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

ABSTRACT: 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.

ORGANISM(S): Candida albicans

PROVIDER: GSE74011 | GEO | 2015/12/28

SECONDARY ACCESSION(S): PRJNA298734

REPOSITORIES: GEO

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Interlocking Transcriptional Feedback Loops Control White-Opaque Switching in Candida albicans

Project description:The human pathogen Candida albicans can assume either of two distinct cell types, designated ‘‘white’’ and ‘‘opaque.’’ Each cell type is maintained for many generations; switching between them is rare and stochastic, and occurs without any known changes in the nucleotide sequence of the genome. The two cell types differ dramatically in cell shape, colony appearance, mating competence, and virulence properties. In this work, we investigate the transcriptional circuitry that specifies the two cell types and controls the switching between them. First, we identify two new transcriptional regulators of white-opaque switching, Czf1 and white-opaque regulator 2 (Wor2). Analysis of a large set of double mutants and ectopic expression strains revealed genetic relationships between CZF1, WOR2, and two previously identified regulators of white-opaque switching, WOR1 and EFG1. Using chromatin immunoprecipitation, we show that Wor1 binds the intergenic regions upstream of the genes encoding three additional transcriptional regulators of white-opaque switching (CZF1, EFG1, and WOR2), and also occupies the promoters of numerous white- and opaque-enriched genes. Based on these interactions, we have placed these four genes in a circuit controlling white-opaque switching whose topology is a network of positive feedback loops, with the master regulator gene WOR1 occupying a central position. Our observations indicate that a key role of the interlocking feedback loop network is to stably maintain each epigenetic state through many cell divisions. Keywords: ChIP-chip

2007-10-01 | GSE8709 | 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.

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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

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Glucose depletion enables Candida albicans mating independent of the epigenetic white-opaque switch

Project description:The human fungal pathogen Candida albicans can switch stochastically and heritably between a “white” phase and an “opaque” phase. Opaque cells are the mating-competent form of the species whereas white cells are essentially “sterile”. Here, we report that glucose depletion, a common nutrient stress, enables C. albicans white cells to undergo efficient sexual mating. The relative expression levels of pheromone-sensing and mating-associated genes (including STE2/3, MFA1, MFalpha1, FIG1, FUS1, and CEK1/2) were increased under glucose depletion conditions, while expression of mating repressors TEC1 and DIG1 was decreased. We show that Cph1 and Tec1, factors that act downstream of the pheromone MAPK pathway, play opposite roles in regulating white cell mating as TEC1 deletion or CPH1 overexpression promoted white cell mating. Moreover, inactivation of the Cph1 repressor Dig1 increased white cell mating ~4,000 fold in glucose-depleted medium relative to that in the presence of glucose. These findings reveal that the white-to-opaque epigenetic switch may not be a prerequisite for sexual mating in C. albicans in nature. Given parallels between C. albicans white cell mating to that of other yeast species, this mechanism of mating could represent a more ancient strategy of sexual reproduction in C. albicans.

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2014-10-23 | E-GEOD-56039 | biostudies-arrayexpress

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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

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

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