Description
- Abstract:
- Candida albicans is a major human fungal pathogen capable of undergoing white-opaque phenotypic switching, a stable, heritable, and reversible transition between two distinct cell states that influences mating, host colonization, and immune evasion. The master transcriptional activator of the opaque program, WOR1, resides on Chromosome 1 (Chr1), yet strains carrying three copies of Chr1 (trisomy) show severely reduced switching frequencies, while loss of the extra Chr1 copy drives hyperswitching. This observation suggests that dosage-sensitive repressors encoded on Chr1 outweigh the additional WOR1 copy in the trisomic state, resulting in net suppression of switching. To identify the chromosomal regions responsible for this suppression, fluorescent reporter strains carrying mNeonGreen and mScarlet markers on distinct Chr1 homologs were engineered to enable live tracking of Chr1 copy number. CRISPR/Cas9-mediated segmental deletions of four Chr1 regions (A, B, C, and D) revealed that regions B and D harbor the dominant switching suppressors. Single deletions of either region produced moderate increases in switching frequency, while their combined deletion in strain BD19 induced hyperswitching approaching that observed upon full Chr1 loss, without requiring deletion of regions A or C. Heterozygous knockout of TUP1, a candidate repressor in region D, produced variable switching outcomes attributable to spontaneous Chr1 arm loss rather than TUP1 dosage alone, consistent with a distributed suppression model. Telomere-mediated chromosomal truncation is under development to dissect the minimal suppressive sub-intervals within regions B and D at higher resolution. Together, these findings demonstrate that Chr1 encodes a distributed network of dosage-sensitive repressors, concentrated in regions B and D, that collectively set the transcriptional threshold for white-opaque switching in C. albicans.
- Notes:
- Thesis (Sc. M.)--Brown University, 2026
Citation
Maharjan, Kritika,
"Chromosome 1 Aneuploidy Regulates White–Opaque Switching in Candida albicans"
(2026).
Biology and Medicine Theses and Dissertations, Biotechnology.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:ajxtjecq/
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