Identification of mechanism(s) of miRNA- mediated repression of translation

Lead Research Organisation: University of Nottingham
Department Name: Sch of Pharmacy

Abstract

Recently, a completely new way of controlling gene expression has been identified. This has come to light after the discovery of a whole new class of genes comprising very small RNA molecules, that unlike most genes do not produce proteins. There are at least 800 of these small RNA molecules within the human genome which have different effects. They work by binding to the mRNA of other genes and inhibiting the target genes from being made into proteins. Each of these 800 small molecules is believed to interact with 100 other genes, thus adding to the complexity of the regulation of the human genome. Already it has become clear that malfunction of miRNA regulation is associated with a growing list of human disease, including: cancer; diabetes; and viral infections. In 2002 Science magazine called miRNA the breakthrough of the year and these small RNA molecular have been termed the 'Dark Matter of the cell'. At present there is great controversy within the scientific community over how these small RNA molecules repress gene expression. Laboratories around the world have shown conflicting data for how this repression mechanism functions, and have failed to reproduce each other's data. We have, for the first time, been able to shown both repression mechanisms operating and determined how these difference are occurring. We are now in a unique position to investigate the different mechanisms and to determine which genes are regulated by the different repression systems. This will lead to a great impact on the way in which we understand gene expression and the complexity of the human genome.

Technical Summary

microRNAs comprise of 2-3% of the cellular genome and exert their phenotype influence via interacting with imperfect complementary to the 3`untranslated regions (UTR) of mRNAs. It has been suggested that between 74-92% of mRNAs are regulated by microRNAs. The mechanisms of regulation appear to occur primarily at the level of translation. However there is a dispute in the field about the mechanism(s) used to achieve miRNA-mediated repression with data from some laboratories suggesting a block at translation initiation whilst other data strongly showing a post-initiation inhibition. We have been able to show that the promoter element dictates whether the repression mechanisms occur at the level of initiation or post initiation. We are now in a unique position to investigate both the factors which mediate this types of regulation and which genes are controlled by the two different mechanisms.

Publications

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Ferland-McCollough D (2010) The involvement of microRNAs in Type 2 diabetes. in Biochemical Society transactions

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Fonseca BD (2014) The ever-evolving role of mTOR in translation. in Seminars in cell & developmental biology

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Kong YW (2012) microRNAs in cancer management. in The Lancet. Oncology

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Meijer HA (2014) Regulation of miRNA strand selection: follow the leader? in Biochemical Society transactions

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Wilczynska A (2015) The complexity of miRNA-mediated repression. in Cell death and differentiation

 
Description Meijer HA, Kong YW, Lu WT, Wilczynska A, Spriggs RV, Robinson SW, Godfrey JD, Willis AE, Bushell M*. Translational repression and eIF4A2 activity are critical for microRNA-mediated gene regulation. Science, 2013, 340:82-5.
First description of the central role of a DEAD-box RNA helicase in miRNA-mediated repression. We demonstrated that translation repression is a prerequisite to subsequent mRNA decay. 5'UTR structure was shown to correlate with presence of miRNA target sites within the 3'UTR of an mRNA.
Exploitation Route We are still investigating outputs from this award. This has led to drug discovery activities in this area with Cancer Research Technology
Sectors Manufacturing

including Industrial Biotechology

 
Description This research has greatly enhanced our research understanding of how microRNAs control gene expression. It has in part lead to a publication in Science
First Year Of Impact 2013
Sector Manufacturing, including Industrial Biotechology
 
Description Research collaboration resulting in a BBSRC grant 
Organisation Medical Research Council (MRC)
Department MRC Centre for Obesity and Related Metabolic Diseases
Country United Kingdom 
Sector Academic/University 
PI Contribution I was a co-PI on this two site award
Collaborator Contribution This award is a joint proposal and split 50/50
Impact 2 BBSRC grants 2 research papers
Start Year 2006
 
Description Invited talk at the Mellanby Centre for Bone Research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk on miRNA mechanisms
Year(s) Of Engagement Activity 2017