Transcription of hepatitis B virus covalently closed circular DNA is regulated by CpG methylation during chronic infection.
Transcription of hepatitis B virus covalently closed circular DNA is regulated by CpG methylation during chronic infection.
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慢性感染过程中乙型肝炎病毒共价闭合环状DNA的转录受CpG甲基化调节
DOI：
10.1371/journal.pone.0110442
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zhang Y;Mao R;Yan R;Cai D;Zhang Y;Zhu H;Kang Y;Liu H;Wang J;Qin Y;Huang Y;Guo H;Zhang J
乙型肝炎病毒 (HBV) 感染的持续存在是由核病毒共价闭合环状 DNA (cccDNA) 维持的，它充当病毒 mRNA 的转录模板。先前的研究表明cccDNA含有易于甲基化的CpG岛，并且cccDNA的微型染色体结构受到DNA甲基化的表观遗传调控。然而，每个 CpG 岛甲基化对 cccDNA 活性的调节作用仍然难以捉摸。在本研究中，我们分析了患者样本中 cccDNA 内 CpG 甲基化的分布，并研究了 CpG 岛甲基化对 cccDNA 驱动的病毒复制的影响。我们的研究揭示了以下观察结果：1) 对慢性乙型肝炎患者的 cccDNA 进行亚硫酸氢盐测序表明 CpG 岛 I 很少甲基化，2) CpG 岛 II 甲基化与患者血清 HBV DNA 水平低相关，体外甲基化研究证实 CpG 岛 II 甲基化显着降低 cccDNA 转录和随后的病毒核心 DNA 复制，3) CpG 岛 III 甲基化与低血清 HBsAg 滴度相关，4) 此外，我们发现 HBV 基因型、HBeAg 阳性、患者年龄和肝纤维化阶段也与 cccDNA CpG 甲基化状态相关。因此，我们清楚地证明了cccDNA甲基化的状态与HBV的生物学行为有关。总而言之，我们的研究提供了 HBV cccDNA 内 CpG 岛甲基化的完整概况，以及 CpG 甲基化在调节 HBV cccDNA 转录中的功能的新见解。
The persistence of hepatitis B virus (HBV) infection is maintained by the nuclear viral covalently closed circular DNA (cccDNA), which serves as transcription template for viral mRNAs. Previous studies suggested that cccDNA contains methylation-prone CpG islands, and that the minichromosome structure of cccDNA is epigenetically regulated by DNA methylation. However, the regulatory effect of each CpG island methylation on cccDNA activity remains elusive. In the present study, we analyzed the distribution of CpG methylation within cccDNA in patient samples and investigated the impact of CpG island methylation on cccDNA-driven virus replication. Our study revealed the following observations: 1) Bisulfite sequencing of cccDNA from chronic hepatitis B patients indicated that CpG island I was seldom methylated, 2) CpG island II methylation was correlated to the low level of serum HBV DNA in patients, and in vitro methylation studies confirmed that CpG island II methylation markedly reduced cccDNA transcription and subsequent viral core DNA replication, 3) CpG island III methylation was associated with low serum HBsAg titers, and 4) Furthermore, we found that HBV genotype, HBeAg positivity, and patient age and liver fibrosis stage were also relevant to cccDNA CpG methylation status. Therefore, we clearly demonstrated that the status of cccDNA methylation is connected to the biological behavior of HBV. Taken together, our study provides a complete profile of CpG island methylation within HBV cccDNA and new insights for the function of CpG methylation in regulating HBV cccDNA transcription.
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影响因子：
5.4
作者：
Mao, Richeng;Zhang, Jiming;Guo, Haitao
通讯作者：
Guo, Haitao
影响因子：
30.8
作者：
Jones, PL;Veenstra, GJC;Wolffe, AP
通讯作者：
Wolffe, AP
影响因子：
16.6
作者：
Lieber MR
通讯作者：
Lieber MR
DOI：
10.1073/pnas.0908365106
发表时间：
2009-11-24
影响因子：
11.1
作者：
Belloni, Laura;Pollicino, Teresa;Levrero, Massimo
通讯作者：
Levrero, Massimo
影响因子：
3.7
作者：
Guo, Yan-Hai;Li, Yong-Nian;Yan, Zhen
通讯作者：
Yan, Zhen