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(BBSRC DTP) Tackling the genomic dark matter through system engineering of ncRNAs in yeast


Faculty of Biology, Medicine and Health

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Prof D Delneri , Prof P Cai No more applications being accepted Competition Funded PhD Project (Students Worldwide)
Manchester United Kingdom Biochemistry Bioinformatics Cell Biology Computational Chemistry Evolution Genetics Microbiology Molecular Biology Synthetic Chemistry

About the Project

Non-coding RNAs (ncRNAs) are thought as of genomic "dark matter" for which the biological significance has been largely underestimated. A bulk of recent literature has showed how some ncRNAs are important players in cellular regulation and fitness. Rapid advances in DNA synthesis techniques have now made it possible to chemically synthesize and modify biochemical pathways and reconstruct genomes. The world’s first designer genome has been recently synthesized by an international consortium of scientists within the framework of the synthetic yeast Sc2.0 project (1,2). To gain a comprehensive view of ncRNAs function a more systematic approach is required. In this project, we propose to employ synthetic genomics methods to engineer lncRNAs in the yeast genome, and to dissect their functional roles and synergies.

Novel classes of lncRNAs have been recently identified according to their half -life in the cell, the stable unannotated transcripts (SUTs) and the cryptic unstable transcripts (CUTs). A collection of ncRNAs mutants have been recently created to facilitate large-scale functional analysis of these molecules (3, 4). Preliminary RNASeq data for lncRNA mutants suggests that roughly 45% of SUTs and CUTs are affecting transcription in distant genes and therefore likely to work in trans. Here, we propose to standardise these lncRNAs parts and combinatorially assemble them with promoters of various strength to modulate their expressions. We will build a neochromosome to host these lncRNAs and remove them from the genome, so that we can systematically profile their impact on fitness under optimal and stress conditions. Whole genome transcriptome profiling will be employed to identify dysregulations of gene expression caused by the ncRNA neochromosomes. Alongside the genomic profiling, we will establish extensive phenotyping pipelines to measure solid and liquid fitness, as well as competitive fitness of the engineered yeast strains in various conditions (5).

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

References

1. Richardson SM, Mitchell LA, Stracquadanio G, Yang K, Dymond JS, DiCarlo JE, Lee D, Huang CL, Chandrasegaran S, Cai Y, Boeke JD, Bader JS (2017) Design of a synthetic yeast genome. Science, 355:1040-1044
2. Liu W, Luo Z, Wang Y, Pham NT, Tuck L, Pérez-Pi I, Liu L, Shen Y, French C, Auer M, Marles-Wright J, Dai J, Cai Y. (2018) Rapid pathway prototyping and engineering using in vitro and in vivo synthetic genome SCRaMbLE-in methods.
Nat Commun. 9: 1936
3. Parker S., Fraczek M. et al. …,Delneri D* and O’Keefe RT* (2018) Large-scale profiling of noncoding RNA function in yeast PLoS Genetics 14: e1007253 (*co-corresponding authors).
4. Hooks K.B., Naseeb S., Parker S., Griffiths-Jones S., and Delneri D. (2016) Novel intronic RNA structures contributes to maintenance of phenotype in Saccharomyces cerevisiae, Genetics 203: 1469-1481
5. Delneri D., Hoyle D.C., et al. …and Oliver S.G. (2008). Identification and characterisation of high flux control (HFC) genes of Saccharomyces cerevisiae through competition analyses in continuous cultures. Nat. Genet., 40: 113-117
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