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Interlocking transcriptional feedback loops control white-opaque switching in Candida albicans.

ABSTRACT: 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.

SUBMITTER: Zordan RE

PROVIDER: S-EPMC1976629 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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

Transcriptional loops meet chromatin: a dual-layer network controls white-opaque switching in Candida albicans.

Project description:The human pathogen Candida albicans is able to undergo a reversible switch between two distinct cell types called white and opaque, which are considered different transcriptional states of cells harbouring identical genomes. The present model of switching regulation includes the bistable expression of a master switch gene that is controlled by multiple transcriptional feedback loops. Here, we show that chromatin-modifying enzymes constitute an additional important regulatory layer of morphogenetic switching. We identify eight chromatin modifiers as switching modulators. Extensive epistasis analysis maps them into at least two independent signalling pathways overlaying the known transcriptional network. Interestingly, we identify the conserved Set3/Hos2 histone deacetylase complex as a key regulator relying on the methylation status of histone H3 lysine 4 for switching modulation. Furthermore, we demonstrate that opaque to white switching is facilitated by the presence of adenine in vitro, but adenine has no effect on switching once the Set3/Hos2 complex is disrupted. Our observations postulate that chromatin modifications may serve as a means to integrate environmental or host stimuli through the underlying transcriptional circuits to determine cell fate in C. albicans.

| S-EPMC2764112 | biostudies-literature

Structure of the transcriptional network controlling 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 primary DNA sequence of the genome. Previous work identified six key transcriptional regulators important for white-opaque switching: Wor1, Wor2, Wor3, Czf1, Efg1, and Ahr1. In this work, we describe the structure of the transcriptional network that specifies the white and opaque cell types and governs the ability to switch between them. In particular, we use a combination of genome-wide chromatin immunoprecipitation, gene expression profiling, and microfluidics-based DNA binding experiments to determine the direct and indirect regulatory interactions that form the switch network. The six regulators are arranged together in a complex, interlocking network with many seemingly redundant and overlapping connections. We propose that the structure (or topology) of this network is responsible for the epigenetic maintenance of the white and opaque states, the switching between them, and the specialized properties of each state.

| S-EPMC3888361 | biostudies-literature

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. 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

Epigenetic properties of white-opaque switching in Candida albicans are based on a self-sustaining transcriptional feedback loop.

Project description:White-opaque switching in the human fungal pathogen Candida albicans is an alternation between two distinct types of cells, white and opaque. White and opaque cells differ in their appearance under the microscope, the genes they express, their mating behaviors, and the host tissues for which they are best suited. Each state is heritable for many generations, and switching between states occurs stochastically, at low frequency. In this article, we identify a master regulator of white-opaque switching (Wor1), and we show that this protein is a transcriptional regulator that is needed to both establish and maintain the opaque state. We show that in opaque cells, Wor1 forms a positive feedback loop: It binds its own DNA regulatory region and activates its own transcription leading to the accumulation of high levels of Wor1. We further show that this feedback loop is self-sustaining: Once activated, it persists for many generations. We propose that this Wor1 feedback loop accounts, at least in part, for the heritability of the opaque state. In contrast, white cells (and their descendents) lack appreciable levels of Wor1, and the feedback loop remains inactive. Thus, this simple model can account for both the heritability of the white and opaque states and the stochastic nature of the switching between them.

| S-EPMC1535343 | biostudies-literature

Environmental induction of white-opaque switching in Candida albicans.

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

CO(2) regulates white-to-opaque switching in Candida albicans.

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

Farnesol and phosphorylation of the transcriptional regulator Efg1 affect Candida albicans white-opaque switching rates.

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.

| S-EPMC9858334 | biostudies-literature

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 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

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

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