Chen Cuncun, Wu Min, Zhang Wen, Lu Wei, Zhang Min, Zhang Zhanqing, Zhang Xiaonan, Yuan Zhenghong
Institute of Medical Microbiology and Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
Key Laboratory of Medical Molecular Virology, Ministry of Education and Health, Shanghai Medical College of Fudan University, Shanghai, China.
Sci Rep. 2016 Oct 25;6:35974. doi: 10.1038/srep35974.
Multi-layered mechanisms of virus host interaction exist for chronic hepatitis B virus (HBV) infection, which have been typically manifested at the microRNA level. Our previous study suggested that miRNA-939 (miR-939) may play a potential role in regulating HBV replication. Here we further investigated the mechanism by which miR-939 regulates HBV life cycle. We found that miR-939 inhibited the abundance of viral RNAs without direct miRNA-mRNA base pairing, but via host factors. Expression profiling and functional validation identified Jmjd3 as a target responsible for miR-939 induced anti-HBV effect. Jmjd3 appeared to enhance the transcription efficiency of HBV enhancer II/core promoter (En II) in a C/EBPα-dependent manner. However, the demethylase activity of Jmjd3 was not required in this process. Rather, Jmjd3's transactivation activity depended on its interaction with C/EBPα. This coordinated action further recruited the Brm containing SWI/SNF chromatin remodeling complex which promoted the transcription of HBV RNAs. Taken together, we propose that the miR-939-Jmjd3 axis perturbs the accessibility of En II promoter to essential nuclear factors (C/EBPα and SWI/SNF complex) therefore leading to compromised viral RNA synthesis and hence restricted viral multiplication.
慢性乙型肝炎病毒（HBV）感染存在多层病毒-宿主相互作用机制，这些机制通常在微小RNA水平上表现出来。我们之前的研究表明，miRNA-939（miR-939）可能在调节HBV复制中发挥潜在作用。在此，我们进一步研究了miR-939调节HBV生命周期的机制。我们发现，miR-939不是通过直接的miRNA- mRNA碱基配对，而是通过宿主因子来抑制病毒RNA的丰度。表达谱分析和功能验证确定Jmjd3是负责miR-939诱导的抗HBV效应的靶点。Jmjd3似乎以依赖C/EBPα的方式增强HBV增强子II/核心启动子（En II）的转录效率。然而，在此过程中不需要Jmjd3的去甲基酶活性。相反，Jmjd3的反式激活活性取决于其与C/EBPα的相互作用。这种协同作用进一步招募了含有Brm的SWI/SNF染色质重塑复合物，从而促进了HBV RNA的转录。综上所述，我们提出miR-939-Jmjd3轴扰乱了En II启动子对必需核因子（C/EBPα和SWI/SNF复合物）的可及性，因此导致病毒RNA合成受损，从而限制了病毒增殖。
