Regulation of hepatitis B virus replication by epigenetic mechanisms and microRNAs

The hepatitis B virus (HBV) genome forms a covalently closed circular DNA (cccDNA) minichromosome that persists in the nucleus of virus-infected hepatocytes. HBV cccDNA serves as the template for viral mRNA synthesis and is subject to epigenetic regulation by several mechanisms, including DNA methylation and histone acetylation. Recently, microRNAs (miRNAs), a class of small non-coding RNAs, were also directly connected to the epigenetic machinery through a regulatory loop. Epigenetic modifications have been shown to affect miRNA expression, and a sub-group of miRNAs (defined as epi-miRNAs) can directly target effectors of the epigenetic machinery. In this review, we will summarize recent findings on the epigenetic mechanisms controlling HBV cccDNA function, primarily focusing on the epi-miRNA functions operating in HBV replication. Investigation of the epigenetic regulation of HBV replication may help to discover novel potential therapeutic targets for drug development with the goal to eradicate the HBV cccDNA pool in hepatocytes.