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Discovery of a "White-Gray-Opaque" Tristable Phenotypic Switching System in Candida Albicans: Roles of Non-Genetic Diversity in Host Adaption

ABSTRACT: The capacity of the commensal yeast Candida albicans to grow in several forms, referred to as phenotypic plasticity, is critical for its survival, and abilities to thrive and cause infection in the human host. In this study, we report a novel phenotype of C. albicans, referred as the “gray” phenotype. The gray cell type, together with the previously discovered “white” and “opaque” cell types, forms a tristable phenotypic switching system. The three phenotypes differ in cellular and colony appearance, global transcriptional profiles, secreted aspartyl proteinase (Sap) activities and virulence in different infection models. The addition of the gray cell type to the phenotypic transition systems may enhance fitness and confers an adaptive advantage for C. albicans in the host. We further demonstrate that two key regulators of white-opaque switching, Wor1 and Efg1, are not required for maintenance of the gray phenotype, suggesting that a different regulatory circuitry may be involved in the regulation of gray cell formation. Our study provides an example of multiple stable and heritable switching systems, indicating that the regulation of morphological forms to adapt to environmental changes could be much more elaborate than previously thought.

ORGANISM(S): Candida albicans

PROVIDER: GSE53671 | GEO | 2014/06/30

SECONDARY ACCESSION(S): PRJNA232619

REPOSITORIES: GEO

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Discovery of a "White-Gray-Opaque" Tristable Phenotypic Switching System in Candida Albicans: Roles of Non-Genetic Diversity in Host Adaption

Project description:The capacity of the commensal yeast Candida albicans to grow in several forms, referred to as phenotypic plasticity, is critical for its survival, and abilities to thrive and cause infection in the human host. In this study, we report a novel phenotype of C. albicans, referred as the “gray” phenotype. The gray cell type, together with the previously discovered “white” and “opaque” cell types, forms a tristable phenotypic switching system. The three phenotypes differ in cellular and colony appearance, global transcriptional profiles, secreted aspartyl proteinase (Sap) activities and virulence in different infection models. The addition of the gray cell type to the phenotypic transition systems may enhance fitness and confers an adaptive advantage for C. albicans in the host. We further demonstrate that two key regulators of white-opaque switching, Wor1 and Efg1, are not required for maintenance of the gray phenotype, suggesting that a different regulatory circuitry may be involved in the regulation of gray cell formation. Our study provides an example of multiple stable and heritable switching systems, indicating that the regulation of morphological forms to adapt to environmental changes could be much more elaborate than previously thought. total RNA profiles of 24h old white, gray and opaque cell types

2014-06-30 | E-GEOD-53671 | biostudies-arrayexpress

The gray phenotype in the human fungal pathogen Candida tropicalis

Project description:Phenotypic plasticity, the ability to switch between different morphological types, plays critical roles in environmental adaptation, leading to infections, and allowing for sexual reproduction in pathogenic Candida species. Candida tropicalis, which is both an emerging human fungal pathogen and an environmental fungus, can switch between two heritable cell types termed white and opaque. In this study, we report the discovery of a novel phenotype in C. tropicalis, named the gray phenotype. Similar to Candida albicans and Candida dubliniensis, white, gray, and opaque cell types of C. tropicalis also form a tristable switching system, where gray cells are relatively small and elongated. In C. tropicalis, gray cells exhibit intermediate levels of mating competency and virulence in a mouse systemic infection model compared to the white and opaque cell types, express a set of cell type-enriched genes, and exhibit both common and species-specific biological features. The key regulators of white-opaque transitions, Wor1 and Efg1, are not required for the gray phenotype. A comparative study of the gray phenotypes in C. tropicalis, C. albicans, and C. dubliniensis provides clues to explain the species differences in terms of virulence, ecological niches, and prevalence among these three species.

2017-01-30 | GSE81514 | GEO

White-Opaque Switching in Natural MTLa/alpha Isolates of Candida albicans: Evolutionary Implications for Roles in Host Adaptation, Pathogenesis and Sex

Project description:The discovery of white-opaque switching in natural MTLa/alpha isolates of Candida albicans sheds new light on the evolution of phenotypic plasticity and host adaptation. Comparing gene expression of white and opaque cells of a MTL a/alpha strain

2013-04-01 | E-GEOD-43938 | biostudies-arrayexpress

White-Opaque Switching in Natural MTLa/alpha Isolates of Candida albicans: Evolutionary Implications for Roles in Host Adaptation, Pathogenesis and Sex

Project description:The discovery of white-opaque switching in natural MTLa/alpha isolates of Candida albicans sheds new light on the evolution of phenotypic plasticity and host adaptation.

2013-04-01 | GSE43938 | GEO

pH regulates white-opaque switching and sexual mating in Candida albicans

Project description:As a successful commensal and pathogen of humans, Candida albicans encounters a wide range of environmental changes. Among them, ambient pH is an important factor, which changes frequently and affects many biological processes in this species. The ability to adapt to pH changes is tightly linked with pathogenesis and morphogenesis. In this study, we report that pH has a profound effect on white-opaque switching and sexual mating in C. albicans. Acidic pHs promote white-to-opaque switching but repress sexual mating of opaque cells. The cAMP signaling and Rim101-mediated pH sensing pathways are involved in the regulation of pH-regulated white-opaque switching. Interestingly, white and opaque cells of the cyr1/cyr1 mutant, which is defective in producing cAMP, show distinct growth defects under acidic and alkaline conditions. Phr2 could play a major role in acidic pHs-induced opaque cell formation. We further discover that acidic pH conditions repress sexual mating due to the failure of activation of the Ste2-mediated a-pheromone response pathway. The effects of pH changes on phenotypic switching and sexual mating could be a balance behavior between host adaptation and sexual reproduction.

2015-12-30 | GSE67101 | GEO

TOS9 Regulates White-Opaque Switching in Candida albicans

Project description:In Candida albicans, the a1-alpha2 complex represses white-opaque switching as well as mating. A ChIP-chip strategy was, therefore, used to screen for genes with a1-alpha2 binding sites and expression patterns consistent with a master switch gene (MSG). Of 51 genes identified with an a1-alpha2 binding site, one gene, TOS9, also referred to as EAP2, exhibited an expression pattern consistent with a MSG. TOS9 is expressed in opaque, not white a/a and alpha/alpha cells and Tos9p localizes to the opaque cell nucleus. Deletion of TOS9 blocks cells in the white phase, and misexpression in the white phase of the parent tos9+/tos9+ strain results in mass conversion to opaque. Expression of TOS9 under control of a MET promoter rescues the TOS9 null mutant tos9-/tos9- phenotype. Temperature-induced mass conversion of opaque to white in the parent strain results in the immediate cessation of TOS9 transcription, and loss of Tos9p prior to the point of commitment to white (the switch event), which occurs at the time of the second cell doubling. Misexpression of TOS9, as well as inhibition of the second round of DNA replication inhibits the temperature-induced switch from opaque to white. Based on these observations, a model is developed for the regulation and role of TOS9 in switching. Keywords: ChIP chip

2006-09-19 | GSE5493 | GEO

Ssn6 defines a new level of regulation of white-opaque switching in Candida albicans and is required for the stochasticity of the switch

Project description:The human commensal and opportunistic pathogen Candida albicans can switch between two distinct, heritable cell types, named “white” and “opaque,” which differ in morphology, mating abilities, metabolic preferences, and in their interactions with the host immune system. Previous studies revealed a highly interconnected group of transcriptional regulators that control switching between the two cell types. Here, we identify Ssn6, the C. albicans functional homolog of the Saccharomyces cerevisiae transcriptional co-repressor Cyc8, as a new regulator of white-opaque switching. In a or α mating type strains, deletion of SSN6 results in mass switching from the white to the opaque cell type. Transcriptional profiling of ssn6 deletion mutant strains reveals that Ssn6 represses part of the opaque cell transcriptional program in white cells and the majority of the white cell transcriptional program in opaque cells. Genome-wide chromatin immunoprecipitation experiments demonstrate that Ssn6 is tightly integrated into the opaque cell regulatory circuit and that the positions to which it is bound across the genome strongly overlap with those bound by Wor1 and Wor2, previously identified regulators of white-opaque switching. This work reveals the next layer in the white-opaque transcriptional circuitry by integrating a transcriptional regulator that does not bind DNA directly but instead associates with specific combinations of DNA-bound transcriptional regulators.

2015-12-28 | GSE74011 | GEO

Identification and characterization of Wor4, a new transcriptional regulator of white-opaque switching

Project description:The human fungal pathogen Candida albicans can switch between two cell types, âwhiteâ and âopaque,â each of which is heritable through many cell divisions. Switching between these two cell types is regulated by six transcriptional regulators which form a highly interconnected circuit with multiple feedback loops. Here, we identify a seventh regulator of white-opaque switching, which we have named Wor4. We show that ectopic expression of Wor4 is sufficient to drive switching from the white to the opaque cell type and that deletion of Wor4 blocks switching from the white to the opaque cell type. A combination of ectopic expression and deletion experiments indicates that Wor4 is positioned upstream of Wor1 and that it is formally an activator of the opaque cell type. The combination of ectopic expression and deletion phenotypes for Wor4 is unique; none of the other six white-opaque regulators show this pattern. We determined the pattern of Wor4 binding across the genome by ChIP-seq and found it is highly correlated with that of Wor1 and Wor2, indicating that Wor4 is tightly integrated into the existing white-opaque regulatory circuit. We previously proposed that white-to-opaque switching relies on the activation of a complex circuit of feedback loops that remains excited through many cell divisions. The identification of a new, central regulator of white-opaque switching supports this idea by indicating that the white-opaque switching mechanism is considerably more complex than those controlling conventional, non-heritable patterns of gene expression. C. albicans Wor4-GFP versus untagged control in both white and opaque cell types. Cells grown in SD+aa+Uri at 25Â°C with three technical replicates of each strain/cell type (12 total).

2016-01-11 | E-GEOD-75124 | biostudies-arrayexpress

Identification and characterization of Wor4, a new transcriptional regulator of white-opaque switching

Project description:The human fungal pathogen Candida albicans can switch between two cell types, “white” and “opaque,” each of which is heritable through many cell divisions. Switching between these two cell types is regulated by six transcriptional regulators which form a highly interconnected circuit with multiple feedback loops. Here, we identify a seventh regulator of white-opaque switching, which we have named Wor4. We show that ectopic expression of Wor4 is sufficient to drive switching from the white to the opaque cell type and that deletion of Wor4 blocks switching from the white to the opaque cell type. A combination of ectopic expression and deletion experiments indicates that Wor4 is positioned upstream of Wor1 and that it is formally an activator of the opaque cell type. The combination of ectopic expression and deletion phenotypes for Wor4 is unique; none of the other six white-opaque regulators show this pattern. We determined the pattern of Wor4 binding across the genome by ChIP-seq and found it is highly correlated with that of Wor1 and Wor2, indicating that Wor4 is tightly integrated into the existing white-opaque regulatory circuit. We previously proposed that white-to-opaque switching relies on the activation of a complex circuit of feedback loops that remains excited through many cell divisions. The identification of a new, central regulator of white-opaque switching supports this idea by indicating that the white-opaque switching mechanism is considerably more complex than those controlling conventional, non-heritable patterns of gene expression.

2016-01-11 | GSE75124 | GEO

The APSES Transcription factor Efg1 regulates a novel phenotype switch in Candida parapsilosis [RNA-seq].

Project description:In Candida albicans the Efg1 transcription factor (a member of the APSES family) is an important regulator of hyphal growth, and of the white-to-opaque transition. In contrast, we show that the Efg1 ortholog in Candida parapsilosis is a major regulator of a different morphological switch at the colony level, from a concentric to smooth morphology. The rate of switching is at least 100-fold increased in an efg1 knockout relative to wild type. Deleting efg1 also reduces biofilm formation, and results in increased sensitivity to SDS, Congo red, caspofungin and calcofluor white in cells of both morphologies. Biofilm reduction is more dramatic in in vitro than in in vivo models. We use ChIP-seq to show that Efg1 binds to 502 promoter regions, including 70 potential transcription factors or regulatory proteins. Several of the transcription factors belong to networks that regulate biofilm development and white-opaque switching in C. albicans. Efg1 also binds to its own promoter. The binding site for C. parapsilosis Efg1 resembles that of orthologs in other fungi. Many Efg1 targets are probably also regulated by the Ndt80 transcription factor. We show that a paralog of Efg1 (Efh1) is restricted to Candida species. Efh1 does not regulate concentric-smooth phenotype switching, biofilm formation or stress response in C. parapsilosis. Our analysis supports the hypothesis that Efg1 has an ancient role as regulator of development in fungi, but we have identified a new role in C. parapsilosis as a regulator of colony switching that is distinct from the white-opaque switch in C. albicans. RNA was isolated from C. parapsilosis wild type (three biological replicates, concentric phenotype), and from efg1 deletion strains (three biological replicates from both concentric and smooth phenotype). Gene expression was determined using strand-specific RNA-seq.

2013-06-20 | E-GEOD-41064 | biostudies-arrayexpress

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