title: Inhibition of hepatitis B virus gene expression and replication by hepatocyte nuclear factor 6.
abstract: Hepatitis B virus (HBV), a small enveloped DNA virus, chronically infects more than 350 million people worldwide and causes liver diseases from hepatitis to cirrhosis and liver cancer. Here, we report that hepatocyte nuclear factor 6 (HNF6), a liver-enriched transcription factor, can inhibit HBV gene expression and DNA replication. Overexpression of HNF6 inhibited, while knockdown of HNF6 expression enhanced, HBV gene expression and replication in hepatoma cells. Mechanistically, the SP2 promoter was inhibited by HNF6, which partly accounts for the inhibition on S mRNA. Detailed analysis showed that a cis element on the HBV genome (nucleotides [nt] 3009 to 3019) was responsible for the inhibition of the SP2 promoter by HNF6. Moreover, further analysis showed that HNF6 reduced viral pregenomic RNA (pgRNA) posttranscriptionally via accelerating the degradation of HBV pgRNA independent of La protein. Furthermore, by using truncated mutation experiments, we demonstrated that the N-terminal region of HNF6 was responsible for its inhibitory effects. Importantly, introduction of an HNF6 expression construct with the HBV genome into the mouse liver using hydrodynamic injection resulted in a significant reduction in viral gene expression and DNA replication. Overall, our data demonstrated that HNF6 is a novel host factor that can restrict HBV replication via both transcriptional and posttranscriptional mechanisms.
  
  
  OBJECTIVE
  HBV is a major human pathogen whose replication is regulated by host factors. Liver-enriched transcription factors are critical for many liver functions, including metabolism, development, and cell proliferation, and some of them have been shown to regulate HBV gene expression or replication in different manners. In this study, we showed that HNF6 could inhibit the gene expression and DNA replication of HBV via both transcriptional and posttranscriptional mechanisms. As HNF6 is differentially expressed in men and women, the current results may suggest a role of HNF6 in the gender dimorphism of HBV infection.
authors: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Ruidong
authors: R
authors: Hao
authors: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Jing
authors: J
authors: He
authors: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Xing
authors: X
authors: Liu
authors: Department of Molecular Carcinogenesis, the University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
authors: Guozhen
authors: G
authors: Gao
authors: School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Dan
authors: D
authors: Liu
authors: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Lei
authors: L
authors: Cui
authors: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Guojun
authors: G
authors: Yu
authors: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Wenhui
authors: W
authors: Yu
authors: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China.
authors: Yu
authors: Y
authors: Chen
authors: State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, Hubei, China School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China dguo@whu.edu.cn.
authors: Deyin
authors: D
authors: Guo
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006515:Hepatitis B virus / Q000235:genetics / Q000378:metabolism*; D051559:Hepatocyte Nuclear Factor 6 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases; D008297:Male; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012727:Sex Characteristics; D014162:Transfection / Q000379:methods
chemical_list: D017931:DNA Primers; D051559:Hepatocyte Nuclear Factor 6; D034741:RNA, Small Interfering; D008156:Luciferases
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