Functional Portrait of Irf1 (Orf19.217), a Regulator of Morphogenesis and Iron Homeostasis in Candida albicans
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ABSTRACT:
PROVIDER: PRJNA853553 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19884605_1.fastq.gz | Fastqsanger.gz | |||
| SRR19884605_2.fastq.gz | Fastqsanger.gz | |||
| SRR19884606_1.fastq.gz | Fastqsanger.gz | |||
| SRR19884606_2.fastq.gz | Fastqsanger.gz | |||
| SRR19884607_1.fastq.gz | Fastqsanger.gz |
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Project description:The fungus Candida albicans is part of the human microbiome and mainly colonises the GI tract of healthy individuals. However, when the balance in the GI tract is disturbed, the fungus can switch from a commensal to a virulent lifestyle and can turn into a life-threatening pathogen. Life in the host is characterised by a constant struggle for nutrients, essential trace elements such as iron, copper and zinc are particularly important. To protect itself from pathogens, the human host has developed a strategy to limit the availability of trace elements, this strategy is also described as nutritional immunity. C. albicans has developed a whole range of counter-strategies to obtain sufficient trace elements. In this manuscript, we have characterised the transcription factor Orf19.217, which acts at the interface between trace element scavenging and acquisition and is therefore particularly important in adaptation to life in the host. According to its identified function, we named the transcription factor Irf1, Iron-dependent Regulator of Filamentation. The transcription factor was previously identified in a systematic screen of genes whose overexpression contributes to morphological changes in C. albicans. We have comprehensively investigated the function of Irf1 using state-of-the-art functional genomics approaches, including ChIP-seq, transcriptomics and bioinformatics analyses. Analysis of the Irf1 gene-regulatory network indicates that the transcription factor is involved in the regulation of genes important for iron uptake. Using phenotypic analysis, we confirmed that Irf1 acts in a pathway parallel to known iron uptake regulators and is also required for hyphal formation induced by iron deficiency, a process that allows the fungus to access more viable body niches. Through epistasis experiments, we were also able to identify downstream effectors of Irf1 that are involved in this process. Our study provides new insights into how C. albicans adapts to iron deficiency and establish a direct functional link between hyphal formation and iron uptake.
2022-07-01 | GSE207072 | GEO
Project description:The fungus Candida albicans is part of the human microbiome and mainly colonises the GI tract of healthy individuals. However, when the balance in the GI tract is disturbed, the fungus can switch from a commensal to a virulent lifestyle and can turn into a life-threatening pathogen. Life in the host is characterised by a constant struggle for nutrients, essential trace elements such as iron, copper and zinc are particularly important. To protect itself from pathogens, the human host has developed a strategy to limit the availability of trace elements, this strategy is also described as nutritional immunity. C. albicans has developed a whole range of counter-strategies to obtain sufficient trace elements. In this manuscript, we have characterised the transcription factor Orf19.217, which acts at the interface between trace element scavenging and acquisition and is therefore particularly important in adaptation to life in the host. According to its identified function, we named the transcription factor Irf1, Iron-dependent Regulator of Filamentation. The transcription factor was previously identified in a systematic screen of genes whose overexpression contributes to morphological changes in C. albicans. We have comprehensively investigated the function of Irf1 using state-of-the-art functional genomics approaches, including ChIP-seq, transcriptomics and bioinformatics analyses. Analysis of the Irf1 gene-regulatory network indicates that the transcription factor is involved in the regulation of genes important for iron uptake. Using phenotypic analysis, we confirmed that Irf1 acts in a pathway parallel to known iron uptake regulators and is also required for hyphal formation induced by iron deficiency, a process that allows the fungus to access more viable body niches. Through epistasis experiments, we were also able to identify downstream effectors of Irf1 that are involved in this process. Our study provides new insights into how C. albicans adapts to iron deficiency and establish a direct functional link between hyphal formation and iron uptake.
2022-07-01 | GSE207033 | GEO
Project description:Functional Portrait of Irf1 (Orf19.217), a Regulator of Morphogenesis and Iron Homeostasis in Candida albicans [RNA-Seq]
| PRJNA853561 | ENA
Project description:Functional Portrait of Irf1 (Orf19.217), a Regulator of Morphogenesis and Iron Homeostasis in Candida albicans [ChIP-Seq]
| PRJNA853339 | ENA
Project description:The alternate growth of Candida albicans between a unicellular yeast form and a multicellular hyphal form is crucial for its ability to cause disease. Interestingly, both morphological forms support distinct functions during proliferation in the human host. We previously identified ORF19.217 (C2_08890W_A), encoding a zinc-finger transcription factor of the C2H2 family, in a systematic screen of genes whose overexpression contributes to C. albicans' morphological changes. Conditional overexpression of ORF19.217 with the strong tetracycline-inducible promoter (P TET ) resulted in a hyperfilamentous phenotype. We examined growth of the orf19.217 knockout-mutant in different hypha-inducing conditions and found that the mutant still formed hyphae under standard hypha-inducing conditions. To further investigate the function of Orf19.217 in C. albicans, we combined genome-wide expression (RNA-Seq) and location (ChIP-Seq) analyses. We found that Orf19.217 is involved in regulatory processes comprising hyphal morphogenesis and iron acquisition. Comparative analysis with existing C. albicans hyphal transcriptomes indicates that Orf19.217-mediated filamentation is distinct from a true hyphal program. Further, the orf19.217 knockout-mutant did not show increased sensitivity to iron deprivation, but ORF19.217 overexpression was able to rescue the growth of a hap5-mutant, defective in a subunit of the CCAAT-complex, which is essential for iron acquisition. This suggested that Orf19.217 is involved in regulation of iron acquisition genes during iron deprivation and acts in a parallel pathway to the established CCAAT-complex. Interestingly, the orf19.217-mutant turned out to be defective in its ability to form filaments under iron-deficiency. Taken together our findings propose that the transcription factor Orf19.217 stimulates expression of the hyphal regulators EFG1 and BRG1 to promote filamentous growth under iron deprivation conditions, allowing the fungus to escape these iron-depleted conditions. The transcription factor therefore appears to be particularly important for adaptation of C. albicans to diverse environmental conditions in the human host. In regard to the newly identified functions, we have given the regulator the name Irf1, Iron-dependent Regulator of Filamentation.
| S-EPMC9393397 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-07-01 | GSE207073 | GEO
Project description:Recent cumulative data shows that various transcription factors are recruited to the chromatin in an iron-responsive manner to affect diverse cellular functions in the pathogenic fungus Candida albicans. Here, we identified groups of iron-responsive genes in C. albicans by chromatin remodeling analysis at gene promoters, using micrococcal nuclease (MNase) digestion followed by deep sequencing. Chromatin in the promoter regions of iron uptake and utilization genes showed repressed and active configuration, respectively, under iron-replete conditions. GO Term enrichment analysis of genes with differentially remodeled chromatin, in respective promoter locales, suggested that many genes involved in adhesion are also iron-responsive. C. albicans was observed to be more self-adherent (2-fold increase) and formed higher biofilm mass (77% increase) in the presence of iron. Furthermore, we identified various known and novel adhesion-related genes with iron-dependent active chromatin profiles that are indicative of potential up-regulation under iron-replete conditions. Transcription factor Cph1 that is activated upon Cek1 phosphorylation also showed an active chromatin profile under iron-replete conditions and cells showed iron-responsive Cek1 MAPK phosphorylation in the presence of iron. Thus, iron affects diverse biological functions by modulating chromatin profiles of large gene sets and by signaling through Cek1 MAPK in C. albicans.
2014-11-10 | GSE55819 | GEO
Project description:Iron sequestration by host iron-binding proteins is an important mechanism of resistance to microbial infections. Inside oral epithelial cells, iron is stored within the ferritin, and is therefore usually not accessible to pathogenic microbes. We observed that the ferritin concentration within oral epithelial cells was directly related to their susceptibility to damage by the human pathogenic fungus Candida albicans. Thus, we hypothesized that host ferritin may be used as an iron source by this organism. A screen of C. albicans mutants lacking components of each of the three iron acquisition systems revealed that only the reductive pathway is involved in iron utilization from ferritin by this organism. Transcriptional profiling of wild-type and hyphal-defective C. albicans strains suggested that the C. albicans invasin-like protein Als3 plays a role in ferritin binding.
2008-05-20 | GSE11490 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE34255: Pho85, Pcl1, and Hms1 Signaling Governs Candida albicans Morphogenesis Induced by Elevated Temperature or Hsp90 Compromise [mRNA] GSE34938: Pho85, Pcl1, and Hms1 Signaling Governs Candida albicans Morphogenesis Induced by Elevated Temperature or Hsp90 Compromise [ChIP-chip] Refer to individual Series
2012-03-20 | E-GEOD-34939 | biostudies-arrayexpress
Project description:Candida albicans, the causative agent of mucosal infections including oropharyngeal candidiasis (OPC) as well as bloodstream infections is becoming increasingly resistant to existing treatment options. In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat off label diseases is a promising strategy. C. albicans requires environmental iron for survival and virulence while host nutritional immunity deploys iron-binding proteins to sequester iron and reduce fungal growth. Here we evaluated the role of iron-limitation using Deferasirox (an FDA approved iron chelator for treatment of patients with iron overload) during murine OPC; and assessed Deferasirox-treated C. albicans for its interaction with human oral epithelial (OE), neutrophils, and antimicrobial peptides. Therapeutic Deferasirox treatment significantly reduced salivary iron levels while a non-significant reduction in fungal burden was observed. Preventive treatment that allowed for two additional days of drug administration in our murine model, resulted in significant reduction of C. albicans colony forming units (CFU)/g of tongue tissue, a significant reduction in salivary iron levels, and significantly reduced neutrophil-mediated inflammation. C. albicans harvested from tongues of animals undergoing preventive treatment had differential expression of 106 genes, including those involved in iron metabolism, adhesion, and response to host innate immunity. Moreover, Deferasirox-treated C. albicans cells had two-fold reduction in survival in neutrophil phagosomes (with greater susceptibility to oxidative stress); and reduced adhesion and invasion of OE cells, in vitro. Thus Deferasirox treatment has the potential to alleviate OPC by affecting C. albicans gene expression and reducing virulence
2018-12-04 | GSE123277 | GEO