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Bistable expression of WOR1, a master regulator of white-opaque switching in Candida albicans.

ABSTRACT: Candida albicans, a commensal organism and a pathogen of humans, can switch stochastically between a white phase and an opaque phase without an intermediate phase. The white and opaque phases have distinct cell shapes and gene expression programs. Once switched, each phase is stable for many cell divisions. White-opaque switching is under a1-alpha2 repression and therefore only happens in a or alpha cells. Mechanisms that control the switching are unknown. Here, we identify Wor1 (white-opaque regulator 1) as a master regulator of white-opaque switching. The deletion of WOR1 blocks opaque cell formation. The ectopic expression of WOR1 converts all cells to stable opaque cells in a or alpha cells. In addition, the ectopic expression of WOR1 in a/alpha cells is sufficient to induce opaque cell formation. Importantly, WOR1 expression displays an all-or-none pattern. It is undetectable in white cells, and it is highly expressed in opaque cells. The ectopic expression of Wor1 induces the transcription of WOR1 from the WOR1 locus, which correlates with the switch to opaque phase. We present genetic evidence for feedback regulation of WOR1 transcription. The feedback regulation explains the bistable and stochastic nature of white-opaque switching.

SUBMITTER: Huang G

PROVIDER: S-EPMC1540355 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Overexpression of the White Opaque Switching Master Regulator Wor1 Alters Lipid Metabolism and Mitochondrial Function in Candida albicans

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Project description:Candida albicans is a normal member of the human microbiome and an opportunistic fungal pathogen. This species undergoes several morphological transitions, and here we consider white-opaque switching. In this switching program, C. albicans reversibly alternates between two cell types, named "white" and "opaque," each of which is normally stable across thousands of cell divisions. Although switching under most conditions is stochastic and rare, certain environmental signals or genetic manipulations can dramatically increase the rate of switching. Here, we report the identification of two new inputs which affect white-to-opaque switching rates. The first, exposure to sub-micromolar concentrations of (E,E)-farnesol, reduces white-to-opaque switching by ten-fold or more. The second input, an inferred PKA phosphorylation of residue T208 on the transcriptional regulator Efg1, increases white-to-opaque switching ten-fold. Combining these and other environmental inputs results in a variety of different switching rates, indicating that a given rate represents the integration of multiple inputs.

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Ssn6, a new regulator of white-opaque switching in Candida albicans

Project description:The human fungal pathogen Candida albicans can switch between two phenotypic cell types, termed “white” and “opaque.” Both cell types are heritable for many generations, and the switch between the two types occurs epigenetically, that is, without a change in the DNA sequence of the genome. In this work we describe that SSN6, the C. albicans functional homolog of Saccharomyces cerevisiae Cyc8, is a regulator of the white-opaque switch. Chromatin IP's were performed using the protocol described by Hernday et al (Methods Enzymol. 2010;470:737-58. ). Briefly, log phase cultures were crosslinked with formaldehyde prior to cell lysis, chromatin shearing, and transcription-factor immunoprecipitation. Recovered DNA was amplified, dye-coupled, and competitively hybridized to a 244k-probe tiling array with a non-enriched genomic DNA reference.

2014-06-30 | GSE58054 | GEO

Ssn6, a new regulator of white-opaque switching in Candida albicans

2014-06-30 | E-GEOD-58054 | biostudies-arrayexpress

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.

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