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

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.