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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >SIRT3 restricts hepatitis B virus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3‐9 homolog 1 and SET domain containing 1A histone methyltransferases
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SIRT3 restricts hepatitis B virus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3‐9 homolog 1 and SET domain containing 1A histone methyltransferases

机译：SIRT3限制乙型肝炎病毒转录和通过涉及脉动3-9同源物1的抑制剂的共价闭合圆形DNA的表观遗传调节和含有1A组甲基转移酶的设定结构域

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摘要

Hepatitis B virus (HBV) infection remains a major health problem worldwide. Maintenance of the covalently closed circular DNA (cccDNA), which serves as a template for HBV RNA transcription, is responsible for the failure of eradicating chronic HBV during current antiviral therapy. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications. In this study, we identified silent mating type information regulation 2 homolog 3 (SIRT3) as a host factor restricting HBV transcription and replication by screening seven members of the sirtuin family, which is the class III histone deacetylase. Ectopic SIRT3 expression significantly reduced total HBV RNAs, 3.5‐kb RNA, as well as replicative intermediate DNA in HBV‐infected HepG2‐Na + /taurocholate cotransporting polypeptide cells and primary human hepatocytes. In contrast, gene silencing of SIRT3 promoted HBV transcription and replication. A mechanistic study found that nuclear SIRT3 was recruited to the HBV cccDNA, where it deacetylated histone 3 lysine 9. Importantly, occupancy of SIRT3 on cccDNA could increase the recruitment of histone methyltransferase suppressor of variegation 3‐9 homolog 1 to cccDNA and decrease recruitment of SET domain containing 1A, leading to a marked increase of trimethyl‐histone H3 (Lys9) and a decrease of trimethyl‐histone H3 (Lys4) on cccDNA. Moreover, SIRT3‐mediated HBV cccDNA transcriptional repression involved decreased binding of host RNA polymerase II and transcription factor Yin Yang 1 to cccDNA. Finally, hepatitis B viral X protein could relieve SIRT3‐mediated cccDNA transcriptional repression by inhibiting both SIRT3 expression and its recruitment to cccDNA. Conclusion : SIRT3 is a host factor epigenetically restricting HBV cccDNA transcription by acting cooperatively with histone methyltransferase; these data provide a rationale for the use of SIRT3 activators in the prevention or treatment of HBV infection. (H epatology 2018).
机译：乙型肝炎病毒（HBV）感染仍然是全世界的主要健康问题。维持使用作为HBV RNA转录的模板的共价闭合圆形DNA（CCCDNA），是在当前抗病毒治疗期间消除慢性HBV的破坏。 CCCDNA用细胞组蛋白组装成染色质，但关于HBV染色质的调节，通过组蛋白的后翻译修饰少几乎是已知的。在该研究中，我们鉴定了沉默的交配型信息调节2同源物3（SIRT3）作为限制HBV转录和通过筛选Sirtuin家族的七个成员的宿主因子，这是III类组蛋白脱乙酰化酶。异位SIRT3表达显着减少了总HBV RNA，3.5kb的RNA，以及HBV感染的HEPG2-NA + /牛磺酸酯酸盐酸盐的多肽细胞和原发性人肝细胞中的复制中间DNA。相比之下，SIRT3的基因沉默促进了HBV转录和复制。机械研究发现，核SIRT3被募集到HBV CCCDNA，其中脱乙酰组蛋白3赖氨酸9.重要的是，CCCDNA对SIRT3的占用可以增加vCCDNA的veriegation 3-9同源物1的组蛋白甲基转移酶抑制剂的募集和减少募集设定含有1A的结构域，导致三甲基 - 组蛋白H3（Lys9）的显着增加以及CCCDNA上的三甲基 - 组蛋白H3（Lys4）的降低。此外，SIRT3介导的HBV CCCDNA转录抑制涉及宿主RNA聚合酶II和转录因子yin阳1至CCCDNA的结合降低。最后，乙型肝炎病毒X蛋白可以通过抑制SIRT3表达及其对CCCDNA的募集来缓解SIRT3介导的CCCDNA转录抑制。结论：SIRT3是通过与组甲甲基转移酶协作作用的基因上限制HBV CCCDNA转录的主宿主因子。这些数据提供了在预防或治疗HBV感染中使用SIRT3活化剂的理由。 （2018年Hopatology）。

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  • 来源
  • 作者

    Ren Ji‐Hua; Hu Jie‐Li; Cheng Sheng‐Tao; Yu Hai‐Bo; Wong Vincent Kam Wai; Law Betty Yuen Kwan; Yang Yong‐Feng; Huang Ying; Liu Yi; Chen Wei‐Xian; Cai Xue‐Fei; Tang Hua; Hu Yuan; Zhang Wen‐Lu; Liu Xiang; Long Quan‐Xin; Zhou Li; Tao Na‐Na; Zhou Hong‐Zhong; Yang Qiu‐Xia; Ren Fang; He Lin; Gong Rui; Huang Ai‐Long; Chen Juan;

  • 作者单位

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    State Key Laboratory of Quality Research in Chinese MedicineMacau University of Science and;

    State Key Laboratory of Quality Research in Chinese MedicineMacau University of Science and;

    Department of Liver Disease The Second Hospital of NanjingAffiliated to Southeast;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    Department of Clinical LaboratoryThe Second Affiliated Hospital of Chongqing Medical;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    Department of Epidemiology School of Public Health and ManagementChongqing Medical;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

    The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry;

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  • 中图分类 消化系及腹部疾病;
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