MicroRNA-939 restricts Hepatitis B virus by targeting Jmjd3-mediated and C/EBPα-coordinated chromatin remodeling

Sci Rep. 2016 Oct 25:6:35974. doi: 10.1038/srep35974.

Abstract

Multi-layered mechanisms of virus host interaction exist for chronic hepatitis B virus (HBV) infection, which have been typically manifested at the microRNA level. Our previous study suggested that miRNA-939 (miR-939) may play a potential role in regulating HBV replication. Here we further investigated the mechanism by which miR-939 regulates HBV life cycle. We found that miR-939 inhibited the abundance of viral RNAs without direct miRNA-mRNA base pairing, but via host factors. Expression profiling and functional validation identified Jmjd3 as a target responsible for miR-939 induced anti-HBV effect. Jmjd3 appeared to enhance the transcription efficiency of HBV enhancer II/core promoter (En II) in a C/EBPα-dependent manner. However, the demethylase activity of Jmjd3 was not required in this process. Rather, Jmjd3's transactivation activity depended on its interaction with C/EBPα. This coordinated action further recruited the Brm containing SWI/SNF chromatin remodeling complex which promoted the transcription of HBV RNAs. Taken together, we propose that the miR-939-Jmjd3 axis perturbs the accessibility of En II promoter to essential nuclear factors (C/EBPα and SWI/SNF complex) therefore leading to compromised viral RNA synthesis and hence restricted viral multiplication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • Cell Line
  • Chromatin Assembly and Disassembly*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Hepatitis B virus / immunology
  • Hepatitis B virus / physiology*
  • Hepatocytes / virology
  • Host-Pathogen Interactions*
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • MicroRNAs / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA, Viral / biosynthesis
  • Transcription Factors / metabolism
  • Virus Replication*

Substances

  • CCAAT-Enhancer-Binding Protein-alpha
  • Chromosomal Proteins, Non-Histone
  • MIRN939 microRNA, human
  • MicroRNAs
  • RNA, Viral
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors
  • Jumonji Domain-Containing Histone Demethylases
  • KDM6B protein, human