Department of Molecular, Cellular, and Developmental Biology, Yale Universitygrid.47100.32, New Haven, Connecticut, USA.
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
J Virol. 2022 Apr 27;96(8):e0194621. doi: 10.1128/jvi.01946-21. Epub 2022 Mar 30.
Hepatitis C virus (HCV) is a positive-strand RNA virus that remains one of the main contributors to chronic liver disease worldwide. Studies over the last 30 years have demonstrated that HCV contains a highly structured RNA genome and many of these structures play essential roles in the HCV life cycle. Despite the importance of riboregulation in this virus, most of the HCV RNA genome remains functionally unstudied. Here, we report a complete secondary structure map of the HCV RNA genome , which was studied in parallel with the secondary structure of the same RNA obtained . Our results show that HCV is folded extensively in the cellular context. By performing comprehensive structural analyses on both data and data, we identify compact and conserved secondary and tertiary structures throughout the genome. Genetic and evolutionary functional analyses demonstrate that many of these elements play important roles in the virus life cycle. In addition to providing a comprehensive map of RNA structures and riboregulatory elements in HCV, this work provides a resource for future studies aimed at identifying therapeutic targets and conducting further mechanistic studies on this important human pathogen. HCV has one of the most highly structured RNA genomes studied to date, and it is a valuable model system for studying the role of RNA structure in protein-coding genes. While previous studies have identified individual cases of regulatory RNA structures within the HCV genome, the full-length structure of the HCV genome has not been determined . Here, we present the complete secondary structure map of HCV determined both in cells and from corresponding transcripts generated . In addition to providing a comprehensive atlas of functional secondary structural elements throughout the genomic RNA, we identified a novel set of tertiary interactions and demonstrated their functional importance. In terms of broader implications, the pipeline developed in this study can be applied to other long RNAs, such as long noncoding RNAs. In addition, the RNA structural motifs characterized in this study broaden the repertoire of known riboregulatory elements.
丙型肝炎病毒（HCV）是一种正链 RNA 病毒，仍然是全球慢性肝病的主要病因之一。过去 30 年来的研究表明，HCV 含有高度结构化的 RNA 基因组，其中许多结构在 HCV 生命周期中发挥着重要作用。尽管 RNA 调控在该病毒中非常重要，但 HCV RNA 基因组的大部分仍然没有得到功能研究。在这里，我们报告了 HCV RNA 基因组的完整二级结构图谱，该图谱与从相同 RNA 获得的二级结构平行研究。我们的结果表明，HCV 在细胞环境中广泛折叠。通过对 数据和 数据进行全面的结构分析，我们在整个基因组中鉴定出紧凑且保守的二级和三级结构。遗传和进化功能分析表明，这些元件中的许多在病毒生命周期中发挥着重要作用。除了提供 HCV 中 RNA 结构和 RNA 调控元件的综合图谱外，这项工作还为未来的研究提供了资源，旨在鉴定治疗靶点，并对这一重要的人类病原体进行进一步的机制研究。HCV 是迄今为止研究最多的具有高度结构化 RNA 基因组之一，它是研究 RNA 结构在蛋白质编码基因中的作用的有价值的模型系统。虽然之前的研究已经在 HCV 基因组中鉴定出了单个调节性 RNA 结构，但全长 HCV 基因组的结构尚未确定。在这里，我们展示了在细胞中和从相应的转录本中确定的 HCV 全长二级结构图谱。除了提供整个基因组 RNA 功能二级结构元件的综合图谱外，我们还鉴定了一组新的三级相互作用，并证明了它们的功能重要性。就更广泛的意义而言，本研究中开发的管道可应用于其他长 RNA，例如长非编码 RNA。此外，本研究中表征的 RNA 结构基序拓宽了已知 RNA 调控元件的范围。
