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The genus Flavivirus is a group of single-stranded, positive-sense RNA viruses that includes numerous human pathogens with global impact, such as dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and Zika virus (ZIKV). The approximately 11-kilobase genome is flanked by highly structured untranslated regions (UTRs), which contain various cis-acting RNA elements with unique structures and functions. Moreover, local RNA elements circularize the genome non-covalently through long-range interactions. Interestingly, many flavivirus cis-acting RNA elements contain group-specific motifs or are specific for the given phylogenetic groups, suggesting their potential association with flavivirus evolution and diversification. In this review, we summarize recent advances about the structure and function of cis-acting RNA elements in flavivirus genomes and highlight the potential implications for flavivirus evolution. Finally, the scientific questions remained to be answered in the field are also discussed., (© 2019 John Wiley & Sons, Ltd.) more...

Most mosquito-borne flaviviruses, including Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV), produce long non-coding subgenomic RNAs (sfRNAs) in infected cells that link to pathogenicity and immune evasion. Until now, the structural characterization of these lncRNAs remains limited. Here, we studied the 3D structures of individual and combined subdomains of sfRNAs, and visualized the accessible 3D conformational spaces of complete sfRNAs from DENV2, ZIKV, and WNV by small angle X-ray scattering (SAXS) and computational modeling. The individual xrRNA1s and xrRNA2s adopt similar structures in solution as the crystal structure of ZIKV xrRNA1, and all xrRNA1-2s form compact structures with reduced flexibility. While the DB12 of DENV2 is extended, the DB12s of ZIKV and WNV are compact due to the formation of intertwined double pseudoknots. All 3' stem-loops (3'SLs) share similar rod-like structures. Complete sfRNAs are extended and sample a large conformational space in solution. Our work not only provides structural insight into the function of flavivirus sfRNAs, but also highlights strategies of visualizing other lncRNAs in solution by SAXS and computational methods., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.) more...

The structural flexibility of RNA underlies fundamental biological processes, but there are no methods for exploring the multiple conformations adopted by RNAs in vivo. We developed cross-linking of matched RNAs and deep sequencing (COMRADES) for in-depth RNA conformation capture, and a pipeline for the retrieval of RNA structural ensembles. Using COMRADES, we determined the architecture of the Zika virus RNA genome inside cells, and identified multiple site-specific interactions with human noncoding RNAs. more...