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

作者：Ji‐Hua Ren, Jieli Hu, Sheng‐Tao Cheng, Haibo Yu, Vincent Kam Wai Wong, Betty Yuen Kwan Law, Yongfeng Yang, Ying Huang, Yi Liu, Weixian Chen, Xue‐Fei Cai, Hua Tang, Yuan Hu, Wenlu Zhang, Xiang Liu, Quanxin Long, Li Zhou, Na‐Na Tao, Hong‐Zhong Zhou, Qiu‐Xia Yang, Fang Ren, Lin He, Rui Gong, Ailong Huang, Juan Chen · 发表于：Hepatology · 年份：2018 · DOI：10.1002/hep.29912 · 被引用次数：97 · 研究领域：Hepatitis B Virus Studies、Sirtuins and Resveratrol in Medicine、Hepatitis C virus research

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 repress...