cccDNA
微小染色体
CTCF公司
生物
病毒学
乙型肝炎病毒
寄主因子
HBx公司
小圆圈
细胞生物学
分子生物学
乙型肝炎表面抗原
DNA
病毒
遗传学
增强子
染色质
转录因子
基因
作者
Zhuanchang Wu,Liyuan Wang,Xin Wang,Yang Sun,Haoran Li,Zhaoying Zhang,Caiyue Ren,Mengjie Zhang,Shuangjie Li,Jinghui Liang,Leiqi Xu,Xuetian Yue,Yi Hong,Qiang Li,Haizhen Zhu,Yaoqin Gong,Chengjiang Gao,Huili Hu,Lifen Gao,Xiaohong Liang,Chun Pyo Hong
标识
DOI:10.1016/j.jcmgh.2022.08.002
摘要
Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV), existing as a stable minichromosome in the hepatocyte, is responsible for persistent HBV infection. Maintenance and sustained replication of cccDNA require its interaction with both viral and host proteins. However, the cccDNA-interacting host factors that limit HBV replication remain elusive.Minicircle HBV (MC-HBV), a recombinant cccDNA, was constructed based on chimeric intron and minicircle DNA technology. By mass spectrometry based on pull-down with biotinylated MC-HBV, the cccDNA-hepatocyte interaction profile was mapped. HBV replication was assessed in different cell models that support cccDNA formation.MC-HBV supports persistent HBV replication and mimics the cccDNA minichromosome. The MC-HBV-based screen identified cohesin complex as a cccDNA binding host factor, leading to reduced HBV replication. Mechanistically, with the help of CCCTC-binding factor (CTCF), which has specific binding sites on cccDNA, cohesin loads on cccDNA and reshapes cccDNA confirmation to prevent RNA polymerase II enrichment. Interestingly, HBV X protein transcriptionally reduces structural maintenance of chromosomes complex expression to partially relieve the inhibitory role of the cohesin complex on HBV replication.Our data not only provide a feasible approach to explore cccDNA-binding factors, but also identify cohesin/CTCF complex as a critical host restriction factor for cccDNA-driven HBV replication. These findings provide a novel insight into cccDNA-host interaction and targeted therapeutic intervention for HBV infection.
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