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.
Highlights
Hepatitis B virus (HBV) infection remains as one of the most prevalent viral infection in human beings
Since our previous report indicated that introduction of miR-939 in Huh[7] cells can inhibit the secretion of viral antigens[17], we hypothesized that miR-939 served as a negative regulator of hepatitis B virus (HBV) replication or transcription
A 40% reduction of HBV pregenomic RNA (pgRNA) and other messenger RNA (mRNA) transcripts was observed at 25 nM of miR-939 and up to 80% at 100 nM, compared with mimic control while miR-1290 mimic did not have a significant effect on HBV transcription (Fig. 1A)
Summary
Hepatitis B virus (HBV) infection remains as one of the most prevalent viral infection in human beings. The virion DNA is transported into the nucleus and transforms into covalently closed circular DNA (cccDNA) which serves as genome reservoir and template for transcription of four major transcripts, i.e., 3.5 kb pregenomic RNA (pgRNA) and 2.4 kb, 2.1 kb, 0.7 kb RNAs4. The altered miRNA expression may directly target viral transcripts, or modulate host genes involved in the viral replication machinery. A liver-specific microRNA, miR-122, was found to bind to the highly conserved HBV pregenomic RNA (pgRNA) sequence via base-pairing interactions, inhibiting viral gene expression and replication[15]. We propose that the transcriptional complex composed of Jmjd[3] and C/EBPαcoordinated recruitment of Brm containing SWI/SNF chromatin remodeling complex to HBV DNA
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