Dataset Information

Identification of an Interferon-Stimulated Long Noncoding RNA (LncRNA ISR) Involved in Regulation of Influenza A Virus Replication.

ABSTRACT: Long noncoding RNAs (lncRNAs) are involved in a diversity of biological processes. It is known that differential expression of thousands of lncRNAs occurs in host during influenza A virus (IAV) infection. However, only few of them have been well characterized. Here, we identified a lncRNA, named as interferon (IFN)-stimulated lncRNA (ISR), which can be significantly upregulated in response to IAV infection in a mouse model. A sequence alignment revealed that lncRNA ISR is present in mice and human beings, and indeed, we found that it was expressed in several human and mouse cell lines and tissues. Silencing lncRNA ISR in A549 cells resulted in a significant increase in IAV replication, whereas ectopic expression of lncRNA ISR reduced the viral replication. Interestingly, interferon-? (IFN-?) treatment was able to induce lncRNA ISR expression, and induction of lncRNA ISR by viral infection was nearly abolished in host deficient of IFNAR1, a type I IFN receptor. Furthermore, the level of IAV-induced lncRNA ISR expression was decreased either in retinoic acid-inducible gene I (RIG-I) knockout A549 cells and mice or by nuclear factor ?-light-chain-enhancer of activated B cells (NF-?B) inhibitor treatment. Together, these data elucidate that lncRNA ISR is regulated by RIG-I-dependent signaling that governs IFN-? production during IAV infection, and has an inhibitory capacity in viral replication.

SUBMITTER: Pan Q

PROVIDER: S-EPMC6829313 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Identification of an Interferon-Stimulated Long Noncoding RNA (LncRNA ISR) Involved in Regulation of Influenza A Virus Replication.

Pan Qidong Q Zhao Zhonghui Z Liao Yuan Y Chiu Shih-Hsin SH Wang Song S Chen Biao B Chen Na N Chen Yuhai Y Chen Ji-Long JL

International journal of molecular sciences 20191016 20

Long noncoding RNAs (lncRNAs) are involved in a diversity of biological processes. It is known that differential expression of thousands of lncRNAs occurs in host during influenza A virus (IAV) infection. However, only few of them have been well characterized. Here, we identified a lncRNA, named as interferon (IFN)-stimulated lncRNA (ISR), which can be significantly upregulated in response to IAV infection in a mouse model. A sequence alignment revealed that lncRNA ISR is present in mice and hum ...[more]

PMID: 31623059

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Project description: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.

Project description:BackgroundPorcine reproductive and respiratory syndrome virus (PRRSV) is one of the most significant threats to the global swine industry. It is of great importance to understand viral-host interactions to develop novel antiviral strategies. Long non-coding RNAs (lncRNAs) have emerged as critical factors regulating host antiviral immune responses. However, lncRNAs participating in virus-host interactions during PRRSV infection remain largely unexplored.MethodRNA transcripts of porcine alveolar macrophages (PAMs) infected with two different PRRSV strains, GSWW/2015 and VR2332, at 24 h post-infection were sequenced by high-throughput sequencing. Four programs namely, CNCI, CPC, PFAM, and phyloCSF, were utilized to predict the coding potential of transcripts. mRNAs co-localized or co-expressed with differentially expressed lncRNAs were considered as their targets. Fuction of lncRNAs was predicted by GO and KEGG analysis of their target mRNAs. The effect of LNC_000397 on PRRSV replication was validated by knockdown its expression using siRNA. Target genes of LNC_000397 were identified by RNA-Sequencing and validated by RT-qPCR.ResultIn this study, we analyzed lncRNA and mRNA expression profiles of PRRSV GSWW/2015 and VR2332 infected porcine alveolar macrophages. A total of 1,147 novel lncRNAs were characterized, and 293 lncRNAs were differentially expressed. mRNAs co-localized and co-expressed with lncRNAs were enriched in pathogen-infection-related biological processes such as Influenza A and Herpes simplex infection. Functional analysis revealed the lncRNA, LNC_000397, which was up-regulated by PRRSV infection, negatively regulated PRRSV replication. Knockdown of LNC_000397 significantly impaired expression of antiviral ISGs such as MX dynamin-like GTPase 1 (MX1), ISG15 Ubiquitin-like modifier (ISG15), and radical S-adenosyl methionine domain containing 2 (RSAD2).ConclusionsLNC_000397 negatively regulated PRRSV replication by inducing interferon-stimulated genes (ISGs) expression. Our study is the first report unveiling the role of host lncRNA in regulating PRRSV replication, which might be beneficial for the development of novel antiviral therapeutics.

Dataset Information

Identification of an Interferon-Stimulated Long Noncoding RNA (LncRNA ISR) Involved in Regulation of Influenza A Virus Replication.

Publications

Identification of an Interferon-Stimulated Long Noncoding RNA (LncRNA ISR) Involved in Regulation of Influenza A Virus Replication.

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