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(BBSRC DTP) Partitioning primary and secondary changes of gene expression caused by gene mutations


Project Description

Control of gene expression is a complex cell process, which involves balancing both the synthesis and the degradation of RNA and protein so as to establish optimal levels of each protein. Hence mutations that inactivate or over-activate a gene involved in one of these processes will affect gene expression. Effects can come as direct consequences for its primary target RNAs or proteins, as well as secondary consequences caused by the imbalance to the expression of those targets. How the balance of primary versus secondary impacts of gene-activation mutations combine to cause changes in phenotype or manifest as a disease state is not well explored. This project will fill this gap by studying how defects in a well-characterised simple eukaryotic protein (Puf3) have widespread consequences for cell functions. The approaches developed here could then be applied to other systems including those involved in human disease.

Puf3 is an RNA-binding protein that is implicated in regulating mRNA stability and protein synthesis. It contributes to cell homeostasis and gene expression control on a global scale via regulating expression of nuclear-encoded mitochondrial proteins. In previous papers we have demonstrated that Puf3 may play a broader role and be involved in many more biological processes [1-2]. Hence Puf3 provides a great example to explore the network of interactions that exist to control the overall proteome.

The project will enhance our understanding much further by developing a systemic model of the role of Puf3 in the overall programme of yeast gene expression. The student will undertake a mix of lab and computational experiments including generating and analysing multi-omics data and building a quantitative-informed model of regulation. The project builds on the existing knowledge and complementary expertise of the different laboratories involved. It represents an ideal opportunity for an individual willing to learn a wide range of current experimental methodologies including next-generation sequencing, proteomics as well as systems-biology and mathematical-modelling approaches [3]

https://www.research.manchester.ac.uk/portal/david.talavera.html
https://www.research.manchester.ac.uk/portal/graham.pavitt.html
http://www.bioinf.manchester.ac.uk/schwartz/index.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.


Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Rowe W, Kershaw CJ, Castelli LM, Costello JL, Ashe MP, Grant CM, Sims PFG, Pavitt GD, Hubbard SJ. Puf3p induces translational repression of genes linked to oxidative stress. Nucleic Acids Res. 2014. 42(2):1026-1041.
2. Kershaw CJ, Costello JL, Talavera D, Rowe W, Castelli LM, Sims PFG, Grant CM, Ashe MP, Hubbard SJ, Pavitt GD. Integrated multi-omics analyses reveals pleiotropic nature of control of gene expression by Puf3p. Sci Rep. 2015. 5: 15518.
3. Jarnuczak AF, Eyers CE, Schwartz JM, Grant CM, Hubbard SJ. Quantitative proteomics and network analysis of SSA1 and SSB1 deletion mutants reveals robustness of chaperone HSP70 network in Saccharomyces cerevisiae. Proteomics. 2015. 15: 3126-39.

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