Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Histone acetylases are required for iron homeostasis

ABSTRACT: Histones and their modifications such as methylation and acetylation play an important role in the regulation of gene transcription and cellular metabolism. Cells in response to iron deficiency induce iron metabolism, especially the expression of iron uptake-related genes, but the role of histone modifications in their induction is unclear. We report here that compared to other histone modification enzymes, loss of histone acetylates Gcn5p and Sas2p has a stronger effect on the induction of iron homeostasis genes. Among the studied histone modification enzymes, Gcn5p and Rtt109p have a specific role in regulating the cellular response under the deficiency of the mitochondrial iron-sulfur cluster biosynthesis. Therefore, the histone acetylation, specifically regulated by Gcn5p, Rtt109p and Sas2p, plays an important role in the response to iron-deficiency conditions.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Saccharomyces cerevisiae

SUBMITTER: jian zhang

PROVIDER: E-MTAB-14211 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Histone acetylases are required for iron homeostasis

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