Transcriptional Remodeling in Response to Iron Deprivation inSaccharomyces cerevisiae

Abstract

The budding yeast Saccharomyces cerevisiae responds to depletion of iron in the environment by activating Aft1p, the major iron-dependent transcription factor, and by transcribing systems involved in the uptake of iron. Here, we have studied the transcriptional response to iron deprivation and have identified new Aft1p target genes. We find that other metabolic pathways are regulated by iron: biotin uptake and biosynthesis, nitrogen assimilation, and purine biosynthesis. Two enzymes active in these pathways, biotin synthase and glutamate synthase, require an iron-sulfur cluster for activity. Iron deprivation activates transcription of the biotin importer and simultaneously represses transcription of the entire biotin biosynthetic pathway. Multiple genes involved in nitrogen assimilation and amino acid metabolism are induced by iron deprivation, whereas glutamate synthase, a key enzyme in nitrogen assimilation, is repressed. A CGG palindrome within the promoter of glutamate synthase confers iron-regulated expression, suggesting control by a transcription factor of the binuclear zinc cluster family. We provide evidence that yeast subjected to iron deprivation undergo a transcriptional remodeling, resulting in a shift from iron-dependent to parallel, but iron-independent, metabolic pathways.

Expression Profiling Reveals an Unexpected Growth-Stimulating Effect of Surplus Iron on the Yeast Saccharomyces cerevisiae

“…Fe 3+ is first reduced to Fe 2+ by two plasma membrane proteins, Fre1 and Fre2, then transported by the low-afffinity iron transporter Fet4 (apparent Km of 30 mM) in iron-repleted conditions, or by the multicopper oxidase Fet3, a high afffinity iron system (apparent Km of 0.15 mM) in iron-depleted conditions (De Freitas et al, 2000;Dix et al, 1997). S. cerevisiae uses two iron-responsive transcription factors, Aft1/2, to activate the transcription of a cluster of genes in the iron regulon that is implicated in iron-sulfur biosynthesis, heme utilization, and iron intracellular redistribution (Courel et al, 2005;Rutherford et al, 2003, Shakoury-Elizeh et al, 2004. Almost all studies on iron metabolism have used an iron concentration of 1 mM or lower (Kumanovics et al, 2008;Puig et al, 2008), while the yeast response to 1 mM or higher iron, designated an iron-surplus condition, has not yet been extensively studied.…”

Both Php4 Function and Subcellular Localization Are Regulated by Iron via a Multistep Mechanism Involving the Glutaredoxin Grx4 and the Exportin Crm1

“…RyhB hybridizes to mRNAs encoding iron-using proteins and triggers their degradation through an RNase E-dependent process (21). In Saccharomyces cerevisiae, iron deprivation leads to the activation of the iron-responsive transcription factors Aft1 and Aft2 (22)(23)(24)(25)(26)(27). Once activated, these two regulators induce the expression of several genes, including those encoding proteins that function in iron uptake.…”

Learning Gaussian Graphical Models of Gene Networks with False Discovery Rate Control

“…The iron homeostasis pathway regulates the uptake, storage, and utilization of iron so as to keep it at a non-toxic level. According to [12,20,21,23,24], yeast can use two different high-affinity mechanisms, reductive and nonreductive, to take up iron from the extracellular medium. The former mechanism is composed of the genes in the FRE family, responsible for iron reduction, and the iron transporters FTR1 and FET3, while the latter mechanisms consist of the iron transporters ARN1, ARN2, ARN3 and ARN4.…”

“…According to the Gene Ontology search engine AmiGO [1], FET5, MRS4 and SMF3 are iron transporters, FIT2 and FIT3 facilitate iron transport, PCA1 is involved in iron homeostasis, and ATX1 and CCC2 are involved in copper transport and are required by FET3, which is part of the reductive mechanism. According to [24], BIO2 is involved in biotin synthesis which is regulated by iron, GLT1 and ODC1 are involved in glutamate synthesis which is regulated by iron too, LIP5 is involved in lipoic acid synthesis and regulated by iron, and HEM15 is involved in heme synthesis and regulated by iron too. Also according to [24], TIS11 and the biotin transporter VHT1 are regulated by AFT1, the major iron-dependant transcription factor in yeast.…”

“…According to [24], BIO2 is involved in biotin synthesis which is regulated by iron, GLT1 and ODC1 are involved in glutamate synthesis which is regulated by iron too, LIP5 is involved in lipoic acid synthesis and regulated by iron, and HEM15 is involved in heme synthesis and regulated by iron too. Also according to [24], TIS11 and the biotin transporter VHT1 are regulated by AFT1, the major iron-dependant transcription factor in yeast. Though AFT1 is not depicted in the subgraph in Figure 1, it is noteworthy that it is a neighbor of FET3 in the GGM learnt.…”