Abstract
Epstein-Barr virus (EBV) has been recently found to generate novel circular RNAs (circRNAs) through backsplicing. However, comprehensive catalogs of EBV circRNAs in other cell lines and their functional characterization are still lacking. In this study, we have identified a list of putative EBV circRNAs in GM12878, an EBV-transformed lymphoblastoid cell line, with a significant majority encoded from the EBV latent genes. A novel EBV circRNA derived from the exon 5 of LMP-2 gene which exhibited highest prevalence, was further validated using RNase R assay and Sanger sequencing. This circRNA, which we term circLMP-2_e5, can be universally detected in a panel of EBV-positive cell lines modelling different latency programs. It ranges from lower expression in nasopharyngeal carcinoma (NPC) cells to higher expression in B cells, and is localized to both the cytoplasm and the nucleus. We provide evidence that circLMP-2_e5 is expressed concomitantly with its cognate linear LMP-2 RNA upon EBV lytic reactivation, and may be produced as a result of exon skipping, with its circularization possibly occurring without the involvement of cis elements in the short flanking introns. Furthermore, we show that circLMP-2_e5 is not involved in regulating cell proliferation, host innate immune response, its linear parental transcripts, or EBV lytic reactivation. Taken together, our study expands the current repertoire of putative EBV circRNAs, broadens our understanding of the biology of EBV circRNAs, and lays the foundation for further investigation of their function in the EBV life cycle and disease development.
Highlights
Epstein-Barr virus (EBV) is a lymphotropic DNA herpesvirus that infects approximately 95% of the world’s population[1]
Based on the EBV backspliced junctions (BSJs) detected by psirc and find_circ algorithms, 60% (133/188) and 56% (23/41) of putative circRNAs are produced from EBV latent genes, respectively (Fig. 1a, Tables S1–S2)
A majority of the EBV circRNAs candidates were encoded by EBNAs and most of them fall within the W1–W2 repeats region, with only one exception
Summary
Epstein-Barr virus (EBV) is a lymphotropic DNA herpesvirus that infects approximately 95% of the world’s population[1]. EBV remains latent in infected memory B-cells[4] and with periodic reactivation of lytic replication, the salivary glands within. CircRPMS1_E4_E3a was reported to be one of the most abundant circRNAs found in EBV-positive cell lines of different latencies, NPC and GC patient-derived xenografts, as well as in patient samples from NPC, GC and post-transplant lymphoproliferative disorders (PTLDs)[17,18,19]. We report an in silico analysis of putative EBV circRNAs expressed in the GM12878 cells, an EBVpositive lymphoblastoid cell line with type III latency, and investigate the role of EBV circRNA in regulating host or viral genes and/or signaling pathways. We characterize the expression of circLMP-2_e5 across a panel of cell lines of different EBV latencies as well as in the lytic state, and investigate its biogenesis and potential functions
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