CircRNA Expression Patterns and circRNA-miRNA-mRNA Networks During CV-A16 Infection of SH-SY5Y Cells

Abstract

Coxsackievirus A16 (CV-A16) has caused worldwide epidemics of hand, foot, and mouth disease (HFMD), particularly among infants and preschool children. Circular RNAs (circRNAs) are a recently identified class of noncoding RNA molecules that participate in the occurrence and development of numerous infectious diseases. To date, the function of circRNAs has been a heavily researched topic, and their role in CV-A16 infection has not been fully elucidated. In this study, the viral effects of CV-A16 on the cellular circRNA transcriptome were investigated using next-generation sequencing technology. In this study, a total of 8726, 8611 and 6826 circRNAs were identified in the control, CV-A16-12 h and CV-A16-24 h groups, respectively. Further analysis showed that 1769 and 1192 circRNAs were differentially expressed in the CV-A16-12 h and CV-A16-24 h groups, respectively. Moreover, the common differentially expressed circRNAs were screened out and used for functional annotation analysis, which demonstrated that the parent genes of differentially expressed circRNAs might be associated with the viral infection process, especially the “Immune system process” in GO analysis and the “Inflammation mediated by chemokine and cytokine signaling pathway” in KEGG analysis. Additionally, 6 dysregulated circRNAs were selected for validation and were verified to be consistent with the sequencing results. Additionally, we further constructed a circRNA-miRNA-mRNA regulatory network that suggested the putative function of circRNAs as cellular miRNA decoys to indirectly regulate gene expression during CV-A16 infection, especially the hsa_circ_0004447/hsa-miR-942-5p/MMP2, hsa_circ_0078617/hsa-miR-6780b-5p/MMP2 and hsa_circ_0078617/hsa-miR-5196-5p/MMP2 regulatory axes. Considering all of these results, to the best of our knowledge, this study is the first to present a comprehensive overview of circRNAs induced by CV-A16, and this research demonstrated that a network of enriched circRNAs and circRNA-associated competitive endogenous RNAs (ceRNAs) is involved in the regulation of CV-A16 infection, thereby helping to elucidate the mechanisms underlying CV-A16-host interactions.

Expression Profiles of Differentially Expressed Circular RNAs and circRNA–miRNA–mRNA Regulatory Networks in SH-SY5Y Cells Infected with Coxsackievirus B5

“…Enrichment analysis showed that enriched GO-BP terms mainly focused on the "metabolic process" and "protein modification," which was largely consistent with EV71 or CV-A16 virus infection. However, enrichment analysis of SH-SY5Y cells infected with EV71 or CA-16 indicated association with the "gonadotropin-releasing hormone receptor pathway," "Wnt signaling pathway," "angiogenesis," and "p53 pathway", which were not present in our analysis with CVB5 infection [24,25]. In our study, host genes that correspond to the differentially expressed circRNAs were mainly involved in "ubiquitin mediated proteolysis", "tight junction," and the regulation of other signaling pathways, such as the MAPK pathway.…”