RNA is a dynamic molecule that underpins biological complexity through diverse mechanisms of gene regulation. Our lab studies how RNA transmits information between different genomes, cells, organisms and species.
The primary mechanism of gene regulation that we study is RNA interference (RNAi), where two different RNAs interact within an RNA-induced silencing complex (RISC) to mediate epigenetic, transcriptional or post-transcriptional gene regulation. In some organisms, including nematodes, the gene regulation mediated by RISCs is transmitted between generations (trans-generational epigenetic inheritance). In multi-organism systems (such as the gut) components of RISCs can also be transmitted between cells, organisms or species as a form of communication. We use host-pathogen systems to characterise these “trans-genome” RNA interactions, in order to understand the function and mechanism of RNA communication in living systems.
There are three primary project areas in the lab:
Viral-Host Interactions
Different viruses have evolved to produce short or long RNAs that enter host RISCs and impact gene expression. As intracellular obligate parasites, viruses provide unique models to understand how foreign RNAs can enter host RNAi pathways, how the RNAi pathways are regulated and how RNAi signals are transmitted from one cell to another. We are currently studying the viral-host RNA interactions that enable signalling from infected to uninfected cells in herpesvirus and respiratory virus infection.
Cross-Species RNA Interference
The mammalian gut is a complex ecosystem of different organisms that communicate to share resources, coordinate digestion and maintain homeostasis. In many animals, parasitic worms (helminths) are part of this ecosystem, where they promote tolerance and modulate the local environment to favour their survival. Helminths do this through the secretion of bioactive molecules and we discovered that RNAs are one of the molecules they release to directly modulate host gene expression. We have also found that certain parasitic nematodes release protein components of RISCs (Argonaute proteins), to deliver pre-loaded RISC components to cells. We want to understand how RNA transmission from a nematode to a mammal works and what role RNA communication plays in gut homeostasis and inflammation.
Cell-to-Cell Communication
From our studies of host-pathogen systems, we believe that RNA can be naturally transmitted between mammalian cells as a communication mechanism and pathogens have evolved to exploit this. We are using biochemical and genetic strategies to understand how RISC components (both RNAs and proteins) can be transmitted from one cell to another (inside or outside of extracellular vesicles). Ultimately, we want to understand the evolution of RNA-based communication, its function inside organisms, as well as its role in enabling complex multi-organism communities.