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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
| PRJNA853553 | 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:Functional Portrait of Irf1 (Orf19.217), a Regulator of Morphogenesis and Iron Homeostasis in Candida albicans [RNA-Seq]
| PRJNA853561 | ENA
Project description:Sfl1p and Sfl2p are two homologous heat shock factor-type transcriptional regulators that antagonistically control morphogenesis in Candida albicans, while being required for full pathogenesis and virulence. To understand how Sfl1p and Sfl2p exert their function, we combined genome-wide location and expression analyses to reveal their transcriptional targets in vivo together with the associated changes of the C. albicans transcriptome. We show that Sfl1p and Sfl2p bind to the promoter of at least 113 common targets through divergent binding motifs and modulate directly the expression of key transcriptional regulators of C. albicans morphogenesis and/or virulence. Surprisingly, we found that Sfl2p additionally binds to the promoter of 75 specific targets, including a high proportion of hyphal-specific genes (HSGs; HWP1, HYR1, ECE1, others), revealing a direct link between Sfl2p and hyphal development. Data mining pointed to a regulatory network in which Sfl1p and Sfl2p act as both transcriptional activators and repressors. Sfl1p directly represses the expression of positive regulators of hyphal growth (BRG1, UME6, TEC1, SFL2), while upregulating both yeast form-associated genes (RME1, RHD1, YWP1) and repressors of morphogenesis (SSN6, NRG1). On the other hand, Sfl2p directly upregulates HSGs and activators of hyphal growth (UME6, TEC1), while downregulating yeast form-associated genes and repressors of morphogenesis (NRG1, RFG1, SFL1). Using genetic interaction analyses, we provide further evidences that Sfl1p and Sfl2p antagonistically control C. albicans morphogenesis through direct modulation of the expression of important regulators of hyphal growth. Bioinformatic analyses suggest that binding of Sfl1p and Sfl2p to their targets occurs with the co-binding of Efg1p and/or Ndt80p. We show, indeed, that Sfl1p and Sfl2p targets are bound by Efg1p and that both Sfl1p and Sfl2p associate in vivo with Efg1p. Taken together, our data suggest that Sfl1p and Sfl2p act as central "switch on/off" proteins to coordinate the regulation of C. albicans morphogenesis.
| S-EPMC3744398 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2014-09-18 | GSE61519 | GEO
Project description:Cell-substrate adherence is a fundamental property of microorganisms that enables them to exist in biofilms. Our study focuses on adherence of the fungal pathogen Candida albicans to one substrate, silicone, that is relevant to device-associated infection. We conducted a mutant screen with a quantitative flow-cell assay to identify thirty transcription factors that are required for adherence. We then combined nanoString gene expression profiling with functional analysis to elucidate relationships among these transcription factors, with two major goals: to extend our understanding of transcription factors previously known to govern adherence or biofilm formation, and to gain insight into the many transcription factors we identified that were relatively uncharacterized, particularly in the context of adherence or cell surface biogenesis. With regard to the first goal, we have discovered a role for biofilm regulator Bcr1 in adherence, and found that biofilm regulator Ace2 is a major functional target of chromatin remodeling factor Snf5. In addition, Bcr1 and Ace2 share several target genes, pointing to a new connection between them. With regard to the second goal, our findings reveal existence of a large regulatory network that connects eleven adherence regulators, the zinc-response regulator Zap1, and approximately one quarter of the predicted cell surface protein genes in this organism. This limited yet sensitive glimpse of mutant gene expression changes had thus defined one of the broadest cell surface regulatory networks in C. albicans.
| S-EPMC3280983 | biostudies-literature
Project description:Mediator is a multi-subunit protein complex that regulates gene expression in eukaryotes by integrating physiological and developmental signals and transmitting them to the general RNA polymerase II machinery. We examined, in the fungal pathogen Candida albicans, a set of conditional alleles of genes encoding Mediator subunits of the head, middle, and tail modules that were found to be essential in the related ascomycete Saccharomyces cerevisiae. Intriguingly, while the Med4, 8, 10, 11, 14, 17, 21 and 22 subunits were essential in both fungi, the structurally highly conserved Med7 subunit was apparently non-essential in C. albicans. While loss of CaMed7 did not lead to loss of viability under normal growth conditions, it dramatically influenced the pathogen's ability to grow in different carbon sources, to form hyphae and biofilms, and to colonize the gastrointestinal tracts of mice. We used epitope tagging and location profiling of the Med7 subunit to examine the distribution of the DNA sites bound by Mediator during growth in either the yeast or the hyphal form, two distinct morphologies characterized by different transcription profiles. We observed a core set of 200 genes bound by Med7 under both conditions; this core set is expanded moderately during yeast growth, but is expanded considerably during hyphal growth, supporting the idea that Mediator binding correlates with changes in transcriptional activity and that this binding is condition specific. Med7 bound not only in the promoter regions of active genes but also within coding regions and at the 3' ends of genes. By combining genome-wide location profiling, expression analyses and phenotyping, we have identified different Med7p-influenced regulons including genes related to glycolysis and the Filamentous Growth Regulator family. In the absence of Med7, the ribosomal regulon is de-repressed, suggesting Med7 is involved in central aspects of growth control.
| S-EPMC4222720 | biostudies-literature
Project description:Efg1p is a key transcriptional regulator in Candida albicans which controls various aspects of morphogenesis and metabolism in this organism. Efg1p contains a central basic helix-loop-helix (bHLH) domain, flanked by sequences highly conserved in fungal APSES proteins, as well as polyglutamine stretches at the N- and C-terminal ends. A systematic deletion approach to specify functional domains of Efg1p revealed that the APSES domain is essential for morphogenesis of the normal yeast and true hyphal cell forms and that bHLH flanking sequences are needed for Efg1p stability. Additional C-terminal sequences were required for hyphal formation on some inducing media, and most Efg1p sequences were needed for chlamydospore morphogenesis. Overexpression of EFG1 led to pseudohypha formation only if a functional APSES domain was present, while a switch from the opaque to the white cell type in addition depended on the presence of certain N- and C-terminal segments. Yeast two-hybrid experiments revealed that binding of Efg1p to its antagonist Czf1p required two regions outside of the APSES domain, which did not coincide with Efg1p sequences needed for its transcriptional repressor activity. Binding of the Flo8 transcription factor to Efg1p did not require the APSES domain but appeared to occur at two or more redundant domains. In contrast, DNA binding of Efg1p to an MluI cell cycle box (MCB) element solely required the APSES domain. Overall, these results suggest that functional domains of Efg1p are spread throughout most of its sequences, including the central APSES domain involved in DNA binding, as well as flanking regions required for various protein interactions and regulatory activities.
| S-EPMC2394972 | biostudies-literature