Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE85943 | GEO | 2016/08/29
SECONDARY ACCESSION(S): PRJNA339794
REPOSITORIES: GEO
Similar Datasets
Project description:Comparative analysis of gene expression in bone marrow-derived macrophages (BMDM) from trsp knockout mice (Trspfl/fl-LysM-Cre+/-) and Control (Trspfl/fl-LysM-Cre-/-) mice. Selenium, a micronutrient whose deficiency in the diet causes immune dysfunction and inflammatory disorders, exerts its physiological effects partly in the form of selenium-containing proteins (selenoproteins). Incorporation of selenium into the amino acid selenocysteine (Sec), and subsequently into selenoproteins, is mediated by Sec tRNA[Ser]Sec. To identify macrophage-specific selenoprotein function, we generated mice with the Sec tRNA[Ser]Sec gene specifically deleted in myeloid cells. These mutant mice were devoid of the selenoproteome in macrophages, yet exhibited largely normal inflammatory responses. However, selenoprotein deficiency led to aberrant expression of extracellular matrix-related genes, and diminished migration of macrophages in a protein gel matrix. Therefore, selenium status may affect immune defense and tissue homeostasis through its effect on selenoprotein expression and the trafficking of tissue macrophages. We have generated mice in which we have selectively removed the selenocysteine tRNA gene (trsp) in macrophages under the control of LysM-Cre promoter. Microarray analysis was performed on RNA samples taken from bone marrow-derived macrophages in knockout and control mice. 1. Control unstimulated 2. Knockout unstimulated 3. Control lipopolysaccharide (LPS) stimulated (4h) 4. Knockout LPS stimulated (4h). Three replicates for each condition. Thus, a total of 12 samples.
2009-12-21 | E-GEOD-15610 | biostudies-arrayexpress
Project description:Comparative analysis of gene expression in bone marrow-derived macrophages (BMDM) from trsp knockout mice (Trspfl/fl-LysM-Cre+/-) and Control (Trspfl/fl-LysM-Cre-/-) mice. Selenium, a micronutrient whose deficiency in the diet causes immune dysfunction and inflammatory disorders, exerts its physiological effects partly in the form of selenium-containing proteins (selenoproteins). Incorporation of selenium into the amino acid selenocysteine (Sec), and subsequently into selenoproteins, is mediated by Sec tRNA[Ser]Sec. To identify macrophage-specific selenoprotein function, we generated mice with the Sec tRNA[Ser]Sec gene specifically deleted in myeloid cells. These mutant mice were devoid of the selenoproteome in macrophages, yet exhibited largely normal inflammatory responses. However, selenoprotein deficiency led to aberrant expression of extracellular matrix-related genes, and diminished migration of macrophages in a protein gel matrix. Therefore, selenium status may affect immune defense and tissue homeostasis through its effect on selenoprotein expression and the trafficking of tissue macrophages.
2009-12-22 | GSE15610 | GEO
Project description:Expression of selenoproteins requires the co-translational incorporation of selenocysteine (Sec) in response to an in-frame UGA codon. The machinery of UGA/Sec re-coding is complex and many factors affect the hierarchy of expression among selenoproteins, including modification of tRNA[Ser]Sec. Its hyper-modification in the anticodon stem loop is influenced by selenium bioavailability, and a mutation in adenosine 37 (A37) that abrogates isopentenylation, has a profound effect on selenoprotein expression in mice. Patients with mutations in tRNA-isopentenyl-transferase (TRIT1) show a severe neurological disorder and hence we wondered whether mutations in TRIT1 negatively affected the expression of selenoproteins. Fibroblasts from a patient carrying a pathogenic R323Q mutation in TRIT1 in homozygosity did not show decreased selenoprotein expression, although recombinant TRIT1R323Q had significantly reduced activity in vitro towards anticodon stem-loop substrates. We thus engineered mice conditionally deficient in Trit1 in hepatocytes and neurons. Selenoprotein expression as assessed by western blotting, 75Se metabolic labeling, and ribosomal profiling was not decreased despite the general reduction of N6-isopentenyl-adenosine in tRNAs. We show that 5-methylcarboxymethylation and 2’O-methylation of U34 occur independently of isopentenylation of A37 in tRNA[Ser]Sec. Reanalyzing previously published ribosomal profiling datasets, we demonstrate that (i) failure of 5-carboxymethylation at U34 is associated with reduced expression of GPX1, but not GPX4, and that (ii) FTSJ1 is not the elusive U34-2’O-methyltransferase involved in the methylation of tRNA[Ser]Sec.
2021-11-17 | GSE183923 | GEO
Project description:Trace element selenium (Se) is incorporated as the 21st amino acid, selenocysteine (Sec), into selenoproteins through tRNA[Ser]Sec. Selenoproteins act as gatekeepers of redox homeostasis and modulate immune function to effect anti-inflammation and resolution. However, mechanistic underpinnings involving metabolic reprogramming during inflammation and resolution remain poorly understood. Endotoxin lipopolysaccharide (LPS) activation of murine bone marrow-derived macrophages (BMDMs) cultured in the presence or absence of Se (as selenite) was used to examine temporal changes in the proteome and metabolome by multiplexed tandem mass tag-quantitative proteomics, metabolomics, and machine-learning approaches. Se-dependent modulation of glycolytic, TCA and PPP pathways predisposed BMDMs to preferentially increase OXPHOS to efficiently regulate inflammation and its timely resolution. Use of macrophages lacking selenoproteins, indicated that all three metabolic nodes were sensitive to selenoproteome expression. Furthermore, inhibition of SDH with dimethylmalonate affected the pro-resolving effects of Se by increasing the resolution interval in a murine peritonitis model.
2021-02-09 | PXD023005 | Pride
Project description:Moderate selenium deficiency may lead to an impaired capacity to cope with health challenges. Functional effects of suboptimal selenium intake are not fully known, and biomarkers for an insufficient selenium supply are inadequate. We therefore fed mice diets of moderately deficient or adequate selenium intake for 6 weeks. Changes in global gene expression were monitored by microarray analysis in splenic leukocytes. Genes for four selenoproteins, Sepw1, Gpx1, Selh and Sep15, were the most significantly down-regulated in moderate selenium deficiency, and this was confirmed by quantitative polymerase chain reaction (qPCR). Classification of significantly affected genes revealed that processes related to inflammation, heme biosynthesis, DNA replication and transcription, cell cycle and transport were affected by selenium restriction. Down-regulation by moderate selenium deficiency of specific genes involved in inflammation and heme biosynthesis was confirmed by qPCR. Myeloperoxidase and lysozyme activities were decreased in selenium-restricted leukocytes, providing evidence for functional consequences. Genes for 31 nuclear factor (NF)-κB targets were down-regulated in moderate selenium deficiency, indicating an impaired NF-κB signaling. Together, the observed changes point to a disturbance in inflammatory response. The selenoproteins found here to be sensitive to selenium intake in murine leukocytes might also be useful as biomarkers for a moderate selenium deficiency in humans.
2018-07-13 | GSE117026 | GEO
Project description:SECIS binding protein 2 (SECISBP2) increases the efficiency of recoding of UGA codons as selenocysteine (Sec) during translation of mRNAs containing a selenocysteine insertion sequence (SECIS) in the 3’-untranslated region. Using ribosomal profiling, we have previously studied selenoprotein translation in hepatocyte-specific Secisbp2-deficient mouse liver and neuron-specific Secisbp2-mutant mouse brain. The use of organs carries the limitation of cellular heterogeneity with cells still expressing wild-type SECISBP2 that might potentially confound analyses and conclusions. To address this concern, we studied a haploid human HAP1 cell line carrying a non-functional SECISBP2 protein. These cells are still capable of metabolically incorporating 75Se into selenoproteins. We performed ribosomal profiling, and show that the efficiency of UGA recoding is gene-specific in SECISBP2- deficient cells. Analysis of ribosomes with UGA either at the A-site or the P-site revealed in a transcript-specific manner that SECISBP2 helps to recruit tRNASec and stabilizes mRNA. We propose a new measure to assess UGA/Sec read-through at codon resolution in all selenoproteins, i.e. the proportion of ribosomes carrying UGA in the P-site, pUGA. An additional, new observation is frame- shifting occurring after the UGA/Sec codon in GPX1, SELENOF, and SELENOW in HAP1 cells, a finding corroborated by reanalysis of neuron-specific Secisbp2-mutant brains.
2022-11-02 | GSE145465 | GEO
Project description:Comparative analysis of gene expression in the liver of the Trsp-knockout mice (Trspfl/fl-AlbCre+/+) and A34 (Trspfl/fl-AlbCre+/+-A34t/t), G37L (Trspfl/fl-AlbCre+/+-G37t/t; 2 copies), G37H (Trspfl/fl-AlbCre+/+-G37t/t; 16 copies) transgenic mice with gene expression of wild type mice (Trsp+/+-AlbCre+/+). Sec (selenocysteine) is biosynthesized on its tRNA and incorporated into selenium-containing proteins (selenoproteins) as the 21st amino acid residue. Selenoprotein synthesis is dependent on Sec tRNA and the expression of this class of proteins can be modulated by altering Sec tRNA expression. The gene encoding Sec tRNA (Trsp) is a single-copy gene and its targeted removal in liver demonstrated that selenoproteins are essential for proper function wherein their absence leads to necrosis and hepatocellular degeneration. In the present study, we found that the complete loss of selenoproteins in liver was compensated for by an enhanced expression of several phase II response genes and their corresponding gene products. The replacement of selenoprotein synthesis in mice carrying mutant Trsp transgenes, wherein housekeeping, but not stress-related selenoproteins are expressed, led to normal expression of phase II response genes. Thus the present study provides evidence for a functional link between housekeeping selenoproteins and phase II enzymes. Trsp vs DTrsp; Trsp vs A34; Trsp vs G37L; Trsp vs G37H. Biological replicates from littermates. One replicate per array.
2010-05-25 | E-GEOD-12495 | biostudies-arrayexpress
Project description:Comparative analysis of gene expression in the liver of the Trsp-knockout mice (Trspfl/fl-AlbCre+/+) and A34 (Trspfl/fl-AlbCre+/+-A34t/t), G37L (Trspfl/fl-AlbCre+/+-G37t/t; 2 copies), G37H (Trspfl/fl-AlbCre+/+-G37t/t; 16 copies) transgenic mice with gene expression of wild type mice (Trsp+/+-AlbCre+/+). Sec (selenocysteine) is biosynthesized on its tRNA and incorporated into selenium-containing proteins (selenoproteins) as the 21st amino acid residue. Selenoprotein synthesis is dependent on Sec tRNA and the expression of this class of proteins can be modulated by altering Sec tRNA expression. The gene encoding Sec tRNA (Trsp) is a single-copy gene and its targeted removal in liver demonstrated that selenoproteins are essential for proper function wherein their absence leads to necrosis and hepatocellular degeneration. In the present study, we found that the complete loss of selenoproteins in liver was compensated for by an enhanced expression of several phase II response genes and their corresponding gene products. The replacement of selenoprotein synthesis in mice carrying mutant Trsp transgenes, wherein housekeeping, but not stress-related selenoproteins are expressed, led to normal expression of phase II response genes. Thus the present study provides evidence for a functional link between housekeeping selenoproteins and phase II enzymes.
2008-08-19 | GSE12495 | GEO
Project description:Methanococcus maripaludis utilizes selenocysteine-(Sec-) containing proteins (selenoproteins), mostly active in the organism’s primary energy metabolism, methanogenesis. Under selenium depletion, M. maripaludis employs a set of enzymes containing cysteine (Cys) instead of Sec. The genes coding for these Sec-/Cys-containing isoforms are the only genes known expression of which is influenced by the selenium status of the cell. Using quantitative proteomics and transcriptomics approx. 7% and 12%, respectively, of all genes/proteins were differentially expressed/synthesized in response to the selenium supply. Some of the genes identified involve methanogenesis, nitrogenase functions, and putative transporters. An increase of transcript abundance for putative transporters under selenium-depleted conditions indicated the organism’s effort to tap into alternative sources of selenium. Selenium sources M. maripaludis is known to utilize are selenite and dimethylselenide. To expand this list, a selenium responsive reporter strain was assessed with nine other, environmentally relevant selenium species. While some had a similar biological window as selenite, others were effectively utilized at lower concentrations. Conversely, selenate and seleno-amino acids were only utilized at unphysiologically high concentrations and two compounds were not utilized at all. To address the role of the selenium-regulated putative transporters in selenium transport, M. maripaludis mutant strains lacking one or two of the putative transporters were tested for the capability to utilize the different selenium species. Of the five putative transporters analyzed by loss-of-function mutagenesis, none appeared to be absolutely required for utilizing any of the selenium species tested, indicating they have redundant and/or overlapping specificities, or are not dedicated selenium transporters.
2024-03-27 | PXD047095 | Pride
Project description:Selenoproteins are a small family of proteins containing the trace element selenium in form of the rare amino acid selenocysteine (Sec), which is decoded by the UGA codon. In humans, a number of pathogenic mutations in genes encoding distinct selenoproteins or selenoprotein biosynthesis factors have been identified. Pathogenic mutations in selenocysteine synthase (SEPSECS), which catalyzes the last step in Sec-tRNA[Ser]Sec biosynthesis, were reported in children suffering from progressive cerebello-cerebral atrophy. To understand the underlying mechanisms of SEPSECS mutations, we generated a novel mouse model recapitulating the respective human pathogenic Y334C mutation in the murine Sepsecs gene (SepsecsY334C). Unlike in patients, homozygous mutant pups died perinatally with signs of cardio-respiratory failure. Perinatal death is reminiscent of the Sedaghatian spondylometaphyseal dysplasia disorder in humans, which is caused by inactivating mutations of the gene encoding the selenoprotein and key ferroptosis regulator glutathione peroxidase 4 (GPX4). Protein expression levels of distinct selenoproteins in SepsecsY334C/Y334C mice were found to be generally reduced in brain and isolated cortical neurons, while transcriptomics analysis uncovered an upregulation of NRF2-regulated genes. Crossbreeding of SepsecsY334C/Y334C mice with mice harboring a targeted mutation of the catalytically active site Sec to Cys in GPX4 surprisingly rescued perinatal death of SepsecsY334C/Y334C mice, showing that the cardio-respiratory defects of Sepsecs-mutant mice were caused by the lack of GPX4. Like in SepsecsY334C/Y334C mice, selenoprotein expression levels remained low and NRF2-regulated genes remained highly expressed in these compound mutant mice, indicating that selenium-independent GPX4, along with a sustained antioxidant response are sufficient to compensate for dysfunctional Sec-tRNA[Ser]Sec biosynthesis. Our findings imply that children with mutations in SEPSECS or GPX4 may benefit from treatments partially compensating for impaired GPX4 activity.
2021-11-24 | GSE181852 | GEO