EastBio: Investigating how cell size impacts proteome homoeostasis and cellular signaling.

One of the most obvious differences between cells of different type is their size. Even within a given cell type, there are constant variations in size and, of course, a single proliferating cell will double in size every cell cycle. Cell size sets the scale for organelle structures, surface transport and, most crucially, biosynthetic rates. Protein and mRNA amounts must scale with cell size to maintain constant concentrations, so coordination between cell size and cellular biosynthesis is essential.

We have recently discovered that feedback on mRNA decay reduces global mRNA turnover as cells increase in size and that this ensures that larger cells accumulate more mRNA to keep total mRNA amounts in proportion to their size. However, this size-scaling of mRNA amounts only occurs within a limited size range because this scaling breaks down above a critical cell size so that global mRNA and protein concentrations decrease, the cytoplasm becomes diluted and cellular fitness declines dramatically.

Despite these recent breakthrough discoveries, the mechanisms for these size-dependent changes are not known. This project will address this fundamental question by investigating:

(1) How do the changes in RNA scaling impact proteome homeostasis?

(2) How do growth and stress signalling pathways respond to changes in cell size?

Training opportunities:

The student’s role will be to both design and perform wet lab experiments – principally using budding yeast as a model system – to test key hypotheses addressing the aims outlined above. The precise focus of the project is flexible to a student’s interests and will be developed together with Dr. Swaffer during the initial stages of their PhD. This also includes the possibility to expand on initial findings in yeast with work in mammalian cells.

The project will involve utilising a range of cutting-edge approaches in cell, molecular and systems biology. This includes several functional genomics sequencing-based technologies (e.g., RNA-seq, ChIP-seq, CRAC-seq, Ribo-seq), quantitative proteomics, phospho-proteomics and single-cell imaging. We are looking for highly motivated applicants with some prior lab experience, but no specific expertise in the above techniques is required, as all necessary training will be provided. This project will also allow students to combine wet lab work with the opportunity to develop key skills in computational data analysis and bioinformatics.