Virus manipulation of host non-coding RNA regulatory networks

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It has been known for some years that only ~2% of the human genome encodes for proteins, whereas ~80% is actively transcribed into RNAs with no obvious coding capacities, known as non-coding RNAs (ncRNAs). The importance of this non-coding transcriptome is emphasised due to the fact that ncRNAs are frequently altered in many human diseases, including aging, cancer, auto-immunity and infections. Functional studies have shown that ncRNAs are critical regulators of gene expression. For example, a group of short ncRNAs known as microRNAs (miRNAs), modulate gene expression by binding to their target protein coding transcript, which leads either to the transcript's translation repression, cleavage or decay. As such, research in this area has mainly focussed on identifying the interaction between specific miRNAs and their target transcript(s). However, emerging evidence now suggests the existence of an unexpected interplay between different ncRNAs that strongly influences, for example, how a miRNA can bind to its target. In this case, other ncRNA species, such as circular RNAs and other long ncRNAs, function as competing endogenous RNAs, interacting with miRNAs to sponge or decoy the miRNA, thus inhibiting the miRNA from binding to the target mRNA and preventing its repression. As such, this network of ncRNA-ncRNA interactions can have a profound effect on the regulation of gene expression in many cellular processes.We have exciting preliminary data suggesting that a herpesviruses has evolved ways to manipulate these ncRNA regulatory networks to enhance virus gene expression and modulate the host response to infection. We have demonstrated that during herpesvirus infection several circular RNAs are upregulated whereas the majority of dysregulated miRNAs are downregulated. This suggests that these virus-induced circular RNAs could sponge specific miRNAs to outcompete their binding to target protein coding transcripts and prevent their repression or degradation. We now aim to further investigate these observations and identify the interplay between ncRNA species and their associated regulatory networks which are manipulated by the virus. Furthermore, we will determine why these regulatory networks are altered during infection by determining the role of the target protein-coding transcripts that are aberrantly expressed due to the manipulation of their respective networks. Moreover, we will investigate novel mechanisms of how a virus enhances circular RNA levels during infection. Finally, we have identified a group of miRNAs that in contrast to the majority of downregulated miRNAs are actually increased during infection, which suggests the virus enhances their production to repress or degrade cellular transcripts which are probably detrimental to virus infection. We will determine how the viruses upregulates these miRNAs and also determine the inhibitory role of their target mRNAs in virus replication.In summary, this project will identify novel ways a virus can manipulate the host cell to enhance its own replication and provide a better understanding how the interplay between different ncRNA species can regulate gene expression. A better knowledge of these fundamental processes has the potential for far reaching impacts on our understanding of cell and developmental biology processes, the development of human disease and provide new strategies for therapeutic interventions of important human pathogens.