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.
People |
ORCID iD |
Martin Bushell (Principal Investigator) | |
Anne Willis (Co-Investigator) |
Publications
Ferland-McCollough D
(2010)
The involvement of microRNAs in Type 2 diabetes.
in Biochemical Society transactions
Ferland-McCollough D
(2012)
Programming of adipose tissue miR-483-3p and GDF-3 expression by maternal diet in type 2 diabetes.
in Cell death and differentiation
Fonseca BD
(2014)
The ever-evolving role of mTOR in translation.
in Seminars in cell & developmental biology
King HA
(2014)
Remodelling of a polypyrimidine tract-binding protein complex during apoptosis activates cellular IRESs.
in Cell death and differentiation
Kong YW
(2012)
microRNAs in cancer management.
in The Lancet. Oncology
Kress T
(2011)
The MK5/PRAK Kinase and Myc Form a Negative Feedback Loop that Is Disrupted during Colorectal Tumorigenesis
in Molecular Cell
Meijer H
(2013)
Translational Repression and eIF4A2 Activity Are Critical for MicroRNA-Mediated Gene Regulation
in Science
Meijer HA
(2014)
Regulation of miRNA strand selection: follow the leader?
in Biochemical Society transactions
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 |