Fig. 3

Molecular mechanisms of induction of aberrant DNA methylation by hepatitis B virus (HBV). Two mechanisms of HBV-induced DNA methylation have been proposed: a direct effect via hepatitis B virus protein X (HBx) and an indirect effect via chronic inflammation. In the direct mechanism, after HBV infection of hepatocytes, viral DNA is transferred into the nucleus and transcribed. HBx is translated using the host machinery, transported back to the nucleus, and involved in upregulation of DNMT genes and recruitment of DNMTs to target genes. In the indirect mechanism, chronic inflammation triggered by HBV infection induces NK cell accumulation, increased Ifng expression, and reactive oxygen species (ROS) production. Although the molecular details remain to be elucidated, an NK-cell-dependent innate immune response is important for methylation induction