key: cord-0054135-4ko81hc4 authors: Ginn, Lucy; La Montagna, Manuela; Wu, Qinghua; Shi, Lei title: Diverse roles of long non‐coding RNAs in viral diseases date: 2020-11-27 journal: Rev Med Virol DOI: 10.1002/rmv.2198 sha: 4c1778689f9ff6ff71640d4e4dc78c63a3ee0d13 doc_id: 54135 cord_uid: 4ko81hc4 Viral infection leads to large alterations in the host transcriptome and stimulates an antiviral host immune response involving numerous proteins and signalling pathways. Long non‐coding RNAs (lncRNAs) have emerged as important regulators during viral infection. Emerging data demonstrates that lncRNAs play essential roles at the host pathogen interface modulating viral infection by either antiviral response at distinct level including pathogen recognition receptors or by epigenetic, transcriptional, and post‐transcriptional effects. Furthermore, differentially expressed lncRNAs may be employed as prognostic and diagnostic biomarkers for viral diseases. Here, we summarize the current knowledge of lncRNAs and their functions in viral infections with a specific focus on host‐virus responses. In addition, the potential implications of lncRNAs in severe acute respiratory syndrome coronavirus 2 will be discussed. known, the detailed mechanisms in individual disease and the full role of host factors in the viral response is not fully understood. According to the Encyclopedia of DNA Elements (ENCODE) project, which is the most extensive attempt yet to explore transcription in the human genome, protein-coding genes account for only 2%-3% of the total human genome. 11 In the past decade, advances in transcriptome sequencing have established that more than 90% of the human genome is transcribed and that the majority of transcriptional products are Long non-coding RNAs (lncRNAs). LncRNAs are a subset of RNAs ranging from 200 to 100, 000 nt in length and do not encode proteins. Most lncRNAs are transcribed by RNA polymerase II, are capped at the 5′ end and contain a polyadenylated tail at the 3′ end, similarly to mRNAs. They are classified as sense, antisense, bidirectional, intronic, and intergenic lncRNAs based on their position relative to protein-coding genes. 12, 13 The human genome encodes thousands of lncRNAs that were previously considered 'dark matter' or 'junk DNA' in the genome. 14 The list of annotated and functionally studied lncRNAs has expanded exponentially and it has been well established that these lncRNAs play essential roles in various biological processes, and their dysregulations have been linked to human diseases, including viral diseases. [15] [16] [17] [18] Increasing studies indicate that viruses may regulate host and/or viral gene expression through lncRNAs to maintain virus latency and replication. [19] [20] [21] Modern advances in high throughput sequencing techniques identified that a large number of lncRNAs are involved in viral infections and immunological processes. Having a more detailed understanding of the connection between lncRNAs and viruses would offer a novel perspective and may direct potential strategies for antiviral therapy to reduce the worldwide burden of viral diseases. In this review, we will summarize the role of lncRNAs in viral infection, their underlying mechanisms and discuss the role of lncRNAs in virus-related disease. Recent studies have shown that lncRNAs are important regulatory molecules in various biological and pathological processes and the function of lncRNAs is largely reflected by their subcellular location. 12 The established mechanisms can be broadly grouped into eight distinct categories ( Figure 1 ). (1) Firstly, lncRNAs can regulate chromatin modifications. For example, Rinn et al., reported that lncRNA HOTAIR directly interacts with polycomb repressive complex 2 (PRC2) and further modulates PRC2-mediated chromatin silencing. 22 (2) LncRNAs can induce chromosome looping to regulate gene expression. Xiang et al., observed that lncRNA CCAT1-L, transcribed from a locus 515 kb upstream of MYC, co-operates with the MYC transcriptional repressor CTCF to induce chromatin looping and regulate MYC transcription. 23 (3) LncRNAs can also act as transcriptional regulators. It has been reported that lncRNA MeXis is involved in LXR-dependent transcriptional regulation by recruiting the transcriptional coactivator DDX17 to the promoter of Abca1, which is critical for cholesterol efflux regulation. 24 (4) LncRNAs have also been implicated in RNA processing events such as alternative splicing. The heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds to exon 12 of protein phosphatase 1 regulatory subunit 10 (PPP1R10, also known as PNUTS) and results in an alternative spliced isoform of lncRNA PNUTS. Alternative spliced lncRNA PNUTS competitively binds to hsa-miR-205 and increases ZEB1 expression, which leads to epithelial-mesenchymal transition (EMT) and tumour development. 25 (5) Furthermore, by acting as subcellular structures lncRNAs could serve as decoy, scaffold, guide, and enhancer molecules to control protein and RNA interactions to regulate gene expression. 26 (6) As well as at a transcriptional level, lncRNAs can interact with proteins to regulate post-transcriptional processes and important signalling cascades. 12 (7) LncRNAs can also act as competitive endogenous RNAs (ceRNAs) to soak up or 'sponge' microRNAs (miRNAs) preventing the inhibitory effect of the miRNAs on their target genes. For example, Wang et al., reported that lncRNA NRF could bind hsa-miR-873 and upregulate its target RIPK1/RIPK3 and increase necrosis. 27 (8) Finally, lncRNAs could modulate mRNA stability and translation in the cytoplasm and participate in the regulation of cell-dependent processes such as cell apoptosis, migration/invasion and cell growth. 28, 29 Therefore, lncRNAs can function in many cellular processes through a variety of different mechanisms. Herein, we will summarize the fundamental mechanisms of lncRNAs in viral diseases. Viral infection not only alters host endogenous lncRNA levels but also manipulates the host genome to express viral lncRNAs that are critical for viral infection and pathogenesis. Table 2 shows some critical lncRNAs that are produced by viral infection such as polyadenylated nuclear (PAN) RNA and subgenomic flaviviral RNA (sfRNA). PAN RNA is encoded by the Kaposi sarcoma-associated herpes virus (KSHV) and was first discovered as a novel abundant 1.2 kb RNA that is transcribed by RNA polymerase II. 35 Rossetto and colleagues showed that PAN RNA prevents the repressive histone marker trimethylation of histone H3 on lysine 27 (H3K27me3) binding at the ORF50 promoter, activating KSHV gene expression. They also presented that PAN RNA binds to PRC2 to regulate the cell cycle and inflammatory cytokines. 35, 36 In addition, PAN RNA is able to enhance the stability of viral transcripts by interacting with ORF57 in the nucleus to prevent transcript degradation and facilitate nuclear mRNA export and increase cytoplasmic mRNA levels. The flaviviruses are a group of single-strand positive-sense RNA viruses including yellow fever virus, dengue virus, and West Nile virus, which cause worldwide health threats. 37 sfRNA is generated from the 3'untranslated region (3′UTR) of RNA genome through an incomplete degradation of genomic RNA by the virus 5′-3′ exoribonuclease XRN1. The stem-loop structure in the 3′UTR, which is resistant to nuclease XRN1 degradation, promotes the formation of sfRNA. 38, 39 Fragile X mental retardation protein (FMRP), a known cellular mRNA translational repressor, has been reported as a negative regulator against viral infection. SfRNA directly interacts with FMRP and antagonizes its function and upregulates FMRP target genes in cell culture and mice. 40 Pijlman et al., also demonstrated that the production of sfRNA enhances viral pathogenicity. 41 Therefore, the expression of viral lncRNAs, as well as differentially (2), regulating or binding to transcription factors (3), participating in pre-mRNA alternative splicing (4), acting as decoy, enhancer, scaffold or guide to control gene interaction or expression (5) . Cytoplasmic lncRNAs control gene expression by interacting with protein (6), serving as sponge of miRNAs (7), and promoting or inhibiting mRNA stability (8) . lncRNAs, Long non-coding RNAs expressed host lncRNAs, are important in viral gene expression and the viral response. To produce a successful infection, viruses must interfere with host cells to facilitate viral replication. 42 and A2/B1 in cytosolic and nuclear compartments to regulate immune genes and inflammatory response ( Figure 2 ). 65 Although the TLR induced viral response leads to the upregulation of lncRNAs that modulate the innate immune response, the precise downstream mechanisms of lncRNAs/TLRs in antiviral immune response have yet to be fully explored and further study is required. Interferons are leading pro-inflammatory cytokines and immunomodulatory factors in antiviral immune response. 66 (Figure 3a) . 76 On the other hand, HIV-induced NEAT1 could inhibit HIV production by increasing nucleus-to-cytoplasm export of instability element HIV RNAs into paraspeckles and further modulate HIV1 mRNAs. 77 Figure 3b ). 79 that modulate viral replication and immune responses positively or negatively, further study is required to investigate the crosstalk between lncRNAs and NF-κB transcriptional regulation. Increasing studies made over the past decade support the idea that lncRNAs control transcription via chromatin modification, and this may be a key method of lncRNA regulation in the antiviral response. 80 Lastly, the ongoing SARS-CoV-2 pandemic causes a significant threat to human health however, the biology and mechanism of pathogenicity are limited. Although little is known about SARS-CoV-2 antiviral response, information can most likely be extrapolated from SARS-CoV and MERS-CoV based mechanisms. 108, 109 Type I and II IFNs responses, the production of cytokines and chemokines and the activations of key transcriptions factors like NF-κB and AP-1 may help SARS-CoV-2 to escape from the host immune surveillance and eventually enhance viral replication. The well-established functions of lncRNAs in these biological processes may offer a tool to further understand the antiviral innate immunity upon coronavirus infection. Extensive evidence strongly supports the key roles of lncRNAs in transcription, replication, and immunity during the antiviral response. However, the function of virus regulated lncRNAs with experimentally verified functions remain to be further investigated. In conclusion, a more extensive comprehension gained on the roles of lncRNAs in viral diseases may help identify potential therapeutic strategies in the future. 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The authors declare that they have no competing interests. Lei Shi revised each step in the work and was responsible for the final revision. Data sharing is not applicable to this article as no new data were created or analysed in this study. https://orcid.org/0000-0003-4027-2396