Inhibition of histone acetyltransferase GCN5 by a transcription factor FgPacC controls fungal adaption to host-derived iron stress
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ABSTRACT:
ORGANISM(S): Fusarium graminearum PH-1
PROVIDER: GSE203093 | GEO | 2022/06/29
REPOSITORIES: GEO
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Project description:Iron is an essential cofactor for a wide range of cellular processes. Previous studies have shown that siderophore-mediated uptake and intracellular handling of iron are crucial for virulence of Aspergillus fumigatus. Here we show that the bzip-type transcription factor HapX plays a crucial role in the transcriptional remodeling required for adaption to iron starvation in this opportunistic fungal pathogen. HapX was found to be interconnected in a negative feed-back loop with the previously identified iron regulator SreA: SreA repressed expression of hapX during iron sufficiency and HapX repressed sreA during iron starvation. Genome-wide transcriptional profiling and analysis of selected metabolites (protophorphyrine IX, siderophores and amino acids) indicated extensive metabolic remodeling in response to iron starvation. HapX was found to participate in both, repression and activation of genes during iron starvation. HapX was in particular required for repression of iron-dependent and mitochondrial-localized activities including respiration, TCA cycle, amino acid metabolism, iron-sulfur-cluster biosynthesis and heme biosynthesis. Pathways positively affected by HapX included production of siderophores and the ribotoxin and major allergen AspF1. Analysis of the free amino acid pool revealed HapX-dependent coordination of the production of siderophores with the supply of its precursor ornithine. Consistent with the hapX expression pattern, HapX-deficiency was deleterious with respect to growth rate and conidiation during iron depleted but not iron-replete conditions. HapX-deficiency caused significant attenuation of virulence in a murine model aspergillosis underlining that A. fumigatus faces iron starvation in the host and that the HapX-dependent metabolic reprogramming is therefore crucial for virulence. A. fumigatus 293 and hapX mutants were grown in the presence and absence of iron and in cultures shifted from no iron to iron-containing conditions after 1 h incubation. Hybridizations were performed with biological replicates for wt vs hapX +/- iron. For the iron-shift experiments, there were biological replicates for wt in both conditions and for hapX in -iron but there was only a single biological sample for hapX iron-shift sample. All hybs were performed with flip-dye pairs.
2010-07-01 | E-GEOD-22052 | biostudies-arrayexpress
Project description:Iron is an essential cofactor for a wide range of cellular processes. Previous studies have shown that siderophore-mediated uptake and intracellular handling of iron are crucial for virulence of Aspergillus fumigatus. Here we show that the bzip-type transcription factor HapX plays a crucial role in the transcriptional remodeling required for adaption to iron starvation in this opportunistic fungal pathogen. HapX was found to be interconnected in a negative feed-back loop with the previously identified iron regulator SreA: SreA repressed expression of hapX during iron sufficiency and HapX repressed sreA during iron starvation. Genome-wide transcriptional profiling and analysis of selected metabolites (protophorphyrine IX, siderophores and amino acids) indicated extensive metabolic remodeling in response to iron starvation. HapX was found to participate in both, repression and activation of genes during iron starvation. HapX was in particular required for repression of iron-dependent and mitochondrial-localized activities including respiration, TCA cycle, amino acid metabolism, iron-sulfur-cluster biosynthesis and heme biosynthesis. Pathways positively affected by HapX included production of siderophores and the ribotoxin and major allergen AspF1. Analysis of the free amino acid pool revealed HapX-dependent coordination of the production of siderophores with the supply of its precursor ornithine. Consistent with the hapX expression pattern, HapX-deficiency was deleterious with respect to growth rate and conidiation during iron depleted but not iron-replete conditions. HapX-deficiency caused significant attenuation of virulence in a murine model aspergillosis underlining that A. fumigatus faces iron starvation in the host and that the HapX-dependent metabolic reprogramming is therefore crucial for virulence.
2010-07-01 | GSE22052 | GEO
Project description:Histone acetyltransferases (HATs) GCN5/PCAF and CBP/p300 are transcription coactivators. However, how these HATs regulate ligand-induced nuclear receptor target gene expression remains unclear. Here we show in mouse embryonic fibroblasts (MEFs), deletion of GCN5/PCAF specifically eliminates acetylation on H3K9 (H3K9Ac) while deletion of CBP/p300 selectively reduces acetylation on H3K18 and H3K27 (H3K18/27Ac). Treating MEFs with a specific ligand for nuclear receptor PPARdelta induces sequential increases of H3K18/27Ac and H3K9Ac on the promoter of PPARdelta target gene Angptl4, which correlates with a robust ligand-induced Angptl4 expression. Inhibiting transcription elongation blocks ligand-induced H3K9Ac but not H3K18/27Ac on Angptl4 promoter. Finally, we show CBP/p300 and their HAT activities are required, while GCN5/PCAF and H3K9Ac are dispensable, for ligand-induced PPARdelta target gene expression in MEFs. These results highlight the substrate and site specificities of HATs in cells, and suggest that GCN5/PCAF- and CBP/p300-mediated histone acetylations play distinct roles in regulating ligand-induced nuclear receptor target gene expression.
2013-12-31 | GSE20008 | GEO
Project description:Histone acetyltransferases (HATs) GCN5/PCAF and CBP/p300 are transcription coactivators. However, how these HATs regulate ligand-induced nuclear receptor target gene expression remains unclear. Here we show in mouse embryonic fibroblasts (MEFs), deletion of GCN5/PCAF specifically eliminates acetylation on H3K9 (H3K9Ac) while deletion of CBP/p300 selectively reduces acetylation on H3K18 and H3K27 (H3K18/27Ac). Treating MEFs with a specific ligand for nuclear receptor PPARdelta induces sequential increases of H3K18/27Ac and H3K9Ac on the promoter of PPARdelta target gene Angptl4, which correlates with a robust ligand-induced Angptl4 expression. Inhibiting transcription elongation blocks ligand-induced H3K9Ac but not H3K18/27Ac on Angptl4 promoter. Finally, we show CBP/p300 and their HAT activities are required, while GCN5/PCAF and H3K9Ac are dispensable, for ligand-induced PPARdelta target gene expression in MEFs. These results highlight the substrate and site specificities of HATs in cells, and suggest that GCN5/PCAF- and CBP/p300-mediated histone acetylations play distinct roles in regulating ligand-induced nuclear receptor target gene expression. PCAF and GCN5 have some redundant function. To identify PCAF/GCN5-regulated genes, immortalized MEFs with PCAF knockout and GCN5 conditional knockout were infected with retroviruses expressing either Cre recombinase or vector alone. We prepared duplicated RNAs from either vector or Cre infected cells (PCAF-/-;GCN5+/- or PCAF-/-;GCN5+/-) and RNAs from either Vector or Cre infected the other independently immortalized cells for 6 affymetrix microarray.
2013-12-31 | E-GEOD-20008 | biostudies-arrayexpress
Project description:Adaptation to alkalinization of the medium in fungi involves an extensive remodeling of gene expression. Komagataella phaffii is an ascomycetous yeast that has become an organism widely used for heterologous protein expression. We explore here the transcriptional impact of moderate alkalinization in this yeast. In spite of a minor effect on growth, shifting the cultures from pH 5.5 to 8.0 or 8.2 provokes significant changes in the mRNA levels of over 700 genes. Functional categories such as arginine and methionine biosynthesis, non-reductive iron uptake and phosphate metabolism are enriched in induced genes, whereas many genes encoding iron-sulfur proteins or members of the respirasome were repressed. We also show that alkalinization is accompanied by oxidative stress and we propose this circumstance as a common trigger of a subset of the observed changes. PHO89, encoding a Na+/Pi cotransporter, appears among the most potently induced genes by high pH. We demonstrate that this response is mainly based on two calcineurin-dependent response elements located in its promoter, thus indicating that alkalinization triggers a calcium-mediated signal in K. phaffii. Further characterization of alkaline pH responsive promoters may lead to developing novel pH-controlled systems for heterologous protein expression in this fungus.
2023-04-12 | GSE224427 | GEO
Project description:The data provide information of Gcn5 enrichment, H3K18 and H4K16 acetylation level and Histone H3 density for 5 different physioloigcal conditions during stress adpatation and stress recovery (normal growth, during stress adaptation, after stress adaptation, under stress recovery, after stress recovery) in yeast. The purpose of the study is to understand how histone acetyltransferase HATs (Gcn5) apply it is function in gene regulation by changing global or local histone acetylation level under different physiological conditions. Gcn5 enrichment, H3K18 and H4K16 acetylation level and Histone H3 density are mearured and compared to input signal for 5 different physioloigcal conditions (normal growth, during stress adaptation, after stress adaptation, under stress recovery, after stress recovery). Replicates are used.
2013-07-22 | E-GEOD-36600 | biostudies-arrayexpress
Project description:Iron is essential for almost all organisms, but can be toxic in excess. Cells use regulatory mechanisms to control the iron uptake, iron utilization and iron release mechanisms to ensure the availability of enough iron to be used for biological processess but minimizing the oxidative stress caused by the oxidation of free molecules of iron. In this paper we show that TroR is a transcription factor from the conserved family of proteins DtxR that directly binds the promoter of a set of genes involved in iron homeostasis meanwhile SirR is not a major regulator of iron homeostasis in the halophilic archaeon Haloferax volcanii.
2023-11-16 | GSE240518 | GEO
Project description:More than half of women will experience a urinary tract infection (UTI) with uropathogenic Escherichia coli (UPEC) causing ~80% of uncomplicated cases. Iron acquisition systems are essential for uropathogenesis, and UPEC encode functionally redundant iron acquisition systems, underlining their importance. However, a recent UPEC clinical isolate, HM7 lacks this functional redundancy and instead encodes a sole siderophore, enterobactin. To determine if E. coli HM7 possesses unidentified iron acquisition systems, we performed RNA-sequencing under iron-limiting conditions and demonstrated the ferric citrate uptake system (fecABCDE and fecIR) was highly upregulated. Importantly, there are high levels of citrate within urine, some of which is bound to iron, and the fec system is highly enriched in UPEC isolates compared to commensal or fecal strains. Therefore, we hypothesized that HM7 and other similar strains use the fec system to acquire iron in the host. Deletion of both enterobactin biosynthesis and ferric citrate uptake (ΔentB/ΔfecA) abrogates use of ferric citrate as an iron source and fecA provides an advantage in pooled human urine in absence of enterobactin. However, in a UTI mouse model, fecA is a fitness factor independent of enterobactin production, likely due to the action of host Lipocalin-2 chelating ferrienterobactin. These findings indicate that ferric citrate uptake is used as an iron source when siderophore efficacy is limited, such as in the host during UTI. Defining these novel compensatory mechanisms and understanding the nutritional hierarchy of preferred iron sources within the urinary tract are important in the search for new approaches to combat UTI.
2021-11-06 | GSE188170 | GEO
Project description:Nontypeable Haemophilus influenzae (NTHi) is a commensal microorganism of the normal human nasopharyngeal flora, yet also an opportunistic pathogen of the upper and lower respiratory tracts. Changes in gene expression patterns in response to host microenvironments are likely critical for persistence. One such system of gene regulation is the ability to carefully regulate iron uptake. A central regulatory system that controls iron uptake, mediated by the ferric uptake regulator Fur, is present in multiple bacteria, including NTHi. To understand the regulation of iron homeostasis in NTHi, fur was deleted in the prototypic NTHi clinical isolate, 86-028NP. Using an NTHi-specific microarray, we identified genes whose expression was repressed or activated by Fur.
2013-02-05 | GSE39874 | GEO