Variation in transcription regulator expression underlies differences in white-opaque switching between the SC5314 reference strain and the majority of Candida albicans clinical isolates.
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ABSTRACT:
ORGANISM(S): Candida albicans
PROVIDER: GSE241766 | GEO | 2023/08/29
REPOSITORIES: GEO
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Project description:Candida albicans, a normal member of the human microbiome and an opportunistic fungal pathogen, undergoes several morphological transitions. One of these transitions is white-opaque switching, where C. albicans alternates between 2 stable cell types with distinct cellular and colony morphologies, metabolic preferences, mating abilities, and interactions with the innate immune system. White-to-opaque switching is regulated by mating type; it is repressed by the a1/α2 heterodimer in a/α cells, but this repression is lifted in a/a and α/α mating type cells (each of which are missing half of the repressor). The widely used C. albicans reference strain, SC5314, is unusual in that white-opaque switching is completely blocked when the cells are a/α; in contrast, most other C. albicans a/α strains can undergo white-opaque switching at an observable level. In this paper, we uncover the reason for this difference. We show that, in addition to repression by the a1/α2 heterodimer, SC5314 contains a second block to white-opaque switching: 4 transcription regulators of filamentous growth are upregulated in this strain and collectively suppress white-opaque switching. This second block is missing in the majority of clinical strains, and, although they still contain the a1/α2 heterodimer repressor, they exhibit a/α white-opaque switching at an observable level. When both blocks are absent, white-opaque switching occurs at very high levels. This work shows that white-opaque switching remains intact across a broad group of clinical strains, but the precise way it is regulated and therefore the frequency at which it occurs varies from strain to strain.
| S-EPMC10627253 | biostudies-literature
Project description:Variation in transcription regulator expression underlies differences in white-opaque switching between the SC5314 reference strain and the majority of Candida albicans clinical isolates.
| PRJNA1009828 | ENA
Project description:In Candida albicans, the a1-alpha2 complex represses white-opaque switching, as well as mating. Based upon the assumption that the a1-alpha2 corepressor complex binds to the gene that regulates white-opaque switching, a chromatinimmunoprecipitation-microarray analysis strategy was used to identify 52 genes that bound to the complex. One of these genes, TOS9, exhibited an expression pattern consistent with a "master switch gene." TOS9 was only expressed in opaque cells, and its gene product, Tos9p, localized to the nucleus. Deletion of the gene blocked cells in the white phase, misexpression in the white phase caused stable mass conversion of cells to the opaque state, and misexpression blocked temperature-induced mass conversion from the opaque state to the white state. A model was developed for the regulation of spontaneous switching between the opaque state and the white state that includes stochastic changes of Tos9p levels above and below a threshold that induce changes in the chromatin state of an as-yet-unidentified switching locus. TOS9 has also been referred to as EAP2 and WOR1.
| S-EPMC1595353 | biostudies-literature
Project description:Candida albicans strains that are homozygous at the mating type locus (MTLa or MTLalpha) can spontaneously switch at a low frequency from the normal yeast cell morphology (white) to an elongated cell type (opaque), which is the mating-competent form of the fungus. The ability to switch reversibly between these two cell types also contributes to the pathogenicity of C. albicans, as white and opaque cells are differently adapted to specific host niches. We found that in strain WO-1, a strain in which genomic alterations have occurred, but not in other tested strains, switching from the white to the opaque phase can also be induced by environmental conditions. Transient incubation of white cells under anaerobic conditions programmed the cells to switch en masse to the opaque phase. The anaerobic induction of white-opaque switching was controlled by the transcription factor CZF1, which in heterozygous MTLa/alpha cells regulates filamentous growth under embedded, hypoxic conditions. Intriguingly, passage of white cells of strain WO-1 through the mouse intestine, a host niche in which the cells are likely to be exposed to anaerobic conditions, resulted in a strongly increased frequency of switching to the opaque phase. These results demonstrate that white-opaque switching is not only a spontaneous process but, in combination with genomic alterations, can also be induced by environmental signals, suggesting that switching and mating of C. albicans may occur with high efficiency in appropriate niches within its human host.
| S-EPMC2405950 | biostudies-literature
Project description:To mate, Candida albicans must undergo homozygosis at the mating type-like locus MTL[1, 2], then switch from the white to opaque phenotype [3, 4]. Paradoxically, when opaque cells are transferred in vitro to 37 degrees C, the temperature of their animal host, they switch en masse to white [5-7], suggesting that their major niche might not be conducive to mating. It has been suggested that pheromones secreted by opaque cells of opposite mating type [8] or the hypoxic condition of host niches [9, 10] stabilize opaque cells. There is, however, an additional possibility, namely that CO(2), which achieves levels in the host 100 times higher than in air [11-13], stabilizes the opaque phenotype. CO(2) has been demonstrated to regulate the bud-hypha transition in C. albicans[14, 15], expression of virulence genes in bacteria [16], and mating events in Cryptococcus neoformans[14, 17]. We tested the possibility that CO(2) stabilizes the opaque phenotype, and found that physiological levels of CO(2) induce white-to-opaque switching and stabilize the opaque phenotype at 37 degrees C. It exerts this control equally under anaerobic and aerobic conditions. These results suggest that the high levels of CO(2) in the host induce and stabilize the opaque phenotype, thus facilitating mating.
| S-EPMC2667266 | biostudies-literature
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.
| S-EPMC1976629 | biostudies-literature
Project description:As a successful commensal and pathogen of humans, Candida albicans encounters a wide range of environmental conditions. Among them, ambient pH, which changes frequently and affects many biological processes in this species, is an important factor, and 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 pH promotes white-to-opaque switching under certain culture conditions but represses sexual mating. The Rim101-mediated pH-sensing pathway is involved in the control of pH-regulated white-opaque switching and the mating response. Phr2 and Rim101 could play a major role in acidic pH-induced opaque cell formation. Despite the fact that the cyclic AMP (cAMP) signaling pathway does not play a major role in pH-regulated white-opaque switching and mating, white and opaque cells of the cyr1/cyr1 mutant, which is defective in the production of cAMP, showed distinct growth defects under acidic and alkaline conditions. We further discovered that acidic pH conditions repressed sexual mating due to the failure of activation of the Ste2-mediated α-pheromone response pathway in opaque A: cells. The effects of pH changes on phenotypic switching and sexual mating could involve a balance of host adaptation and sexual reproduction in C. albicans.
| S-EPMC4621312 | biostudies-literature
Project description:Cells of Candida albicans WO-1 switch spontaneously and frequently between a white and an opaque CFU. Recently, an opaque-phase-specific cDNA, PEP1, was cloned and was demonstrated to code for a pepsinogen. By using a differential hybridization screen, a second opaque-phase-specific cDNA, Op4, has been isolated and its corresponding gene has been cloned. Op4 is coordinately regulated with PEP1 but resides on a different chromosome. During temperature-induced mass conversion from opaque to white, transcription of PEP1 and Op4 is immediately inhibited by the increase in temperature, but transcription of both genes can be rapidly reestablished by a downshift in temperature prior to phenotypic commitment. However, the capacity to rapidly induce both PEP1 and Op4 is lost coincidentally with the second semisynchronous round of cell division and phenotypic commitment during mass conversion. Op4 shows no significant base or amino acid sequence homology with a known gene or protein, respectively. However, the deduced Op4 protein exhibits several interesting characteristics, including a hydrophobic amino terminus with 26 amino acids, a pI of 10.73 for the last 100 amino acids, two serine repeats adjacent to alanine repeats, and the potential for alpha-helical conformation within the alanine-rich sequences. No genomic reorganization was evident in the proximity of Op4 during transcriptional activation and deactivation accompanying the white-opaque transition.
| S-EPMC280771 | biostudies-other
Project description:Phenotypic transitions play critical roles in host adaptation, virulence, and sexual reproduction in pathogenic fungi. A minority of natural isolates of Candida albicans, which are homozygous at the mating type locus (MTL, a/a or ?/?), are known to be able to switch between two distinct cell types: white and opaque. It is puzzling that white-opaque switching has never been observed in the majority of natural C. albicans strains that have heterozygous MTL genotypes (a/?), given that they contain all of the opaque-specific genes essential for switching. Here we report the discovery of white-opaque switching in a number of natural a/? strains of C. albicans under a condition mimicking aspects of the host environment. The optimal condition for white-to-opaque switching in a/? strains of C. albicans is to use N-acetylglucosamine (GlcNAc) as the sole carbon source and to incubate the cells in 5% CO2. Although the induction of white-to-opaque switching in a/? strains of C. albicans is not as robust as in MTL homozygotes in response to GlcNAc and CO2, opaque cells of a/? strains exhibit similar features of cellular and colony morphology to their MTL homozygous counterparts. Like MTL homozygotes, white and opaque cells of a/? strains differ in their behavior in different mouse infection models. We have further demonstrated that the transcriptional regulators Rfg1, Brg1, and Efg1 are involved in the regulation of white-to-opaque switching in a/? strains. We propose that the integration of multiple environmental cues and the activation and inactivation of a set of transcriptional regulators controls the expression of the master switching regulator WOR1, which determines the final fate of the cell type in C. albicans. Our discovery of white-opaque switching in the majority of natural a/? strains of C. albicans emphasizes its widespread nature and importance in host adaptation, pathogenesis, and parasexual reproduction.
| S-EPMC3608550 | biostudies-literature
Project description:Candida albicans is a commensal yeast that inhabits the gastrointestinal tract of humans. The master regulator of the white-opaque transition WOR1 has been implicated in the adaptation to this commensal status. A proteomic analysis of cells overexpressing this transcription factor (WOR1OE) suggested an altered metabolism of carbon sources and a phenotypic analysis confirmed this alteration. The WOR1OE cells are deficient in using trehalose and xylose and are unable to use 2C sources, which is consistent with a reduction in the amount of Icl1, the isocitrate lyase enzyme. The icl1Δ/Δ mutants overexpressing WOR1 are deficient in the production of phloxine B positive cells, a main characteristic of opaque cells, a phenotype also observed in mating type hemizygous mtla1Δ icl1Δ/Δ cells, suggesting the involvement of Icl1 in the adaptation to the commensal state. In fact, icl1Δ/Δ cells have reduced fitness in mouse gastrointestinal tract as compared with essentially isogenic heterozygous ICL1/icl1Δ, but overproduction of WOR1 in an icl1Δ/Δ mutant does not restore fitness. These results implicate the glyoxylate shunt in the adaptation to commensalism of C. albicans by mechanisms that are partially independent of WOR1.
| S-EPMC8304919 | biostudies-literature