Gene dosage and protein valency impact phase separation and fungal cell fate

Collin Ganser; Peiling He; Corey Frazer; Damian J Krysan; Richard J Bennett

doi:10.1371/journal.pgen.1011810

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Gene dosage and protein valency impact phase separation and fungal cell fate

Journal article

Open access

Peer reviewed

Gene dosage and protein valency impact phase separation and fungal cell fate

Collin Ganser, Peiling He, Corey Frazer, Damian J Krysan and Richard J Bennett

PLoS genetics, Vol.21(8), e1011810

08/2025

DOI: 10.1371/journal.pgen.1011810

PMCID: PMC12333994

PMID: 40779608

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Abstract

Cell fate decisions in eukaryotes are regulated by interconnected networks of transcription factors (TFs) that drive heritable changes in identity. However, much is unknown about how TFs act together to control cell fate, despite links to cellular dysfunction and disease when TF function is aberrant. Here, we addressed the interplay between TFs that control heritable switching in the diploid fungal pathogen Candida albicans. This species can propagate in two distinct cell states, white and opaque, with epigenetic transitions between states regulated by a core network of eight TFs plus >100 auxiliary TFs. The role of these TFs was dissected using simple and complex haploinsufficiency (CHI) analyses to examine the impact of gene dosage on cell fate. Among single heterozygotes, loss of one allele of WOR1 had the greatest impact on white-opaque switching, consistent with its role as the master opaque regulator, while CHI analysis revealed strong genetic interactions between other core TFs including WOR3 and WOR4. Wor1 function was also highly sensitive to its interaction valency, a measure of the number of inter-molecular interactions it can undergo. Engineered strains with increased Wor1 valency, either via the addition of extra prion-like domains (PrLDs) or by forced dimerization, increased switching frequencies by up to two orders of magnitude. Increasing Wor1 valency increased its propensity to form phase-separated condensates both in vitro and in mammalian cells. Together, these experiments establish that changes to TF gene dosage and TF valency can alter cell fate determination, with these changes linked to the propensity of TFs to undergo condensate formation.

Candida albicans - genetics

Fungal Proteins - genetics

Fungal Proteins - metabolism

Gene Dosage - genetics

Gene Expression Regulation, Fungal

Haploinsufficiency - genetics

Phase Separation

Transcription Factors - genetics

Transcription Factors - metabolism

Details

Title: Subtitle: Gene dosage and protein valency impact phase separation and fungal cell fate
Creators: Collin Ganser - Brown University
Peiling He - Brown University
Corey Frazer - Brown University
Damian J Krysan - University of Iowa
Richard J Bennett - Brown University
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.21(8), e1011810
DOI: 10.1371/journal.pgen.1011810
PMID: 40779608
PMCID: PMC12333994
NLM abbreviation: PLoS Genet
ISSN: 1553-7404
eISSN: 1553-7404
Publisher: PUBLIC LIBRARY SCIENCE
Grant note: Division of Intramural Research, National Institute of Allergy and Infectious Diseases: AI081704, AI141893 NIH/NIAID
This work was supported by NIH/NIAID awards AI081704 and AI141893 to RJB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Language: English
Date published: 08/2025
Academic Unit: Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984945085202771

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