Regulation of Interferon-Stimulated Gene BST2 by a lncRNA Transcribed from a Shared Bidirectional Promoter

Abstract

Recent genome-wide studies have revealed the presence of thousands of long non-protein-coding RNAs (lncRNAs), some of which may play critical roles in the cell. We have previously shown that a large number of lncRNAs show differential expression in response to interferon (IFN)α stimulation in primary human cells. Here, we show that a subset of IFN-induced lncRNAs are positioned in proximity of protein-coding IFN-stimulated genes (ISGs). The majority of gene pairs originated from bidirectional promoters and showed positively correlated expression. We focused our analysis on a pair consisting of the known protein-coding ISG, BST2, and an un-studied putative lncRNA originating from the promoter region of BST2 in a divergent orientation. We showed that this transcript was a multi-exonic, polyadenylated long RNA that lacked protein-coding capacity. BST2 and the lncRNA were both induced in response to IFNα in diverse cell types. The induction of both genes was mediated through the JAK–STAT pathway, suggesting that IFN-stimulated response elements within the shared promoter activated the transcription of both genes. RNAi-mediated knock-down of the lncRNA resulted in down-regulation of BST2, and we could show that this down-regulation occurred at the level of transcription. Forced overexpression of this lncRNA, which we named BST2 IFN-Stimulated Positive Regulator (BISPR), resulted in up-regulation of BST2, indicating that the regulation of expression of BST2 by BISPR is mediated through interactions involving BISPR RNA itself, rather than the impact of its transcription from an adjacent locus. Importantly, upon IFN stimulation, transcriptional activation of BISPR preceded the induction of BST2, suggesting that expression of BISPR facilitated the initiation of transcription in its paired protein-coding gene. The lncRNA-mediated transcriptional regulation described in this study may help govern the expression of additional protein-coding RNAs involved in IFN response and other cellular processes.

The role of BST‐2/Tetherin in host protection and disease manifestation

“…BISPR is expressed from same promoter as BST‐2 but on the opposite direction and its transcription precedes that of BST‐2 174, 175. BISPR and BST‐2 are correlatively upregulated and post‐transcriptional inhibition of BISPR results in reductions in BST‐2 mRNA levels 174.…”

Long noncoding RNA #32 contributes to antiviral responses by controlling interferon-stimulated gene expression

“…Influenza A virus-induced lncRNA (NRAV) inhibits the host response to viral infection by suppressing ISG expression (21). bone marrow stromal cell antigen 2 (BST2) IFN-stimulated positive regulator (BISPR) was identified as a positive regulator of BST2 expression (22,23).…”

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

“…To date, several lncRNAs have been shown to play an important role in the innate immune response against influenza virus and be associated with viral pathogenesis, including NRAV (negative regulator of antiviral response)[11], NEAT1 (nuclear enriched abundant transcript 1)[30], Bst2/BISPR (bone marrow stromal cell antigen 2 IFN-stimulated positive regulator) [31,32] and VIN (virus inducible lincRNA)[33]. NRAV inhibits the transcription of interferon-stimulated genes via affecting histone modification of these genes (mainly MxA and IFITM3), resulting in the manipulation of the antiviral response[11].…”

“…LncRNA Bst2/BISPR is activated upon infection with the recombinant influenza virus that is deficient in the interferon (IFN) response blocking and after treatment with type I IFN. Bst2/BISPR regulates the expression of genomically neighboring protein-coding gene in an IFN-stimulated gene, cis bone marrow stromal cell antigen 2 (bst2), while the expression of other genes adjacent to bst2 was not affected [31,32]. It is worth noting that the host innate immune response can be regulated by the expression of NRAV, NEAT1 or Bst2/BISPR.…”

“…As far as we known, only a few lncRNAs, such as NRAV (negative regulator of antiviral response)[11], NEAT1 (nuclear enriched abundant transcript 1)[30], Bst2/BISPR (bone marrow stromal cell antigen 2 IFN-stimulated positive regulator) [31,32] and VIN (virus inducible lincRNA) [33] have been demonstrated to be associated with the innate immunity against influenza virus and viral pathogenesis. Therefore, studies are still needed to better understand the potential roles of other lncRNAs in the pathogenesis of influenza virus.…”