I carried out my PhD from 1998-2001 with Professor Anne Willis at the University of Leicester on internal ribosome entry site (IRES)-mediated translation. Following my PhD I obtained a Wellcome Trust International Research Fellowship, which provided funding for me to work as a postdoctoral researcher with Professor Peter Sarnow at Stanford University, USA from 2002-5. At Stanford, I worked on a liver-specific microRNA, miR-122, and demonstrated that it interacts directly with hepatitis C virus (HCV) RNA and has an essential positive role in HCV replication. I spent the final year of my fellowship in Professor Richard Jackson's group at the University of Cambridge, where I continued with my previous research. In 2007 I came to Nottingham as part of the RNA Biology Group, and was awarded a BBSRC David Phillips Fellowship to start my own research group, with a focus on understanding miRNA regulation of viral replication. This ran from September 2008 to August 2013. In September 2013 I was appointed Lecturer in the School of Pharmacy.
I convene the Future Medicines module in year 4 of the MPharm course, and also teach gene therapy and RNA therapeutics material within this module.
I convene, and teach virology in, the Infection and Immunity module in year 2 of the MSci course.
Hepatitis C virus (HCV) is a hepatotropic, positive sense, RNA virus that infects 2% of the global population. HCV frequently establishes chronic infections that eventually lead to liver cirrhosis… read more
ZHUANG X, MAGRI A, HILL M, LAI AG, KUMAR A, RAMBHATLA SB, DONALD CL, LOPEZ-CLAVIJO AF, RUDGE S, PINNICK K, CHANG WH, WING PAC, BROWN R, QIN X, SIMMONDS P, BAUMERT TF, RAY D, LOUDON A, BALFE P, WAKELAM M, BUTTERWORTH S, KOHL A, JOPLING CL, ZITZMANN N and MCKEATING JA, 2019. The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication. Nature communications. 10(1), 377
DHIR A, DHIR S, PROUDFOOT NJ and JOPLING CL, 2015. Microprocessor mediates transcriptional termination of long noncoding RNA transcripts hosting microRNAs. Nature structural & molecular biology. 22(4), 319-327
School of Pharmacy Building, East Drive, University Park, Nottingham, NG7 2RD
Hepatitis C virus (HCV) is a hepatotropic, positive sense, RNA virus that infects 2% of the global population. HCV frequently establishes chronic infections that eventually lead to liver cirrhosis and hepatocellular carcinoma. Current treatments are often ineffective and have high associated toxicity, and a greater understanding of viral biology is necessary to develop improved therapies.
MicroRNAs (miRNAs) are 21-23 nucleotide (nt) single-stranded RNA molecules that have recently been identified in a broad range of eukaryotic organisms. They are encoded as part of longer transcripts that undergo successive nuclear and cytoplasmic processing steps to yield a mature miRNA, which functions in association with a complex of proteins known as the miRNP. In animals most miRNAs have been found to function by associating with imperfect complementarity with sites in the 3' untranslated regions (UTRs) of mRNA targets. This results in the repression of gene expression by a process that is not yet fully understood, although inhibition of translation and RNA degradation are both implicated.
Mammalian miRNAs show a high degree of specificity of expression, both by developmental stage and by tissue type. miR-122 is a highly liver-specific miRNA that accounts for 70% of the total miRNA content of the liver. My postdoctoral research showed that miR-122 binds directly to two adjacent sites in the 5'UTR of HCV RNA, and that this binding is required to maintain HCV RNA levels in Huh7 cells. MiR-122 appears to act at the level of viral replication, as translation is unaffected. This positive role in viral replication is a novel mode of action for a miRNA.
Regulation of HCV by miR-122
One focus of current research is understanding the mechanism of miR-122 regulation of HCV in more detail and identifying the RNA and protein factors that are involved.
We are also interested in understanding the biogenesis of miR-122 and other miRNAs. miR-122 is located within a long noncoding (lnc)RNA primary (pri-miRNA) transcript. In collaboration with Nick Proudfoot at the University of Oxford, we found that pri-miR-122 and other lnc-pri-miRNAs use an unusual method of transcription termination that is directly driven by excision of the precursor miRNA hairpin by the Microprocessor complex. We are now investigating the interplay between cotranscriptional processes and miRNA biogenesis in different classes of miRNA gene.
miRNA subcellular localisation
Our third area of research focuses on understanding miRNA function at different locations within the cell.