How fungi navigate their environment: what drives gene expression patterns in new lab infection models of a major fungal pathogen?

Fungi growing in different environmental conditions undergo huge changes in gene expression and cell shape, despite being genetically identical. These responses are affected by the history of cell growth, i.e. by the environment both before and after the change. For example, in the major human fungal pathogen Cryptococcus neoformans, starved cells exposed to bacterial cell wall components form very large Titan cells, and both parts of this stimulus are necessary. This means that we need to move beyond the standard approach of growing cells in nutrient-rich conditions, then transferring them to a single stress condition, to understand how a fungus behaves in the wild.

This project will study how Cryptococcus regulates gene expression in dynamic and varied environments, using high-throughput sequencing and proteomics. Time-course experiments in many different media conditions will dissect key stimuli that lead to large changes in gene expression and cell fate. You will use new functional genomics tools to understand the mechanistic basis of these responses: a library of gene deletion mutants, CRISPR/Cas9 transformation to generate new mutants, and novel reporter gene systems. The combination of ecological insight, big data, and new methods should produce a step change in our understanding of how Cryptococcus navigates environmental niches both outside and inside hosts. Fungal pathogens are a global threat to human, animal, and plant health, and this kind of new understanding is essential to countering this threat.

The project relies on making hundreds of RNA-sequencing libraries, so requires fastidious organization. You will use automation, including pipetting robots, to maximize your productivity. The data analysis side will also be intense, using bioinformatics and statistics software, and organizing the data into a resource for the entire community. There will be opportunities to use microscopy to assess changes in cell morphology. Our group will be excited to teach the experimental skills to a motivated student with a computational background, or vice versa, but either laboratory or programming/bioinformatics experience will be important to establishing the project.

This interdisciplinary project would suit a student with a sense of adventure, also because wild Cryptococcus is associated with pigeons, so it may be important to use foraged media such as pigeon guano, as well as creatively approaching defined media formulations in the laboratory. Your sense of adventure will likewise be important in analysing your data, as unexpected gene regulation patterns can be discovered in big rich datasets, and we would like to do that too. The supervisors will support your career development including laboratory, programming, presentation and writing skills. You will be encouraged to build a network of scientific colleagues in Edinburgh, Birmingham, and more widely, including presenting your work at conferences.

This project will be supervised by Dr. Edward Wallace (https://ewallace.github.io/), with second supervisor Dr. Elizabeth Ballou in Birmingham (https://www.birmingham.ac.uk/staff/profiles/biosciences/ballou-elizabeth.aspx). Interested candidates should enquire to us by email, describing your interest in this project in specific terms (see https://www.ed.ac.uk/informatics/postgraduate/apply/contacting-supervisors). The ideal email would say why you are interested in the subject matter (i.e. some combination of fungi, pathogens, stress adaptation, RNA, and sequencing methods), and also briefly describe your experimental and computational skills.