Microbes are constantly subjected to changes in their environment and have to rapidly alter their transcriptome to adapt efficiently. Post-transcriptional regulation by RNA-binding proteins (RBPs) plays a key role during this adaptation. By shaping the expression of stress-responsive genes, RBPs are thought to enable organisms to respond faster to environmental changes than transcriptional control alone.
We have recently shown in S. cerevisiae that RBPs Nrd1/Nab3/Sen1 complex (NNS) can pre-maturely terminate transcription of stress-responsive genes, which has a pronounced effect on their steady-state expression kinetics (Nues et al., 2017). The biological significance of this observation, however, remained unclear.
The ability to accurately regulate levels of expression during stress is often limited by the stochastic nature of transcriptional regulation. This stochasticity can lead to substantial cell-to-cell variability (noise) in gene expression, which can be detrimental to fitness.
Our current working model is that Nrd1/Nab3 affect the kinetics of gene expression to reduce this noise.
The first goal of the PhD project is to quantify the extent of noise suppression by the NNS complex and unravel the mechanism behind it. To pursue these goals, single-cell reporter systems involving state-of-the-art microscopy methodologies will be employed (Crane et al., 2014) to determine if noise suppression occurs during transcription and to determine how prevalent this activity might be in yeast through finding the requirements for efficient noise suppression using a mathematical model.
The second part of the project is to ascertain whether the NNS complex can be used to simplify the design of gene expression systems for biotechnology. The yeast Saccharomyces cerevisiae has several properties that make it an excellent host for heterologous expression of proteins and biosynthetic pathways. However, engineering metabolic pathways often involves combining multiple promoters with different strengths, which can be a tedious process. Additionally, many of the widely used promoters show significant cell-to-cell variability in expression levels, which can impact the production yield.
The student will test whether yeast’s own NNS transcription termination system can be hijacked to predictably and more precisely control expression of heterologous proteins. The ultimate goal is to develop a Synthetic Biology toolbox that can improve and greatly simplify expression of heterologous genes.
This project is interdisciplinary, involving yeast genetics, biochemistry, bioinformatics, quantitative microscopy, mathematical modelling, and analysis of both single-cell time-lapse and large next-generation sequencing data.
Thus, it provides a unique learning opportunity for students interested in Systems and Synthetic Biology.
The “Visit Website” button will take you to our Online Application checklist. Complete each step and download the checklist which will provide a list of funding options and guide you through the application process. Follow the instructions on the EASTBIO website (you will be directed here from our application checklist), ensuring you upload an EASTBIO application form and transcripts to your application, and ticking the box to request references. Your referees should upload their references using the EASTBIO reference form, in time for the 5th January deadline so please give them plenty of time to do this by applying early.
Crane MM, Clark IBN, Bakker E, Smith S, Swain PS. 2014. A microfluidic system for studying ageing and dynamic single-cell responses in budding yeast. PLoS One 9:e100042.
Nues R van, Schweikert G, Leau E de, Selega A, Langford A, Franklin R, Iosub I, Wadsworth P, Sanguinetti G, Granneman S. Kinetic CRAC uncovers a role for Nab3 in determining gene expression profiles during stress. Nat Commun 8:12. doi:10.1038/s41467-017-00025-5
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