Retinoid X Receptor α-Dependent HBV Minichromosome Remodeling and Viral Replication

Abstract

Background and aim. The HBV covalently closed circular DNA (cccDNA) is organized into a minichromosome in the nuclei of infected hepatocytes through interactions with histone and nonhistone proteins. Retinoid X receptor a (RXRa), a liver-enriched nu-clear receptor, participates in regulation of HBV replication and transcription through modulation of HBV enhancer 1 and core promoter activity.Material and methods. This study investigated RXRa involvement in HBV cccDNA epigenetic modifications. Quantitative cccDNA chromatin immunoprecipitation (ChIP) was applied to study the recruitment of RXRa, histones, and chromatin-modifying enzymes to HBV minichromosome in HepG2 cells after transfection of the linear HBV genome.Results. RXRa was found to directly bind to HBV cccDNA; recruitment of RXRa to HBV minichromosome paralleled HBV replication, histone recruitment, and histone acetylation in HBVcccDNA. Moreover, RXRa overexpression or knock-down significantly increased or impaired the recruitment of the p300 acetyltransferase to cccDNAminichromosome.Conclusions. Our results confirmed the regulation of RXRa on HBV replication in vitro and demonstrated the modulation of RXRa on HBV cccDNA epigenetics. These findings provide a profound theoretical and experimental basis for late-model antiviral treatment acting on the HBV cccDNA and minichromosome.

Keywords

• Hepatitis B virus (HBV)
• Covalently closed circular DNA (cccDNA)
• Retinoid X receptor α (RXRα)
• Viral minichromosome remodeling