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EASTBIO: Protein makeover: re-distribution of translational resources upon cell perturbations.

  • Full or part time
    Prof C Romano
    Prof I Stansfield
    Prof F Davidson
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Supervisors:

Professor M Carmen Romano (University of Aberdeen)
https://www.abdn.ac.uk/ncs/profiles/m.romano/

Professor Ian Stansfield (University of Aberdeen)
https://www.abdn.ac.uk/people/i.stansfield

Professor Fordyce Davidson (University of Dundee)

One of the central questions in biology is how changes in cellular gene expression cause changes in the composition of the proteome as translational resources are re-distributed across the mRNA population; this project will use an integrated mathematical and experimental approach to answer this question.

The process of translation by which a protein is made using an mRNA template cannot be considered in isolation. Translation is a global process, and thousands of mRNAs compete for the pool of ribosomes and tRNAs needed to perform translation, producing global coupling effects between the translation of each mRNA.

Therefore, there is a clear question of how translational resources are distributed among different kinds of mRNAs, and how this distribution is affected by global alterations in gene expression that change the mRNA composition of a cell. For example, by producing a heterologous protein at a high level, translational resources that would have been otherwise available to endogeneous mRNAs, are not anymore available at the same level. How is this finite pool of translational resources re-distributed among different kinds of mRNAs? Is the translation rate of certain mRNAs more resilient than others to a decrease in numbers of ribosomes and tRNAs? Are there any feedback mechanisms in the cell activated to compensate for the loss of translational resources availability? These questions are crucial to understand how the cell reacts upon perturbations, and to shed light on the cell strategies to optimise survival rates.

In order to address these questions, we will use a global mathematical model of translation that the Romano and Stansfield groups have recently developed as a result of a long-standing collaboration that integrates theoretical and experimental approaches [1,2]. Our mathematical model is based on a transport model of particles (ribosomes) along a 1-dimensional track (mRNA), which has attracted much attention in physics due to its wide applicability. The model has been extended to include crucial components that make the model biologically relevant, such as the charging process of tRNAs with amino acids, or ribosome drop-off events. Model simulation allows the evaluation of the protein production rate of all different kinds mRNAs included in the set up. Importantly, we will extend the model to include different types of feedbacks or regulatory mechanisms affecting main translational resources, such as ribosomes and tRNAs. Model parameters will be estimated using biological data and simulations results will be directly compared with experimental results obtained in the Stansfield lab.

Previous approaches to address these questions have been used and attracted much attention in the biology community (see e.g. [3]). However, the mathematical models proposed in those works are phenomenological and lack detail to draw conclusions about e.g. how the production of different proteins belonging to different functional categories are affected.

This project will provide the student with research training in the areas of physics, mathematical and computational modelling of biological systems, as well as with fundamental concepts of the biological process relevant for control of gene expression.

Application Procedure:
http://www.eastscotbiodtp.ac.uk/how-apply-0

Please send your completed EASTBIO application form, along with academic transcripts and CV to Alison McLeod at . Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to .

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership. This opportunity is only open to UK nationals (or EU students who have been resident in the UK for 3+ years immediately prior to the programme start date) due to restrictions imposed by the funding body. Queries on eligibility? Email Alison McLeod ().

Candidates should have (or expect to achieve) a minimum of a First Class Honours degree in a relevant subject. Applicants with a minimum of a 2:1 Honours degree may be considered provided they have a Distinction at Masters level.

References

[1] Ciandrini, L., Stansfield, I. & Romano, MC. (2013). 'Ribosome traffic on mRNAs maps to gene ontology: genome-wide quantification of translation initiation rates and polysome size regulation'. PLoS Computational Biology, vol 9, no. 1, e1002866.

[2] McFarland, M. R., Keller, C. D., Childers, B. M., Corrigall, H., Raguin, A., Romano, M. C. & Stansfield, I., (2019) ‘The molecular aetiology of tRNA synthetase depletion: induction of a GCN4 amino acid starvation response despite homeostatic maintenance of charged tRNA levels’, bioRxiv.

[3] Matthew Scott,Carl W. Gunderson,Eduard M. Mateescu, Zhongge Zhang, Terence Hwa, (2010), ‘Interdependence of Cell Growth and Gene Expression: Origins and Consequences’, Science, Vol 330, 1099.

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