title: A Multistate Toggle Switch Defines Fungal Cell Fates and Is Regulated by Synergistic Genetic Cues.
abstract: Heritable epigenetic changes underlie the ability of cells to differentiate into distinct cell types. Here, we demonstrate that the fungal pathogen Candida tropicalis exhibits multipotency, undergoing stochastic and reversible switching between three cellular states. The three cell states exhibit unique cellular morphologies, growth rates, and global gene expression profiles. Genetic analysis identified six transcription factors that play key roles in regulating cell differentiation. In particular, we show that forced expression of Wor1 or Efg1 transcription factors can be used to manipulate transitions between all three cell states. A model for tristability is proposed in which Wor1 and Efg1 are self-activating but mutually antagonistic transcription factors, thereby forming a symmetrical self-activating toggle switch. We explicitly test this model and show that ectopic expression of WOR1 can induce white-to-hybrid-to-opaque switching, whereas ectopic expression of EFG1 drives switching in the opposite direction, from opaque-to-hybrid-to-white cell states. We also address the stability of induced cell states and demonstrate that stable differentiation events require ectopic gene expression in combination with chromatin-based cues. These studies therefore experimentally test a model of multistate stability and demonstrate that transcriptional circuits act synergistically with chromatin-based changes to drive cell state transitions. We also establish close mechanistic parallels between phenotypic switching in unicellular fungi and cell fate decisions during stem cell reprogramming.
authors.affiliation: Department of Microbiology and Immunology, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Matthew Z
authors.initials: MZ
authors.lastname: Anderson
authors.affiliation: Department of Microbiology and Immunology, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Porman
authors.affiliation: Department of Microbiology and Immunology, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mancera
authors.affiliation: Department of Microbiology and Immunology, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Denis
authors.identifier: http://orcid.org/0000-0001-8344-3605
authors.initials: D
authors.lastname: Huang
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: Christina A
authors.identifier: http://orcid.org/0000-0002-5778-960X
authors.initials: CA
authors.lastname: Cuomo
authors.affiliation: Department of Microbiology and Immunology, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bennett
mesh_terms: D002176:Candida albicans / Q000235:genetics / Q000254:growth & development; D041022:Candida tropicalis / Q000235:genetics / Q000254:growth & development; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D044127:Epigenesis, Genetic; D005656:Fungal Proteins / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D015966:Gene Expression Regulation, Fungal; D005812:Genes, Switch / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C121438:EFG1 protein, Candida albicans; D005656:Fungal Proteins; D014157:Transcription Factors