Cytoplasmic regulation of mRNAs during early vertebrate development: Mechanisms and roles of RNA-protein interactions
Lead Research Organisation:
MRC Human Genetics Unit
Abstract
The control of protein production in the body is vital for health. All proteins are products of particular genes and these have to be turned on at the right times, places and in the right amount to ensure proper cell function. This process is called gene expression. One level at which gene expression is controlled is called translation, in which mRNA templates copied from genes are used as instructions to build proteins. Recent research has shown that when the processes that control translation fail, it can lead to a wide variety of human diseases including cancers, neurological, metabolic and reproductive disorders.|By focusing on related families of translational regulators, we aim to discover the general mechanisms by which these classes of proteins function and also to increase our knowledge of pathways leading to a variety of genetic disorders. This may ultimately lead to better treatment.
Technical Summary
The overall scientific aim of this program is to understand the fundamental mechanisms and roles of regulating mRNA translation. Recent data suggests that 40-60% of vertebrate mRNAs are controlled at the level of translation and that breakdowns in this process can lead to disease. Despite this, the roles and underlying mechanisms of translational control are poorly understood. Thus dissecting their contribution to normal biology and human disease is a priority. We focus on three basic questions regarding RNA-protein complexes that regulate translation of specific mRNAs. Firstly, the identification of trans-acting factors that regulate translation. Secondly, the mechanisms by which these RNA-protein complexes function. Thirdly, what are the roles of these RNA-protein complexes in biological processes such as development and in disease.
People |
ORCID iD |
| Nicola Gray (Principal Investigator) |
Publications
Burgess HM
(2010)
mRNA-specific regulation of translation by poly(A)-binding proteins.
in Biochemical Society transactions
Burgess HM
(2011)
Nuclear relocalisation of cytoplasmic poly(A)-binding proteins PABP1 and PABP4 in response to UV irradiation reveals mRNA-dependent export of metazoan PABPs.
in Journal of cell science
Collier B
(2005)
The DAZL family proteins are PABP-binding proteins that regulate translation in germ cells.
in The EMBO journal
Dickson KS
(2001)
Poly(A) polymerase and the regulation of cytoplasmic polyadenylation.
in The Journal of biological chemistry
Dinour D
(2010)
Homozygous SLC2A9 mutations cause severe renal hypouricemia.
in Journal of the American Society of Nephrology : JASN
Gorgoni B
(2011)
Poly(A)-binding proteins are functionally distinct and have essential roles during vertebrate development.
in Proceedings of the National Academy of Sciences of the United States of America
Gorgoni B
(2004)
The roles of cytoplasmic poly(A)-binding proteins in regulating gene expression: a developmental perspective.
in Briefings in functional genomics & proteomics
Gorgoni B
(2005)
The stem-loop binding protein stimulates histone translation at an early step in the initiation pathway.
in RNA (New York, N.Y.)
Gray NK
(2000)
Multiple portions of poly(A)-binding protein stimulate translation in vivo.
in The EMBO journal
| Description | Biochemical Society |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Membership of a guideline committee |
| Description | Biochemical Society |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Membership of a guideline committee |
| Description | Biochemical Society |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Membership of a guideline committee |
| Description | Biochemical Society |
| Geographic Reach | Multiple continents/international |
| Policy Influence Type | Participation in a advisory committee |
| Description | BBSRC repsonsive mode |
| Amount | £792,997 (GBP) |
| Funding ID | BB/P022065/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2017 |
| End | 09/2020 |
| Description | Marie Curie |
| Amount | £185,000 (GBP) |
| Funding ID | MARS |
| Organisation | European Union |
| Sector | Public |
| Country | European Union (EU) |
| Start | 04/2017 |
| End | 04/2019 |
| Description | Program grant |
| Amount | £1,868,414 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2012 |
| End | 03/2016 |
| Description | Project grant |
| Amount | £293,130 (GBP) |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2011 |
| End | 07/2013 |
| Description | Project grant PABP5 |
| Amount | £657,064 (GBP) |
| Funding ID | BB/J01687X/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 02/2013 |
| End | 01/2016 |
| Description | Wellcome Trust Project Grant (Translational control by the multi-functional Herpes Simplex Virus Type I protein, ICP27) |
| Amount | £225,871 (GBP) |
| Funding ID | 084359 |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 08/2008 |
| End | 07/2011 |
| Description | Wellcome Trust Project Grant (Translational regulation in germ cells, the DAZL family of RNA-binding proteins) |
| Amount | £220,867 (GBP) |
| Funding ID | 081709/Z/06/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2007 |
| End | 03/2012 |
| Title | In vivo assay for initiation |
| Description | An assay to determine the contribution of a translation initiation factor in mRNA specific control in vivo |
| Type Of Material | Technology assay or reagent |
| Provided To Others? | No |
| Impact | only way of determining metric is to look at each paper which cites us and to read in detail to see if for method or other information.... |
| Title | New Xenoups facility |
| Description | A facility to permit research using Xenopus, a non-mammlain vertebrate model was established. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2006 |
| Provided To Others? | Yes |
| Impact | In addition to our own publications, this facility provides facilitates research for other Edinburgh University Xenopus users enabling their research and fostering a collaborative environment. Collaboration also allows for 3Rs- by reduction (i.e. material/animal can be shared between multiple groups) |
| Title | PABP-specific antibodies |
| Description | Antibodies which can distinguish between PABP family members in multiple species |
| Type Of Material | Antibody |
| Year Produced | 2008 |
| Provided To Others? | Yes |
| Impact | Has enabled several publications and the securing of future funding |
| Description | HSV-1 |
| Organisation | University of Glasgow |
| Department | Institute of Biomedical and Life Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have directed the majority of research but have benifited from the facilities and knowledge of our collaborator |
| Collaborator Contribution | Resulted in publications and project grant applications |
| Impact | 20573819 18631144 Another submitted publication under revision |
| Start Year | 2006 |
| Description | HSV-1 |
| Organisation | University of Glasgow |
| Department | Institute of Infection, Immunity and Inflammation |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have contributed to three primary papers, one of which is submitted, two of which are in submission. We have also co-authored a review |
| Collaborator Contribution | A post-doc was in my lab on secondment |
| Impact | We have contributed to three primary papers, one of which is submitted, two of which are in submission. We have also co-authored a review (18631144) |
| Start Year | 2006 |
| Description | HSV-1 translation |
| Organisation | University of Glasgow |
| Department | Institute of Infection, Immunity and Inflammation |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have contributed to three papers which are submitted or in preparation. One of these was almost entirely from our laboratory. Some reviews on this topic have also been written. |
| Collaborator Contribution | A post-doctoral worker was seconded to my lab. |
| Impact | Several papers publiches, One grant awarded by WT, one awarded by BBSRC |
| Start Year | 2006 |
| Description | PABP localisation |
| Organisation | University of Glasgow |
| Department | Institute of Biomedical and Life Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have directed the majority of this research but benifited from the knowledge of our collaborator |
| Collaborator Contribution | We have been able to understand how are protein is moved in respeonse to cell stress a paper is in preparation |
| Impact | Work published |
| Start Year | 2008 |
| Description | PABP phenotypes |
| Organisation | University of Wisconsin-Madison |
| Department | Department of Biochemistry |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | We have provided the majority of the work on understanding the phenotypes caused by PABP loss of function |
| Collaborator Contribution | Allowed experiments to be performed that were not easily within our technical expertise |
| Impact | Work published |
| Start Year | 2008 |
| Description | SLC2A9 |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Human Genetics Unit |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Undertaking assays in oocytes to determine the functional impact of newly identified human mutations |
| Collaborator Contribution | Publications and methodology development |
| Impact | 19926891 Second paper in process of submission |
| Start Year | 2008 |
| Description | SLC2A9 and Gout |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Human Genetics Unit |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We established an assay which permitted us to show that SLC2A9 transports urate explaining its association with Gout |
| Collaborator Contribution | This has promoted the adaption of a new assay within the lab |
| Impact | 18327257 |
| Start Year | 2007 |
| Description | SUA and gout |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Human Genetics Unit |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We set up and performed functional assays using micor-injection of oocytes |
| Collaborator Contribution | We showed that a gene associated with gout can transport urate providing a functional understanding of its link to this condition |
| Impact | 18327257 |
| Start Year | 2007 |
| Description | SUA levels and renal failure |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Human Genetics Unit |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We utilised an assay which we developed for a previous publication and established a new assay within th elab, this allowed us to identifying the fucntional effect of a mutation which causes renal failure |
| Collaborator Contribution | This project made us explore immunofluroesence in oocytes and has resulted in a technique which we can now use to answer other questions. |
| Impact | 19926891 |
| Start Year | 2009 |
| Description | Tex-19 |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Human Genetics Unit |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We explored the putative function of Tex19, which was knocked-out in mice as part of the study |
| Collaborator Contribution | This has opened a potential new area of research which maybe the subject of a collaborative grant |
| Impact | 18802469 |
| Start Year | 2007 |
| Description | Tex-19 |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Human Genetics Unit |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We were involved in the basic functional analysis of Tex-19 which was knocked-out in mice. |
| Collaborator Contribution | This has opened up a potential new area that may be subject to a grant application depending on preliminary data |
| Impact | 18802469 |
| Start Year | 2007 |
| Title | Antibodies |
| Description | Have been asked to provide several antibodies commercially, discussions ongoing. |
| Type | Diagnostic Tool - Imaging |
| Current Stage Of Development | Initial development |
| Year Development Stage Completed | 2010 |
| Development Status | Under active development/distribution |
| Impact | N/A - not yet in market |
| Title | PABP specific antibodies |
| Description | Antibodies being licenced to commerical company |
| Type | Products with applications outside of medicine |
| Current Stage Of Development | Initial development |
| Year Development Stage Completed | 2010 |
| Development Status | Under active development/distribution |
| Impact | To early to determine |
| Description | Keynote translation 2015 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Keynote talk |
| Year(s) Of Engagement Activity | 2015 |
| Description | Public Engagment committee |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | Yes |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | As a committee we co-ordinated and organised public engagement events such as the MRC contribution to the science festival. Difficult to assess, although returning numbers to the science festival suggest that the event has appeal. |
| Year(s) Of Engagement Activity | 2006,2007 |
| Description | Science Festival |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | Yes |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | MRC stand at science festival, designed by units and manned by students and post-docs. In some years I have been dorectly involved in stand design in terms of scientific message. Unaware |
| Year(s) Of Engagement Activity | 2006,2007,2008,2009 |
| Description | Science Festival |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | Yes |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | Members of the laboratory (student and post-doc) manned the MRC exhibit at the science festival. This is difficult to ascertain, children and adults were engaged but the long-term impact is not clear. |
| Year(s) Of Engagement Activity | 2006,2007,2008,2009 |
| Description | Science festival |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | Yes |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | Post-doc on my Senior manned the exhibit at the Edinburgh Science Festival. Difficult to ascertain the long term impact |
| Year(s) Of Engagement Activity | 2007 |
| Description | TV appearance (BBC Scotland) |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | No measurable feedback was intreview to explain the results of research in response to press release No measurable feedback |
| Year(s) Of Engagement Activity | 2007 |
| Description | women in science |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Postgraduate students |
| Results and Impact | Approximately 2007, panel member in Women in Science Question and Answer session for the Biochemical Society. Biochemical Society have followed up with articles and information pertaining to careers in science |
| Year(s) Of Engagement Activity | 2007 |