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GSE101569
Mus musculus
32 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Cytokine-induced signal transduction is executed by natural biological switches, which among many others control immune related processes. To construct a biological device, that simulates cytokine signaling, we utilized nanobodies to generate synthetic cytokine receptors (SyCyR). High affinity GFP- and mCherry-nanobodies were selected and extracellularly fused to trans-membrane and intracellular domains of IL-23 cytokine receptors. Soluble homo- and heterodimeric GFP:mCherry fusion proteins served as SyCyR ligands. Heterodimeric GFP-mCherry and homodimeric GFP fusion proteins efficiently phenocopied IL-23 signal transduction, respectively, as demonstrated by STAT3-, ERK- and Akt-activation, SOCS3 expression and transcriptome profiling. Interestingly, the homodimeric GFP fusion protein induced IL-23 receptor homo-dimerization and activation of IL-23-like signal transduction
Publication Title
Synthetic cytokine receptors transmit biological signals using artificial ligands.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 26 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Cytokine signaling is transmitted by cell surface receptors which function as natural biological switches to control among others mainly immune related processes. Recently, we have designed synthetic cytokine receptors (SyCyRs) consisting of GFP- and mCherry-nanobodies fused to trans-membrane and intracellular domains of cytokine receptors, which phenocopied cytokine signaling induced by non-physiological homo- and heterodimeric GFP-mCherry ligands. Interleukin 22 signals via IL-22Rα1 and the common IL-10R2, belongs to the IL-10 cytokine family and is critically involved in tissue regeneration. IL-22 SyCyRs phenocopied native IL-22 signal transduction as shown by induction of cytokine-dependent cellular proliferation, signal transduction and transcriptome analysis. Whereas homodimeric IL-22Rα1 SyCyRs failed to activate signaling, homodimerization of the second IL-22 signaling chain, SyCyR(IL-10R2), which was considered to not induce signal transduction, lead to induction of signal transduction. Interestingly, the SyCyR(IL-10R2) and SyCyR(IL-22Rα1) were able to form functional heterodimeric receptor signaling complexes with the synthetic IL-6 receptor chain SyCyR(gp130). In summary, we demonstrated that IL-22 signaling can be phenocopied by synthetic cytokine receptors. Further we identified a novel IL-10R2 homodimeric receptor complex and receptor cross-talk with gp130.
Publication Title
Synthetic interleukin 22 (IL-22) signaling reveals biological activity of homodimeric IL-10 receptor 2 and functional cross-talk with the IL-6 receptor gp130.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The key lipid metabolism transcription factor sterol regulatory element-binding protein (SREBP)-1a integrates gene regulatory effects of hormones, cytokines, nutrition and metabolites as lipids, glucose or cholesterol via stimuli specific phosphorylation by different MAPK cascades. We have formerly reported the systemic impact of phosphorylation in transgenic mouse models with liver-specific overexpression of the N-terminal transcriptional active domain of SREBP-1a (alb-SREBP-1a) or a MAPK kinase phosphorylation sites deficient variant (alb-SREBP-1aP; (S63A, S117A, T426V)), respectively. Here we investigated the molecular basis of the systemic observation in holistic hepatic gene expression analyses and lipid degrading organelles involved in the pathogenesis of metabolic syndrome, i.e. peroxisomes, by 2D-DIGE and mass spectrometry analyses. Although alb-SREBP-1a mice develop a severe phenotype with visceral adipositas and hepatic lipid accumulation featuring a fatty liver, the hepatic differential gene expression and alterations in peroxisomal protein patterns compared to control mice were surprisingly relative low. In contrast, phosphorylation site deficient alb-SREBP-1aP mice, protected from hepatic lipid accumulation phenotype, showed gross alteration in hepatic gene expression and peroxisomal proteome. Further knowledge based analyzes revealed that overexpression of SREBP-1a favored mainly acceleration in lipid metabolism and indicated a regular insulin signaling, whereas disruption of SREBP-1a phosphorylation resulted in massive alteration of cellular processes including signs for loss of lipid metabolic targets. These results could be the link to a disturbed lipid metabolism that overall resembles a state of insulin resistance.
Publication Title
Inactivation of SREBP-1a Phosphorylation Prevents Fatty Liver Disease in Mice: Identification of Related Signaling Pathways by Gene Expression Profiles in Liver and Proteomes of Peroxisomes.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Genome U95 Version 2 Array (hgu95av2)
Description
Lipodystrophies resemble syndromes of disturbed adipocyte biology or development and severe congenital forms (CGL) lack adipose tissue. The ubiquitous immediate-early gene c-fos is one essential transcription factor to initiate adipocyte differentiation. In a CGL patient we identified a single homozygous point mutation in the promoter of c-fos gene. The mutation facilitates the formation of a novel specific protein/ DNA complex and ubiquitously reduces basal and inducible c-fos transcription activity.
Publication Title
A mutation in the c-fos gene associated with congenital generalized lipodystrophy.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Major causes of lipid accumulation in liver are increased import, synthesis or decreased catabolism of fatty acids. The latter is caused by dysfunction of cellular organelle controlling energy homeostasis, i.e. mitochondria. However, peroxisomes appear to be an important organelle in lipid metabolism of hepatocytes, but little is known about their role in the development of non-alcoholic fatty liver disease (NAFLD). To investigate the role of peroxisomes next to mitochondria in excessive hepatic lipid accumulation we used the leptin resistant db/db mice on C57BLKS background, a mouse model that develops hyperphagia induced diabetes with obesity and NAFLD.
Publication Title
Peroxisomes compensate hepatic lipid overflow in mice with fatty liver.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U95 Version 2 Array (hgu95av2)
Description
Inherited genetic variants of insulin receptor induced cellular signaling have long been suspected to contribute to the development of type-2- diabetes mellitus. In this report we discuss a heterozygous mutation in the first coding exon of the proto-oncogene Ha-Ras (Ha-RasA11P) that we have identified in a patient with familial premature aging syndrome. The patient has atopic sklerodermic skin alterations, insulin resistance as well as disturbances in lipid metabolism. In vitro analyzes have shown that this mutation disrupted not only the signal transduction of the insulin receptor but also other receptor tyrosine kinases, such as IGF-1, EGF, PDGF. These results demonstrate that HA-Ras has a significant role in insulin sensitivity in humans.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Purpose: MetS consist of five risk factors: elevated blood pressure and fasting glucose, visceral obesity, dyslipidemia and hypercholesterinemia. The physiological impact of lipid metabolism indicated as visceral obesity and hepatic lipid accumulation is still under debate. One major cause of disturbed lipid metabolism might be dysfunction of cellular organelles controlling energy homeostasis, i.e. mitochondria and peroxisomes.
Publication Title
Alteration of Liver Peroxisomal and Mitochondrial Functionality in the NZO Mouse Model of Metabolic Syndrome.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Background and aim: The Insulin-like growth factor (IGF) axis is increasingly suggested to be involved in fatty liver disease and progression. We identified IGFBP2 as transcriptional regulatory effect network in liver steatosis and conducted a translational approach of its role in liver pathology from mouse to human, and whether it is influenced by conventional clinical intervention that mitigate hepatic steatosis. Methods: Primary hepatocytes from either C57Bl6 controls, alb-SREBP-1c mice with moderate transgene induced hepatic lipid accumulation or aP2-SREBP-1c mice with massive ectopic hepatic lipid accumulation, were analyzed to identify regulatory networks based on differentially regulated hepatic gene expression. In a translational approach, serum of morbidly obese patients with and without diabetes and biopsy-proven NAFLD were used for ELISA-based validation of mouse data. Moreover, sera of patients undergoing intervention were analyzed and correlated to liver fat content. Results: Comparative knowledge-based transcriptome analysis identified IGFBP2 as top score regulatory effect network between moderate and aggravated fatty liver in mouse models. The reduced expression of IGFBP2 in aP2-SREPB-1c progressed fatty liver associated with Igfbp2 promoter hypermethylation. Reduced secretion of IGFBP2 from aP2-SREBP-1c hepatocytes was reflected in the circulation of the animals. In this phenotype, reductions of IGFBP2 were accompanied by reduced fatty acid oxidation and increased methyltransferase and SIRT activity. Physiologically, IGFBP2 has no direct impact on lipid metabolism but might modulate IGF1 action on de novo lipogenesis. In humans, IGFBP2 levels declined from non-obese men to morbidly obese men with NAFLD and NASH. In intervention study reductions in liver fat correlated with restoration of IGFBP2 serum levels to values found in healthy individuals in morbidly obese patients following bariatric surgery. Conclusion: In hepatic metabolism changes of IGFBP2 abundance is connected to lipid metabolism whereas changes in IGFBP2 secretion were directly reflected in the circulation. IGFBP2 serum concentration correlates with the degree of fatty liver, which seems to be related to plasticity of the adipose tissue. These data provide IGFBP2 as a potential non-invasive biomarker for fatty liver disease directly reflecting the degree of impaired liver function with the potential to indicate progressed fatty liver disease.
Publication Title
Physiological Disturbance in Fatty Liver Energy Metabolism Converges on IGFBP2 Abundance and Regulation in Mice and Men.
Sample Metadata Fields
Sex, Age
View Samples- Mus musculus
- 17 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
Understanding the transcriptional regulation of pluripotent cells is of fundamental interest and will greatly inform efforts aimed at directing differentiation of embryonic stem (ES) cells or reprogramming somatic cells. We first analyzed the transcriptional profiles of mouse ES cells and primordial germ cell (PGCs) and identified genes up-regulated in pluripotent cells both in vitro and in vivo. These genes are enriched for roles in transcription, chromatin remodeling, cell cycle and DNA repair. We developed a novel computational algorithm, CompMoby, which combines analyses of sequences both aligned and non-aligned between different genomes with a probabilistic segmentation model to systematically predict short DNA motifs that regulate gene expression. CompMoby was used to identify conserved over-represented motifs in genes up-regulated in pluripotent cells. We show that the motifs are preferentially active in undifferentiated mouse ES and Embryonic Germ cells in a sequence-specific manner, and that they can act as enhancers in the context of an endogenous promoter. Importantly, the activity of the motifs is conserved in human ES cells. We further show that the transcription factor NF-Y specifically binds to one of the motifs, is differentially expressed during ES cell differentiation and is required for ES cell proliferation. This study provides novel insights into the transcriptional regulatory networks of pluripotent cells. Our results suggest that this systematic approach can be broadly applied to understanding transcriptional networks in mammalian species.
Publication Title
Systematic identification of cis-regulatory sequences active in mouse and human embryonic stem cells.
Sample Metadata Fields
Age, Specimen part, Time
View Samples- Mus musculus
- 1 Downloadable Sample
Illumina HiSeq 2000
Description
This is polyA mRNA-seq of a clonal MIN6 beta cell line that expresses EGFP under the control of the insulin promoter and mCherry under control of the RSV promoter.
Publication Title
No associated publication
Sample Metadata Fields
Sex, Specimen part
View Samples