Sterol biosynthesis is regulated by a sophisticated regulatory network involving multiple transcription factors in fungi
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ABSTRACT:
PROVIDER: PRJNA1089543 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28386505_1.fastq.gz | Fastqsanger.gz | |||
| SRR28386505_2.fastq.gz | Fastqsanger.gz | |||
| SRR28386506_1.fastq.gz | Fastqsanger.gz | |||
| SRR28386506_2.fastq.gz | Fastqsanger.gz | |||
| SRR28386507_1.fastq.gz | Fastqsanger.gz |
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Project description:Ergosterol, a pivotal constituent of the fungal cell membrane, plays a crucial role in diverse cellular activities. Fungi inherently regulate ergosterol homeostasis, a process traditionally associated with the control of a major transcription factor, like SREBP, activated in response to ergosterol depletion, regardless of which ergosterol biosynthesis step is affected. Contrary to the established paradigm, our investigation demonstrates that the inhibition of ergosterol biosynthesis at specific steps triggers distinct transcriptional responses in erg genes across fungi, including Neurospora crassa, Aspergillus fumigatus, and Fusarium verticillioides. In N. crassa, the targeted responses are orchestrated by several transcription factors that have undergone functional rewiring. Specifically, ERG24 inhibition by amorolfine activates transcription factors SAH-2 and AtrR, resulting in the upregulation of erg24, erg2, erg25 and erg3. Additionally, ERG11 inhibition by azoles activates transcription factor NcSR, leading to the upregulation of erg11 and erg6. Our findings unveil a novel sophisticated regulation model of sterol biosynthesis in fungi which potentially enhances fungal survival in complex environments, thus providing new insights into sterol homeostasis maintenance and a deeper understanding of drug resistance mechanisms in fungi.
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Project description:Resistance to agricultural fungicides in the field has created a need for discovering fungicides with new modes of action. DNA microarrays, because they provide information on expression of many genes simultaneously, could help to identify the modes of action. To begin an expression pattern database for agricultural fungicides, transcriptional patterns of Saccharomyces cerevisiae strain S288C genes were analysed following 2-h treatments with I50 concentrations of ergosterol biosynthesis inhibitors commonly used against plant pathogenic fungi. Eight fungicides, representing three classes of ergosterol biosynthesis inhibitors, were tested. To compare gene expression in response to a fungicide with a completely different mode of action, a putative methionine biosynthesis inhibitor (MBI) was also tested. Expression patterns of ergosterol biosynthetic genes supported the roles of Class I and Class II inhibitors in affecting ergosterol biosynthesis, confirmed that the putative MBI did not affect ergosterol biosynthesis, and strongly suggested that in yeast, the Class III inhibitor did not affect ergosterol biosynthesis. The MBI affected transcription of three genes involved in methionine metabolism, whereas there were essentially no effects of ergosterol synthesis inhibitors on methionine metabolism genes. There were no consistent patterns in other up- or downregulated genes between fungicides. These results suggest that inspection of gene response patterns within a given pathway may serve as a useful first step in identifying possible modes of action of fungicides. agricultural sterol biosynthesis inhibitor fungicides. Keywords = agriculture Keywords = ergosterol Keywords = methionine Keywords = fungicide Keywords = Saccharomyces cerevisiae S288C Keywords = biosynthesis
2010-06-10 | E-GEOD-2412 | biostudies-arrayexpress
Project description:Resistance to agricultural fungicides in the field has created a need for discovering fungicides with new modes of action. DNA microarrays, because they provide information on expression of many genes simultaneously, could help to identify the modes of action. To begin an expression pattern database for agricultural fungicides, transcriptional patterns of Saccharomyces cerevisiae strain S288C genes were analysed following 2-h treatments with I50 concentrations of ergosterol biosynthesis inhibitors commonly used against plant pathogenic fungi. Eight fungicides, representing three classes of ergosterol biosynthesis inhibitors, were tested. To compare gene expression in response to a fungicide with a completely different mode of action, a putative methionine biosynthesis inhibitor (MBI) was also tested. Expression patterns of ergosterol biosynthetic genes supported the roles of Class I and Class II inhibitors in affecting ergosterol biosynthesis, confirmed that the putative MBI did not affect ergosterol biosynthesis, and strongly suggested that in yeast, the Class III inhibitor did not affect ergosterol biosynthesis. The MBI affected transcription of three genes involved in methionine metabolism, whereas there were essentially no effects of ergosterol synthesis inhibitors on methionine metabolism genes. There were no consistent patterns in other up- or downregulated genes between fungicides. These results suggest that inspection of gene response patterns within a given pathway may serve as a useful first step in identifying possible modes of action of fungicides. agricultural sterol biosynthesis inhibitor fungicides. Keywords = agriculture Keywords = ergosterol Keywords = methionine Keywords = fungicide Keywords = Saccharomyces cerevisiae S288C Keywords = biosynthesis
2005-05-01 | GSE2412 | GEO
Project description:Membranes require continuous reorganization of lipid components, including sterols, to dynamically alter their rigidity to deform and bend during scission events which occur during fundamental cellular functions such as endocytosis. While diseases of cholesterol biosynthesis result in reduced cellular cholesterol and accumulation of precursor sterols, limited studies have addressed the intracellular consequences of disease-associated sterol changes on the ability of eukaryotic cellular membranes to function and signal normally. Here, we utilized bone marrow-derived macrophages (BMDMs) to investigate how altered sterol content impacts macrophage signaling and membrane function. Through pharmacological inhibition of cholesterol biosynthetic enzymes, reduced cholesterol and increased levels of disease-associated sterol intermediates coincided with reduced expression of immunogenic surface markers and impaired macropinocytosis. Macropinocytic activity was sensitive to both reduced plasma membrane cholesterol and sterols containing functional groups substituted for the C3 hydroxyl group. Transcriptomic analyses of cholesterol-inhibited BMDMs revealed alterations in immune and chemokine signaling pathways. Decreased cholesterol was also associated with dysregulated vesicular sorting pathways and elevated expression of endosomal/lysosomal markers. Disrupted endosomal sorting and impaired macropinocytosis was also observed in BMDMs from mouse models of the cholesterol biosynthesis disorder Smith-Lemli-Opitz syndrome (SLOS). Our findings detail an important connection between sterol imbalance, membrane dynamics, and immune cell function.
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Project description:In this study, C. albicans regulates its methionine biosynthetic pathways using the transcription factors Met4 and Cbf1. This circuitry appears more complex than that of filamentous fungi, which use orthologs of the Met4 transcription factor, but lack versions of Cbf1, but is considerably less complex than that of S. cerevisiae, which 2 requires two transcription complexes, involving Cbf1 and Met31/32 as DNA binding modules, and Met4 and the Met4 ortholog Met28 as co-activators, to regulate Met biosynthesis. Although C. albicans contains Met31/32 and Met28 orthologs, they do not appear to be linked to regulation of the methionine circuit. Thus, the phylogenetic progression from filamentous fungi to S. cerevisiae is characterized by increasing complexity of the regulators, although the structural elements of the pathways are fundamentally the same.
2020-11-26 | GSE162171 | GEO
Project description:To determine how the fungal sterol homeostasis pathway contributes to the fungal pH response. To do so, we compared the transcriptomes of the sre1∆ mutant strain to that of the WT H99 strain in acidic (pH 4) and alkaline (pH 8) conditions.
2020-03-18 | GSE147109 | GEO
Project description:All but a few eukaryotes die without oxygen and respond dynamically to changes in the level of oxygen available to them. One ancient oxygen-requiring biochemical pathway in eukaryotes is the pathway for the biosynthesis of sterols, leading to cholesterol in animals and ergosterol in fungi. Mutations in this pathway are a frequent cause of azole drug resistance in pathogenic fungi. The regulatory mechanism for the sterol pathway is also widely conserved between animals and fungi and is centred on a transcription activator, SREBP, that forms part of a sterol-sensing complex. However, in one group of yeasts – the Saccharomycotina, which includes the major pathogen Candida albicans – control of the sterol pathway has been taken over by an unrelated regulatory protein, Upc2. We show here by analysis of the yeast Yarrowia lipolytica that the evolutionary switch from SREBP to Upc2 was a two-step process in which Upc2 appeared in an ancestor of Saccharomycotina, and SREBP subsequently degenerated and lost its sterol-regulatory function while retaining an ancient role in filamentation.
2013-11-19 | GSE47433 | GEO
Project description:All but a few eukaryotes die without oxygen and respond dynamically to changes in the level of oxygen available to them. One ancient oxygen-requiring biochemical pathway in eukaryotes is the pathway for the biosynthesis of sterols, leading to cholesterol in animals and ergosterol in fungi. Mutations in this pathway are a frequent cause of azole drug resistance in pathogenic fungi. The regulatory mechanism for the sterol pathway is also widely conserved between animals and fungi and is centred on a transcription activator, SREBP, that forms part of a sterol-sensing complex. However, in one group of yeasts M-bM-^@M-^S the Saccharomycotina, which includes the major pathogen Candida albicans M-bM-^@M-^S control of the sterol pathway has been taken over by an unrelated regulatory protein, Upc2. We show here by analysis of the yeast Yarrowia lipolytica that the evolutionary switch from SREBP to Upc2 was a two-step process in which Upc2 appeared in an ancestor of Saccharomycotina, and SREBP subsequently degenerated and lost its sterol-regulatory function while retaining an ancient role in filamentation. RNA was isolated from Y. lipolytica wildtype (JMY2900) in normoxia (21% oxygen, 4 biological replicates), wildtype (JMY2900) in hypoxia (1% oxygen, 5 biological replicates), upc2 deletion (SMY2) in hypoxia (1% oxygen, 3 biological replicates), and from sre1 (SMY5, SMY8) deletion in hypoxia (1% oxygen, 2 biological replicates). Gene expression was determined using strand-specific RNA-seq.
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