Episomal HBV persistence within transcribed host nuclear chromatin compartments involves HBx

Epigenetics Chromatin. 2018 Jun 22;11(1):34. doi: 10.1186/s13072-018-0204-2.


Background: In 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.

Results: To 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.

Conclusions: As 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.

Keywords: Chromatin fiber loops; Epigenome; Episome; HBxAg; Host–pathogen interaction; Oncogene; Supranucleosomal structure; TADs; Transcription factories; X-protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line
  • Cell Nucleus / genetics*
  • Cell Nucleus / metabolism
  • Chromatin Immunoprecipitation
  • DNA, Viral / metabolism
  • Hep G2 Cells
  • Hepatitis B virus / genetics*
  • Hepatitis B virus / metabolism
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Hepatocytes / virology*
  • Host-Pathogen Interactions
  • Humans
  • Plasmids / metabolism*
  • Protein Domains
  • Sequence Analysis, RNA
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Viral Regulatory and Accessory Proteins


  • DNA, Viral
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein