Episomal HBV persistence within transcribed host nuclear chromatin compartments involves HBx

Abstract

BackgroundIn hepatocyte nuclei, hepatitis B virus (HBV) genomes occur episomally as covalently closed circular DNA (cccDNA). The HBV X protein (HBx) is required to initiate and maintain HBV replication. The functional nuclear localization of cccDNA and HBx remains unexplored.ResultsTo identify virus–host genome interactions and the underlying nuclear landscape for the first time, we combined circular chromosome conformation capture (4C) with RNA-seq and ChIP-seq. Moreover, we studied HBx-binding to HBV episomes. In HBV-positive HepaRG hepatocytes, we observed preferential association of HBV episomes and HBx with actively transcribed nuclear domains on the host genome correlating in size with constrained topological units of chromatin. Interestingly, HBx alone occupied transcribed chromatin domains. Silencing of native HBx caused reduced episomal HBV stability.ConclusionsAs part of the HBV episome, HBx might stabilize HBV episomal nuclear localization. Our observations may contribute to the understanding of long-term episomal stability and the facilitation of viral persistence. The exact mechanism by which HBx contributes to HBV nuclear persistence warrants further investigations.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0204-2) contains supplementary material, which is available to authorized users.

Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex

“…Left, Transcriptionally inactive cccDNA has a preponderance of hypoacetylated histones (empty circles) and associates with specific factors ((histone deacetylases (HDACs), transcriptional repressors, and methyltransferases)] such as HDAC1 and Nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase sirtuin 1 (Hsirt1) [10], yin yang 1 (YY1) and enhancer of zeste homolog 2 (Ezh2) [111], protein arginine methyltransferase 1 (PRMT1) [109], and PRMT5 [110]. Right, Alternatively, transcriptionally active cccDNA contains a preponderance of hyperacetylated histones (filled circles) and associates with other factors including cyclic adenosine monophosphate (cAMP) responsive element binding protein 1 (CREB) [108], CREB binding protein (CBP), P300, P300/CBP-associated factor (pCAF), PSME4 (red font, identified in this study) and HBx [10,11]. We propose that PSME4 is a viral restriction factor because of its ability to degrade acetylated histones [70,71], thereby helping to return cccDNA to an inactive state unless HBx is present to promote the degradation of PSME4.…”

A polypeptide D-TTK001 targeting HBx controls cccDNA against HBV

“…HBV X protein (HBx) as a multifunctional HBV protein is crucial for HBV replication, pathogenesis, and hepatocyte carcinogenesis 10 . HBx interacts with cccDNA and activates transcription 11 . Multiple evidence from our team and others demonstrate that HBx is a key antiviral target 2,12-14 .…”

Yin-Yang 1 and HBx protein activate HBV transcription by mediating the spatial interaction of cccDNA minichromosome with cellular chromosome 19p13.11

“…As an episomal minichromosome, we speculated whether cccDNA in nucleus can be recruited to specific nuclear regions. Currently, two studies had demonstrated that HBV cccDNA is associated with highly active transcription sites on host chromosomes [ 17 , 18 ], but the role of one specific host chromatin on HBV cccDNA has never been mentioned or analysed. In the present study, we are interested in determining whether cccDNA can make interaction with a cellular chromatin to regulate its transcriptional activity.…”