RNA interference (RNAi) is a fundamental mechanism of genome regulation whereby small RNAs direct silencing of target loci based on sequence complementarity. Our aim is to understand the diverse mechanisms and functions of small RNA-mediated regulation, which plays important roles in gene regulation, genome stability and host-pathogen interactions.
We have recently begun investigating RNAi in Cryptococcus neoformans, an opportunistic human fungal pathogen responsible for ~15% of HIV/AIDS-related deaths worldwide. Genome sequencing of different environmental and clinical isolates has revealed that while most Cryptococcus strains appear to encode functional RNAi pathways, some have lost RNAi, hinting at possible links between RNAi, genome stability and pathogenicity. We are therefore keen to understand the function of RNAi in Cryptococcus strains that retain RNAi, and the consequences of its loss. To this end, we have begun studies in a lab strain that retains a full complement of RNAi components, including two of each of the core RNAi pathway components, Dicer and Argonaute. Our preliminary analyses of deletion mutants suggest that these proteins are involved in processing small RNAs corresponding to overlapping but distinct sets of genomic loci. However, the function of these pathways remains poorly understood.
The aim of this project is to further investigate the function of RNAi in Cryptococcus. We will begin by interrogating recently acquired small RNA sequencing data to analyse relationships between small RNAs, biogenesis factors and target sequences, to characterise functional pathways. Where functional specificity is observed, e.g. between Ago1 and Ago2, we will assess features and potential drivers of this specificity. These computational approaches will be coupled with experimental work to explore the functional consequences of loss of RNAi components, determine molecular mechanisms of RNAi-mediated regulation, and identify and characterise further novel components contributing to RNAi function. We expect the outcomes of this project to advance understanding of both fundamental mechanisms of RNAi, and the biology of a medically-significant fungal pathogen.
This interdisciplinary project will provide training in a broad range of molecular biology techniques including CRISPR-Cas9 genome editing, DNA, RNA and protein analyses, chromatin-IP, proteomics, and next-generation sequencing approaches. It will also provide training in bioinformatic analysis and statistics, data visualisation, and programming using the R framework. The focus of the project including the balance between experimental and computational approaches can also be tailored to the particular interests of the student.
http://bayne.bio.ed.ac.uk/
https://www.research.ed.ac.uk/en/persons/cei-abreu-goodger
https://scholar.google.com/citations?user=tAeWw8AAAAAJ&hl=en
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