Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease
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ABSTRACT:
PROVIDER: PRJNA627459 | ENA |
REPOSITORIES: ENA
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Project description:Background: Iron trafficking and accumulation has been associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterised, making it difficult to explore these in existing datasets. Results: We identified sets of genes predicted to contain Iron Responsive Elements (IREs), and used these to explore iron dyshomeostasis responses in transcript datasets involving (1) cultured cells under iron overload and deficiency treatments, (2) post-mortem brain tissues from AD and other neuropathologies, (3) 5XFAD transgenic mice modelling AD pathologies, and (4) a zebrafish knock-in model of early-onset, familial AD (fAD). IRE gene sets were sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, we see changes in 3’ IRE transcript abundance as amongst the earliest observable in zebrafish fAD-like brains and preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some 3’ IRE transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead show decreased stability, indicating that this is not a generalizable paradigm. Conclusions: Our results reveal iron dyshomeostasis as a likely early driver of fAD and as able to distinguish AD from other brain pathologies. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis responses in different species, tissues, and conditions.
2020-05-06 | GSE149149 | GEO
Project description:Cells transiently adapt to hypoxia by globally decreasing protein translation. However, specific proteins needed to respond to hypoxia evade this translational repression. The mechanisms of this phenomenon remain unclear. We screened for and identified small molecules that selectively decrease HIF-2a translation in an mTOR independent manner, by enhancing the binding of Iron Regulatory Protein 1 (IRP1) to a recently reported Iron-Responsive Element (IRE) within the 5’-untranslated region (UTR) of the HIF-2a message. Knocking down the expression of IRP1 by shRNA abolished the effect of the compounds. Hypoxia de-represses HIF-2a translation by disrupting the IRP1- HIF-2a IRE interaction. Thus, this chemical genetic analysis describes a molecular mechanism by which translation of the HIF-2a message is maintained during conditions of cellular hypoxia through inhibition of IRP-1 dependent repression. It also provides the chemical tools for studying this phenomenon.
2009-01-01 | GSE13818 | GEO
Project description:Cells transiently adapt to hypoxia by globally decreasing protein translation. However, specific proteins needed to respond to hypoxia evade this translational repression. The mechanisms of this phenomenon remain unclear. We screened for and identified small molecules that selectively decrease HIF-2a translation in an mTOR independent manner, by enhancing the binding of Iron Regulatory Protein 1 (IRP1) to a recently reported Iron-Responsive Element (IRE) within the 5â-untranslated region (UTR) of the HIF-2a message. Knocking down the expression of IRP1 by shRNA abolished the effect of the compounds. Hypoxia de-represses HIF-2a translation by disrupting the IRP1- HIF-2a IRE interaction. Thus, this chemical genetic analysis describes a molecular mechanism by which translation of the HIF-2a message is maintained during conditions of cellular hypoxia through inhibition of IRP-1 dependent repression. It also provides the chemical tools for studying this phenomenon. Experiment Overall Design: 3 replicate samples of 786-O human Clear Cell Renal Carcinoma cells untreated, mock treated with DMSO or treated with either of 4 HIF-2a inhibitor compounds identified by chemical genetic screening.
2009-01-14 | E-GEOD-13818 | biostudies-arrayexpress
Project description:To understand the iron-responsive gene expression in Lachancea kluyveri under high and low iron conditions, we perfomred the genome-wide gene expression profiling for the log-phase cells of Lachancea kluyveri wild type, sef1 deletion, aft1 deletion and sef1aft1 double deletion mutants under the YPD+400mM ferrous iron and YPD+ 200 mM BPS conditions.
2019-04-26 | GSE130296 | GEO
Project description:Iron-responsive genes in Lachancea kluyveri
| PRJNA535427 | ENA
Project description:Recent cumulative data shows that various transcription factors are recruited to the chromatin in an iron-responsive manner to affect diverse cellular functions in the pathogenic fungus Candida albicans. Here, we identified groups of iron-responsive genes in C. albicans by chromatin remodeling analysis at gene promoters, using micrococcal nuclease (MNase) digestion followed by deep sequencing. Chromatin in the promoter regions of iron uptake and utilization genes showed repressed and active configuration, respectively, under iron-replete conditions. GO Term enrichment analysis of genes with differentially remodeled chromatin, in respective promoter locales, suggested that many genes involved in adhesion are also iron-responsive. C. albicans was observed to be more self-adherent (2-fold increase) and formed higher biofilm mass (77% increase) in the presence of iron. Furthermore, we identified various known and novel adhesion-related genes with iron-dependent active chromatin profiles that are indicative of potential up-regulation under iron-replete conditions. Transcription factor Cph1 that is activated upon Cek1 phosphorylation also showed an active chromatin profile under iron-replete conditions and cells showed iron-responsive Cek1 MAPK phosphorylation in the presence of iron. Thus, iron affects diverse biological functions by modulating chromatin profiles of large gene sets and by signaling through Cek1 MAPK in C. albicans.
2014-11-10 | GSE55819 | GEO
Project description:Background: Maternal iron deficiency (ID) is associated with poor pregnancy and fetal outcomes. The effect is thought to be mediated by the placenta but there is no comprehensive assessment of placental response to maternal ID. Additionally, whether the influence of maternal ID on the placenta differs by fetal sex is unknown. Objectives: Our primary aim was to identify gene and protein signatures of ID mouse placentas at mid-gestation. A secondary objective was to profile the expression of iron genes in mouse placentas across gestation. Methods: We used a real-time PCR based array to determine the mRNA expression of all known iron genes in mouse placentas at embryonic day (E) 12.5, E14.5, E16.5, and E19.5 (n=3 placentas/time point). To determine the effect of maternal ID, we performed RNA sequencing and proteomics in male and female placentas from ID and iron adequate mice at E12.5 (n=8 dams/diet). Results: In female placentas, six genes including transferrin receptor (Tfrc) and solute carrier family 11 member 2 were significantly changed by maternal ID. An additional 154 genes were altered in male ID placentas. Proteomic analysis quantified 7662 proteins in the placenta. Proteins translated from iron responsive element (IRE) containing mRNAs were altered in abundance; ferritin and ferroportin 1 decreased while TFRC increased in ID placenta. Less than 4% of the significantly altered genes in ID placentas occurred both at the transcriptional and translational levels. Conclusions: Our data demonstrate that the impact of maternal ID on placental gene expression in mice is limited in scope and magnitude at mid-gestation. We provide strong evidence for IRE-based transcriptional and translational coordination of iron gene expression in the mouse placenta. Finally, we discover sexually dimorphic effects of maternal ID on placental gene expression, with more genes and pathways altered in male compared with female mouse placentas.
2021-03-12 | PXD023454 | Pride
Project description:As descirbed in the manuscript "The impact of anaerobiosis on expression of the iron-responsive Fur and RyhB Regulons" we mapped the locations of Fur DNA binding in E. coli K12 under aerobic or anaerobic growth conditions and anerobic iron deficient growth conditions.
2015-12-01 | GSE74932 | GEO
Project description:Purpose: Zinc deficiency (ZnD) and iron deficiency (FeD), excess Zn (ZnE) and cadmium exposure (CdE) are major environmental problems for crop cultivation. Methods: Applying Tag-Seq technology to leaves of Brassica rapa grown under FeD, ZnD, ZnE or CdE conditions, with normal conditions as a control, we examined global gene expression changes and compared the expression patterns of multiple paralogs. Results: We identified 812, 543, 331 and 447 differentially expressed genes under FeD, ZnD, ZnE and CdE conditions, respectively, in B. rapa leaves.Further analysis revealed that genes associated with Zn, Fe and Cd responses tended to be over-retained in the B. rapa genome. Most of these multiple-copy genes showed the same direction of expression change under stress conditions. Conclusion: We conclude that the duplicated genes involved in trace element responses in B. rapa are functionally redundant, making the regulatory network more complex in B. rapa than in Arabidopsis thaliana. In total, there were 15 Digital gene expression libraries, one for each of the three replicates under the four trace metal element treatments and normal nutrient supply conditions as a control.
2014-09-30 | E-GEOD-55264 | biostudies-arrayexpress
Project description:Previous studies have shown that the MpeR transcriptional regulator produced by Neisseria gonorrhoeae represses expression of mtrF, which encodes a putative inner membrane protein that works with the MtrC-MtrD-MtrE efflux pump to allow gonococci to resist high levels of multiple hydrophobic antimicrobials. Regulation of mpeR has been reported to occur by an iron-dependent mechanism involving Fur (Ferric uptake regulator). Collectively, these observations suggest the presence of an interconnected regulatory system in gonococci that modulates expression of drug efflux pump protein-encoding genes in an iron-responsive manner. Herein, we describe this connection and report that levels of gonococcal resistance to a substrate of the mtrCDE-encoded efflux pump can be modulated by MpeR and the availability of free iron. Using microarray analysis, we found that the mtrR gene, which encodes the direct transcriptional repressor (MtrR) of mtrCDE, is an MpeR-repressed determinant in the late-logarithmic phase of growth when free iron levels would be reduced due to bacterial consumption. MpeR-mediated repression of mtrR appeared to be direct, as judged by DNA-binding analyses, and was enhanced by conditions of iron-limitation, which resulted in increased expression of the mtrCDE efflux pump operon. Taken together, our results indicate that both genetic and physiologic parameters can influence expression of the mtr efflux system and that these can modulate levels of gonococcal susceptibility to efflux pump substrates.
2012-04-04 | GSE32717 | GEO