Regulation of Candida albicans Transcription Networks via Phase Separation

Staples, Mae Isabel

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Overview

Year:: 2021
Contributor:: Staples, Mae Isabel (creator); Bennett, Richard (Advisor); Belenky, Peter (Reader); Bliss, Joseph (Reader); Hernday, Aaron (Reader); Brown University. Biology and Medicine: Pathobiology (sponsor)
Genre:: theses
Subject:: Transcription factors; Transcriptional regulation; Candida albicans; liquid-liquid phase separation; Biofilms; Phase separation; Yeast fungi--Genetics; prion-like domains; intrinsically disordered proteins; super-enhancer
Extent:: xvi, 229 p.

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Abstract:: The opportunistic fungal pathogen Candida albicans is capable of colonizing diverse host niches throughout the human body. The ability of C. albicans to undergo a phenotypic “white-opaque” cell state switch, as well as its ability to form biofilms, contribute significantly to fungal host interactions and pathogenicity. At the molecular level, two distinct transcriptional regulatory networks (TRNs) control white-opaque switching and biofilm formation. Within these networks master transcription factors (TFs) control target gene expression through interactions at their own extended regulatory regions as well as interactions at regulatory regions of other TFs. The precise mechanism by which multiple TFs assemble to regulate target genes in TRNs remains unclear. Here, we reveal that many TFs involved in white-opaque cell fate determination and in biofilm development contain intrinsically disordered, prion-like domains (PrLDs) that drive formation of phase-separated condensates. We show that multiple TFs form liquid-like protein droplets in vitro, and that these condensates can incorporate DNA as well as RNA polymerase II. In a live eukaryotic cell system, both white-opaque and biofilm TFs can co-assemble into heterotypic condensates at a synthetic locus, dependent on their PrLDs. Furthermore, specific amino acid mutations within TF PrLDs greatly impact cell fate determination and biofilm formation. Acidic residues in the Wor1 PrLD are required for white-opaque switching and TF interactions, while aromatic residues and polyglutamine tracts in the PrLDs of Efg1, Brg1, and Flo8 mediate robust biofilm development and hyphal cell formation. PrLD mutations that abolish biofilm formation in vitro also reduce C. albicans filamentation during mouse colonization. Together, these studies highlight a role for PrLDs in driving assembly of TF complexes that control fungal cell identity, and suggest that disruption of these domains could mediate virulence in a model eukaryotic pathogen.
Notes:: Thesis (Ph. D.)--Brown University, 2021

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Citation

Staples, Mae Isabel, "Regulation of Candida albicans Transcription Networks via Phase Separation" (2021). Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:7j83gee6/

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Pathobiology Theses and Dissertations

Theses and Dissertations for the Pathobiology department.
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