表达时,Brg1与cccDNA的结合显著增加;而PRMT5敲低时,Brg1与cccDNA的结合显著降低。以上提示PRMT5介导HBV cccDNA转录的表观遗传机制之一与Brg1的SWI/SNF染色质重塑密切相关, 但是hbrm与Brg1不同,hbrm与cccDNA的结合不随PRMT5的改变而发生显著改变[30]

5 结语与展望

随着基因调控的表观遗传学机制研究的不断进展,人们对HBV cccDNA复制与转录的相关机制研究有了更深入的认识。就目前而言,CHB患者的抗病毒疗法都无法达到清除患者体内的cccDNA或者至少完全灭活cccDNA的目标。表观遗传学的飞速发展,为我们提供了一种新角度、新思路和新方向。但是,基因表达调控的过程十分复杂,需要不断地深入探索。期待在未来,能阐明HBV cccDNA特异性表观遗传的调控机制,早日开发能有效清除HBV cccDNA的新型治疗药物或方法,并最终达到治愈CHB的目标。

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文章信息

叶菲, 张欣欣, 于德敏
YE Fei, ZHANG Xinxin, YU Demin
乙型肝炎病毒共价键闭环DNA的表观遗传调控研究进展
Epigenetic regulation of hepatitis B virus covalently closed circular DNA: current progress
微生物与感染, 2019, 14(4): 238-482.
Journal of Microbes and Infections, 2019, 14(4): 238-482.
通信作者
于德敏
E-mail:yby89@163.com
基金项目
"十三五"国家科技重大专项(2018ZX10302205-003-002), 国家自然科学基金(81572047)

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