The zinc cluster transcription factor Rha1 is a positive filamentation regulator in Candida albicans
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ABSTRACT:
PROVIDER: PRJNA601775 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10904940_1.fastq.gz | Fastqsanger.gz | |||
| SRR10904940_2.fastq.gz | Fastqsanger.gz | |||
| SRR10904941_1.fastq.gz | Fastqsanger.gz | |||
| SRR10904941_2.fastq.gz | Fastqsanger.gz | |||
| SRR10904942_1.fastq.gz | Fastqsanger.gz |
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Project description:The regulatory mechanism for filamentation includes a complex network of transcription factors that play roles in regulating hyphae associated genes. We identify here a new regulator of filamentation from the zinc cluster transcription factor family. We present evidence suggesting that this transcription factor assists the Nrg1/Brg1 switch regulating hyphal development.
2020-12-31 | GSE143825 | GEO
Project description:The zinc cluster proteins are a family of transcription factors that are unique to the fungal kingdom. In the pathogenic yeast Candida albicans, zinc cluster transcription factors control the expression of virulence-associated traits and play key roles in the development of antifungal drug resistance. Gain-of-function mutations in several zinc cluster transcription factors, which result in constitutive overexpression of their target genes, are a frequent cause of azole resistance in clinical C. albicans isolates. We found that zinc cluster proteins can also be artificially activated by C-terminal fusion with the heterologous Gal4 activation domain. We used this strategy to create a comprehensive library of C. albicans strains expressing all 82 zinc cluster transcription factors of this fungus in a potentially hyperactive form. Screening of this library identified regulators of invasive filamentous growth and other phenotypes that are important during an infection. In addition, the approach uncovered several novel mediators of fluconazole resistance, including the multidrug resistance regulator Mrr2, which controls the expression of the major C. albicans multidrug efflux pump CDR1. Artificial activation therefore is a highly useful method to study the role of zinc cluster transcription factors in C. albicans and other fungi of medical, agricultural, and biotechnological importance.
2013-07-29 | GSE48259 | GEO
Project description:The zinc cluster proteins are a family of transcription factors that are unique to the fungal kingdom. In the pathogenic yeast Candida albicans, zinc cluster transcription factors control the expression of virulence-associated traits and play key roles in the development of antifungal drug resistance. Gain-of-function mutations in several zinc cluster transcription factors, which result in constitutive overexpression of their target genes, are a frequent cause of azole resistance in clinical C. albicans isolates. We found that zinc cluster proteins can also be artificially activated by C-terminal fusion with the heterologous Gal4 activation domain. We used this strategy to create a comprehensive library of C. albicans strains expressing all 82 zinc cluster transcription factors of this fungus in a potentially hyperactive form. Screening of this library identified regulators of invasive filamentous growth and other phenotypes that are important during an infection. In addition, the approach uncovered several novel mediators of fluconazole resistance, including the multidrug resistance regulator Mrr2, which controls the expression of the major C. albicans multidrug efflux pump CDR1. Artificial activation therefore is a highly useful method to study the role of zinc cluster transcription factors in C. albicans and other fungi of medical, agricultural, and biotechnological importance. In total, 15 samples are analysed: 3 replicates of 5 different strains. The 3 replicates of SC5314 are the wild type reference.
2013-07-29 | E-GEOD-48259 | biostudies-arrayexpress
Project description:Zinc cluster transcription factors (TFs) are essential fungal regulators of gene expression. In the pathogen Candida albicans, the gene orf19.1604 encodes a zinc cluster TF regulating filament development. Hyperactivation of orf19.1604, which we have named RHA1 for Regulator of Hyphal Activity, generates wrinkled colony morphology under nonhyphal growth conditions, triggers filament formation, invasiveness, and enhanced biofilm formation and causes reduced virulence in the mouse model of systemic infection. The strain expressing activated Rha1 shows up-regulation of genes required for filamentation and cell-wall-adhesion-related proteins. Increased expression is also seen for the hyphal-inducing TFs Brg1 and Ume6, while the hyphal repressor Nrg1 is downregulated. Inactivation of RHA1 reduces filamentation under a variety of filament-inducing conditions. In contrast to the partial effect of either single mutant, the double rha1 ume6 mutant strain is highly defective in both serum- and Spider-medium-stimulated hyphal development. While the loss of Brg1 function blocks serum-stimulated hyphal development, this block can be significantly bypassed by Rha1 hyperactivity, and the combination of Rha1 hyperactivity and serum addition can generate significant polarization even in brg1 ume6 double mutants. Thus, in response to external signals, Rha1 functions with other morphogenesis regulators including Brg1 and Ume6, to mediate filamentation.
| S-EPMC8733637 | biostudies-literature
Project description:Hyphal growth is strongly associated with virulence in the human fungal pathogen Candida albicans. While hyphal transcriptional networks have been the subject of intense study, relatively little is known about post-transcriptional regulation. Previous work reported that P-Body (PB) factors Dhh1 and Edc3 were required for C. albicans virulence and filamentation, suggesting an essential role for post-transcriptional regulation of these processes. However, the molecular roles of these factors have not been determined. To further study the function of PB factors in filamentation, we generated homozygous deletions of DHH1 and EDC3 in diverse prototrophic clinical strains using transient CRISPR-Cas9. Homozygous DHH1 deletion strongly impaired growth, altered filamentation, and exhibited unusual colony morphology in response to heat stress in five strain backgrounds. Using RNA-seq, we found DHH1 deletion disrupts the regulation of thousands of genes under both yeast and hyphal growth conditions in SC5314 and P57055. This included upregulation of many stress response genes in the absence of external stress, similar to deletion of the S. cerevisiae DHH1 homolog. In contrast, we found EDC3 was not required for heat tolerance or filamentation in diverse strains. These results support a model in which DHH1, but not EDC3, represses hyphal stress response transcripts in yeast and remodels the transcriptome during filamentation. Our work supports distinct requirements for specific mRNA decay factors, bolstering evidence for post-transcriptional regulation of filamentation in C. albicans.
2025-02-18 | GSE284543 | GEO
Project description:Candida albicans is one of the most common causes of human fungal disease. One of the most studied C. albicans virulence traits is its ability to adopt both yeast and filamentous morphologies. Accordingly, the regulation of the yeast-to-filament transition has been area of intense study in medical mycology. A longstanding mechanistic paradigm in this field is that the cAMP-protein kinase A pathway phosphorylates a master transcriptional regulator of C. albicans filamentation, Efg1, to drive filamentation. This model has been generalized over the years despite the fact that the initial work showed that it applied to only specific in vitro filamentation conditions. Here, we reinvestigated the protein kinase A-Efg1 paradigm by generating new strains containing alleles of EFG1 with the putative protein kinase A phosphorylation site (T208) mutated to either Ala or Glu which blocks or mimics phosphorylation, respectively. We integrated these alleles into efg1∆∆ mutants so that they are expressed from the endogenous promoter. We assayed the effect of these Efg1 mutations on: 1) in vitro filamentation under a wide range of inducing condition; 2) biofilm formation; 3) in vivo filamentation; 4) virulence in a model of disseminated candidiasis; and 5) gene expression during in vitro filamentation. We found no evidence that blocking or mimicking protein kinase phosphorylation of Efg1 affected its function during filamentation, biofilm formation, of infection. These observations indicate that the protein kinase A-Efg1 model for the regulation of C. albicans filamentation should be reconsidered.
2025-10-17 | GSE309112 | GEO
Project description:The ability of the human pathogenic fungus Candida albicans to switch between yeast-like and filamentous forms of growth has long been linked to pathogenesis. Numerous environmental conditions, including growth at high temperatures, nutrient limitation, and exposure to serum, can trigger this morphological switch and are frequently used in in vitro models to identify genes with roles in filamentation. Previous work has suggested that differences exist between the various in vitro models both in the genetic requirements for filamentation and transcriptional responses to distinct filamentation-inducing media. We compared 10 in vitro models for filamentation and found broad genetic and transcriptomic differences between model systems. Methods: Total RNA was extracted from yeast or filamentous cells grown in liquid media or on solid plates. Samples were tested in biological triplicates. RNASeq libraries were generated beginning with 1.8 ng of total RNA following standardized protocols with the TruSeq RNA v2 kit (Illumina, San Diego). Libraries were diluted to a concentration of 6.0 picomoles and sequenced on a HiSeq2500 and 100 bp single reads were generated. Two lanes were used for each sample.
2017-09-28 | GSE99902 | GEO
Project description:Clinical isolates of the human fungal pathogen Candida albicans show significant variation in their ability to undergo in vitro filamentation. In this study, we show that Nrg1, a key repressor of filamentation and filament specific gene expression in standard laboratory strain, has strain dependent functions, especially during infection.
2024-01-20 | GSE253732 | GEO
Project description:The opportunistic pathogenic fungus Candida albicans can cause devastating infections in severely compromised patients. Its ability to undergo a morphogenetic transition from yeast to filamentous forms allows it to penetrate tissues and cause damage, and the expression of a number of pathogenetic mechanisms are also coordinately regulated with this yeast-to-hyphae conversion. Therefore, it is widely considered that filamentation represents one of the main virulence factors of C. albicans. We have previously identified N-[3-(allyloxy)-phenyl]-4-methoxybenzamide (compound 9029936) as the lead compound in a series of small molecule inhibitors of C. albicans filamentation, and characterized its activity, both in vitro and in vivo, as a promising candidate for the development of alternative anti-virulence strategies for the treatment of C. albicans infections. Here we have performed RNA sequencing analysis of samples obtained from C. albicans cells grown under filament-inducing conditions in the presence or absence of this compound. Overall treatment with compound 9029936 resulted in 618 up-regulated and 702 down-regulated genes. Not surprisingly some of the top down-regulated genes included well characterized genes associated with filamentation and virulence such as SAP5, ECE1 (candidalysin), and ALS3, as well as genes that impact metal chelation and utilization. Gene ontology analysis revealed an over-representation of cell adhesion, iron transport, filamentation, biofilm formation, and pathogenesis processes among down-regulated genes as result of treatment with this leading compound. Interestingly, the top up-regulated genes pointed to an enhancement of vesicular transport pathways, and in particular SNARE interactions.
2019-08-22 | GSE136116 | GEO
Project description:Candidiasis affects a wide variety of immunocompromised individuals, including HIV/AIDS patients and cancer patients on chemotherapy. Candida albicans, a major human fungal pathogen, accounts for about 50% of all cases, while the remainder are caused by the less pathogenic non-albicans Candida species (NACS). These species are believed to be less pathogenic, in part, because they do not filament as readily or robustly as C. albicans, although definitive evidence is lacking. To address this question, we used strains for two NACS, Candida tropicalis and Candida parapsilosis, that are genetically engineered to constitutively express the key transcriptional regulator UME6 and drive strong filamentation both in vitro and during infection in vivo. Unexpectedly, both strains showed a dramatic reduction in organ fungal burden and clearance of infection in response to UME6 expression. Consistent with these findings, we observed that a C. tropicalis hyperfilamentous mutant was significantly reduced and a filamentation-defective mutant was slightly increased for organ fungal burden. Comprehensive immune profiling did not reveal any significant changes in the host immune response to UME6 expression in the NACS. Interestingly, however, whole-genome transcriptional profiling indicated that while genes important for filamentation were induced by UME6 expression in C. tropicalis and C. parapsilosis, other genes involved in a variety of processes important for pathogenesis were strongly down-regulated. Our findings are significant because they suggest fundamental evolutionary differences in the relationship between morphology and pathogenicity among Candida species and that NACS do not necessarily possess the same virulence properties as C. albicans.
2019-10-01 | GSE134321 | GEO