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Deciphering the Role of Transcription Factor Binding Site Variation in Phenotypic Diversity of Aspergillus fumigatus
Secondary Supervisor(s): Dr Hung-Ji Tsai
University of Registration: University of Birmingham
BBSRC Research Themes:
Project Outline
Aspergillus fumigatus is a major opportunistic pathogen causing invasive aspergillosis, with marked variability in virulence, stress tolerance, and antifungal resistance. While coding sequence changes explain some of this diversity, many phenotypic differences remain unresolved. Variation in transcription factor binding sites (TFBS) within promoter regions could be a key driver, altering transcription factor affinity and gene regulation without changing protein sequences.
This project will test how TFBS variation shapes A. fumigatus phenotypes by combining comparative genomics with experimental mapping of transcription factor occupancy. A diverse strain panel will be assembled, promoter sequences analysed with motif discovery tools, and variation mapped across virulence and stress-response genes. Selected transcription factors will be targeted with ChIP-seq or CUT&RUN to identify their binding landscapes in multiple strains under baseline and stress conditions. These datasets will validate predicted motifs and reveal condition-dependent regulatory interactions.
RNA-seq will link TFBS variation and binding differences to transcriptional changes, while phenotyping will assess growth, stress responses, secondary metabolism, antifungal susceptibility, and virulence in model hosts. Candidate TFBS variants will be validated using CRISPR-Cas9 editing and promoter–reporter assays to measure functional impact.
The project will deliver the first integrated atlas of TFBS sequence variation, in vivo transcription factor binding, and resulting phenotypic effects in A. fumigatus. This will provide new insight into the regulatory genome of fungal pathogens and identify potential biomarkers and targets for antifungal strategies.