Virus manipulation of circular RNAs (circRNAs) to regulate gene expression

背景。环状rna （circRNAs）是一种丰富的内源性非编码rna，新出现的证据表明它们通过多种过程调节基因表达，包括作为miRNA海绵的功能。我们有令人兴奋的初步数据表明，宿主miRNA表达可能在KSHV裂解复制周期中失调。然而，病毒如何控制miRNA水平尚不清楚。我们的目的是验证KSHV调节circRNA生物发生以控制下游miRNA功能的假设。这将确定一种调节病毒基因表达和病毒复制的新机制。该项目的目的是确定病毒介导的宿主环状rna操纵如何调节病毒和宿主细胞基因表达。此外，该项目有可能鉴定出新的宿主细胞限制因子，以防止疱疹病毒复制，突出了治疗这一重要病毒家族的潜在治疗方法。这个项目非常新颖。一个新兴的研究领域表明，circRNA表达的操纵可以对宿主细胞基因表达产生根本性的影响。因此，该项目将研究病毒调节宿主细胞基因表达的新机制，这可以决定如何调节病毒和宿主细胞转录组以有利于病毒复制。这个项目很及时，因为这是一个新兴的研究领域。circRNAs正在成为基因表达的关键调控因子，circRNAs的异常表达可能与人类疾病有关。实验方法。该项目采用多学科方法和尖端方法，包括CircleSeq分析、生物信息学分析、成像和细胞生物学。研究将为病毒介导的宿主细胞环状rna的失调如何赋予基因表达的调节控制提供基础知识。这些过程的表征将对我们理解环状rna如何调节许多细胞和发育生物学过程并影响人类疾病产生深远的影响。因此，该项目与机械生物学领域高度相关，因为它将为circRNAs如何调节基因表达以及circRNAs表达改变如何与人类疾病相关提供基础见解。因此，该项目将研究调节基因表达的新机制，并为重要病原体提供新的抗病毒试剂。

Background. Circular RNAs (circRNAs) are abundant endogenous non-coding RNAs and emerging evidence suggest they regulate gene expression by multiple processes, including functioning as miRNA sponges. We have exciting preliminary data suggesting that host miRNA expression can be dysregulated during the KSHV lytic replication cycle. However, how the virus controls miRNA levels is unknown. We aim to test the hypothesis that KSHV regulates circRNA biogenesis to control downstream miRNA function. This will identify a novel mechanism which regulates viral gene expression and viral replication.Objectives. The aim of this project is to determine how virus-mediated manipulation of host circRNAs regulate both virus and host cell gene expression. Moreover, the project has potential to identify novel host cell restriction factors which prevent herpesvirus replication, highlighting potential therapeutic approaches for the treatment of this important family of viruses.Novelty. This project is highly novel. An emerging area of research suggests that manipulation of circRNA expression can have fundamental effects on host cell gene expression. The project will therefore investigate novel mechanisms utilised by the virus to regulate host cell gene expression which can dictate how the virus and host cell transcriptome is regulated to benefit virus replication.Timeliness. The project is timely as this is an emerging area of research. circRNAs are emerging as key regulators of gene expression and aberrant expression of circRNAs may be associated with human disease.Experimental Approach. The project utilises a multidisiplinary approach and cutting-edge methodology including CircleSeq profiling, bioinformatic analysis, imaging and cell biology.Research will provide fundamental knowledge into how virus-mediated dysregulation of host cell circRNAs may confer regulatory control in gene expression. The characterisation of these processes will have far reaching impact on our understanding of how circRNAs regulate many cell and developmental biology processes and affect human disease. Therefore this project is highly relevant to the area of mechanistic biology, as it will provide fundamental insights into how circRNAs regulate gene expression and how altered circRNAs expression is related to human disease. Thus the project will investigate novel mechanisms for regulating gene expression and also lead to new antiviral reagents for important pathogens.