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


Project Description

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:
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 Partnership. 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. 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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