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The formation of memory in budding yeast by prion-like proteins

  • Supervisor: Dr Fabrice Caudron
  • Deadline: 31st December 2017
  • Funding: QMUL (UK/EU students only)

Background

We have discovered that budding yeast cells use prion like proteins to establish a molecular memory of a past adaptation to pheromone (Caudron and Barral, 2013). We called this class of proteins mnemons, i.e. proteins that can switch conformation and maintain a long-lasting molecular memory in the cell that learned an adaptation. Mnemons have the interesting property of sustaining a functional switch through a self-templating conformational change that last longer that the lifetime of individual proteins. Whi3 is the first mnemon that we have discovered, yet budding yeast has more than 200 proteins with potential prion-like domains. Adding to this, recent studies have shown that other, less classical, protein domains can confer long lasting epigenetic changes (Chakrabortee et al., 2016). This is not restricted to yeast because many prion-like domains are kept in evolutionarily conserved proteins. Thus, there is a whole new continent of mnemons to discover.
We have already identified new mnemons and our goal is to understand their molecular mechanisms and if and how they interact together. We will also identify the mechanisms that control their activation. We recently observed that the Whi3 mnemon aggregates erratically in old yeast cells (Schlissel et al., 2017) yet we do not know if this is a feature of all mnemons.
Importantly, mnemons are asymmetrically inherited during cell division. Asymmetric cell division generates cell diversity across all kingdoms of life. For example, stem cells divide into daughters that differentiate and others that replenish the stem cell pool. We use Saccharomyces cerevisiae as a model system to understand the mechanisms and functions of asymmetric cell division (Caudron and Barral, 2009; Clay et al., 2014). In response to mating pheromone, haploid yeast cells arrest in G1 and grow towards their partner (Caudron and Barral, 2013). Cells exposed to pheromone in the absence of a mating partner can escape the pheromone arrest, re-enter the cell cycle and produce daughter cells. Mother cells maintain this pheromone-refractory state for the remainder of their life span. In contrast, daughter cells are born naïve and respond to pheromone. What holds mnemons in the mother cell is currently unknown and we aim at understanding this process with a great molecular understanding only available in yeast so far.

Aim of the project

We have identified several levels of regulation of Whi3 activation and retention. You will use mutant strains in order to understand how these regulations occur at the molecular level by analysing the effect of these mutations on Whi3 aggregation at the microscope and at the biochemical level. You will also assess the dynamics of escape to the pheromone arrest and the asymmetric inheritance of the memory during cell division by performing long-term microscopy movies, using microfluidics systems. You will also apply this strategy to other newly identified mnemons. By combining mutations in different mnemons you will be able to understand if they work together or independently. These results will also be driven by a genetic screen that we are performing and will give us an unbiased view of the genes involved in asymmetrically inherited memories in budding yeast.

Funding

The studentship is open to UK and EU nationals. It will cover tuition fees and provide an annual tax-free maintenance allowance for 3 years at Research Councils UK rates (£16,553 in 2017/18).

Eligibility and Applying

Applications are invited from outstanding European/UK students candidates with or expecting to receive a first or upper-second class honours degree in an area relevant to the project (e.g. Biochemistry, Genetics, Molecular/Cellular Biology). A high degree of motivation, and excellent communication and organisational skills are essential. An MSc in a relevant subject and/or prior research experience may be advantageous, but are not essential. 

Informal enquiries can be sent to Dr Fabrice Caudron (f.caudron@qmul.ac.uk). For formal applications, please submit an online application before the stated deadline.

Apply Online

References

  • Caudron, F., and Barral, Y. (2009). Septins and the lateral compartmentalization of eukaryotic membranes. Dev Cell 16, 493–506.
  • Caudron, F., and Barral, Y. (2013). A super-assembly of Whi3 encodes memory of deceptive encounters by single cells during yeast courtship. Cell 155, 1244–1257.
  • Chakrabortee, S., Byers, J.S., Jones, S., Garcia, D.M., Bhullar, B., Chang, A., She, R., Lee, L., Fremin, B., Lindquist, S., et al. (2016). Intrinsically Disordered Proteins Drive Emergence and Inheritance of Biological Traits. Cell 167, 369–381.e12.
  • Clay, L., Caudron, F., Denoth-Lippuner, A., Boettcher, B., Buvelot Frei, S., Snapp, E.L., and Barral, Y. (2014). A sphingolipid-dependent diffusion barrier confines ER stress to the yeast mother cell. Elife 3, e01883.
  • Schlissel, G., Krzyzanowski, M.K., Caudron, F., Barral, Y., and Rine, J. (2017). Aggregation of the Whi3 protein, not loss of heterochromatin, causes sterility in old yeast cells. Science 355, 1184–1187.
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