Abstract
ObjectiveThe Hepatitis B virus genome persists in the nucleus of virus infected hepatocytes where it serves as template for viral mRNA synthesis. Epigenetic modifications, including methylation of the CpG islands contribute to the regulation of viral gene expression. The present study investigates the effects of spontaneous age dependent loss of hepatitis B surface protein- (HBs) expression due to HBV-genome specific methylation as well as its proximate positive effects in HBs transgenic mice.MethodsLiver and serum of HBs transgenic mice aged 5–33 weeks were analyzed by Western blot, immunohistochemistry, serum analysis, PCR, and qRT-PCR.ResultsFrom the third month of age hepatic loss of HBs was observed in 20% of transgenic mice. The size of HBs-free area and the relative number of animals with these effects increased with age and struck about 55% of animals aged 33 weeks. Loss of HBs-expression was strongly correlated with amelioration of serum parameters ALT and AST. In addition lower HBs-expression went on with decreased ER-stress. The loss of surface protein expression started on transcriptional level and appeared to be regulated epigenetically by DNA methylation. The amount of the HBs-expression correlated negatively with methylation of HBV DNA in the mouse genome.ConclusionsOur data suggest that methylation of specific CpG sites controls gene expression even in HBs-transgenic mice with truncated HBV genome. More important, the loss of HBs expression and intracellular aggregation ameliorated cell stress and liver integrity. Thus, targeted modulation of HBs expression may offer new therapeutic approaches. Furthermore, HBs-transgenic mice depict a non-infectious mouse model to study one possible mechanism of HBs gene silencing by hypermethylation.
Highlights
Infection with the hepatitis B virus (HBV) is a serious global health problem
The loss of surface protein expression started on transcriptional level and appeared to be regulated epigenetically by DNA methylation
Our data suggest that methylation of specific CpG sites controls gene expression even in hepatitis B surface protein- (HBs)-transgenic mice with truncated HBV genome
Summary
More than 240 million people are currently chronic HBV carriers and 25% of the chronic HBVinfected patients develop severe liver diseases [1], like liver cirrhosis and hepatocellular carcinoma (HCC) [2]. Replication of wildtype HBV is not regarded as being cytopathic, several studies showed that HBV infection in some cases may cause direct liver damage by intracellular accumulation of HBs and subsequently induced ER-stress [5,8,9]. In this regard, model systems like HBs transgenic mice have been used to elucidate underlying mechanisms [5]. Transgenic mice expressing the large HBs protein (LHBs) reflect the situation in the liver of immune-suppressed HBV-infected patients demonstrated strong retention of HBs in hepatocytes especially in late phases of chronic HBV infection [5]
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