RNA Sequencing in LXR agonist fed Atp7b-/- mice (Wilson disease)
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ABSTRACT:
PROVIDER: PRJNA728814 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The goal of the study was find the gene expression of diverse signaling pathways altered in Atp7b-/- mice (murine WD) liver as compared to control mice and how LXR agonist treatment will improve/ameliorate WD phenotype in Atp7b-/- mice. Activation of LXR/RXR using synthetic LXR agonist ameliorates liver inflammation and fibrosis in murine WD by changing gene expression.
2022-10-26 | GSE174015 | GEO
Project description:To find new genes that might be targeted for reduction of Copper (Cu) toxicity in Wilson disease we employed genome-wide shRNA screening in ATP7B-KO HepG2 cells, a bona fide WD cell model. Cells were screened using the Dharmacon™ Decode™ Pooled Lentiviral shRNA Screening Library targeting 18205 human genes (Dharmacon #RHS6083). The Lentiviral RNAi screening library is made of 10 pools of 9570 GIPZ short hairpin RNAs (shRNAs) packaged into high-titer lentiviral particles. Genomic DNA was isolated from the cells and read counts for each shRNAs were obtained by deep sequencing to determine the abundance of each shRNA in the Cu-treated cells compared to controls. This analysis allowed the identification of genes whose downregulation promoted survival of ATP7B-KO cells upon Cu overload. To exclude that some shRNAs would have been responsible for ATP7B-KO survival by suppressing generic proapoptotic genes, we run the same screening with the proapoptotic drug vinblastine instead of CuCl2. Genes, whose suppression allowed cell to resist Cu but not vinblastine were considered as Cu-specific hits and through this approach we identified PrP as a suitable target for reduction of Cu toxicity in WD. Indeed, we found that Cu accumulation in ATP7B-KO cells stimulates expression of PrP, which brings to toxic Cu overload while PrP suppression significantly reduces Cu accumulation and toxicity in ATP7B-deficient cells. In sum our data highlight an important regulatory role of PrP in copper metabolism and as a therapeutic tool for Wilson disease.
2024-12-09 | GSE277865 | GEO
Project description:The H1069Q substitution in the liver-specific copper transporter ATP7B represents the major cause of Wilson disease. The mutated ATP7B undergoes rapid degradation in the endoplasmic reticulum (ER) and fails to reach copper excretion compartments thus causing severe copper toxicosis in patients. Modulating the ATP7B-H1069Q interactome was proposed as a rescue strategy but specific binding partners that might be targeted for mutant correction remain elusive. Here we try to identify a mutant-specific interactor for the pharmacological rescue of ATP7B-H1069Q.
2020-12-11 | PXD016816 | Pride
Project description:Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b-/- mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors is decreased in Atp7b-/- mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b-/- mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 weeks on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by LC-MS and correlated with transcriptomic data. Atp7b-/- mice fed a chow diet had lower fat mass and were more glucose tolerant than wild type (WT) littermate controls although body weights did not differ between genotypes. On Western diet, Atp7b-/- mice exhibited reduced adiposity and hepatic steatosis compared with WT controls. Atp7b-/- mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b-/- mice exhibited hypoglycemia after administration of insulin, due to an impaired glucose counter-regulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b-/- mice. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b-/- mice relative with WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity, as well as impaired fasting glucose production in Atp7b-/- mice.
2020-04-14 | GSE125637 | GEO
Project description:We show differences in translatome of the sensory neurons of the DRG primary neurons treated with LXR agonist GW3965.
2022-06-29 | GSE198898 | GEO
Project description:Liver X Receptor (LXR) activation in intestinal epithelial organoids promotes their growth in vitro. To investigate the downstream effect of LXR activation in intestinal epithelial cells and identify potential pathways driving regeneration, we carried out an unbiased transcriptomic analysis of intestinal epithelial organoids stimulated with the LXR agonist GW3965. In detail, wild type small intestinal crypts were seeded in vitro and stimulated with vehicle (DMSO) or GW3965. After six hours, closing crypts (organoids) were collected for RNA extraction and were analyzed by RNA sequencing.
2023-06-11 | GSE152283 | GEO
Project description:To find new genes that might be targeted for reduction of Copper (Cu) toxicity in Wilson disease we employed genome-wide shRNA screening in ATP7B-KO HepG2 cells, a bona fide WD cell model. Cells were screened using the Dharmacon™ Decode™ Pooled Lentiviral shRNA Screening Library targeting 18205 human genes (Dharmacon #RHS6083). The Lentiviral RNAi screening library is made of 10 pools of 9570 GIPZ short hairpin RNAs (shRNAs) packaged into high-titer lentiviral particles. Genomic DNA was isolated from the cells and read counts for each shRNAs were obtained by deep sequencing to determine the abundance of each shRNA in the Cu-treated cells compared to controls. This analysis allowed the identification of genes whose downregulation promoted survival of ATP7B-KO cells upon Cu overload. To exclude that some shRNAs would have been responsible for ATP7B-KO survival by suppressing generic proapoptotic genes, we run the same screening with the proapoptotic drug vinblastine instead of CuCl2. Genes, whose suppression allowed cell to resist Cu but not vinblastine were considered as Cu-specific hits and through this approach we identified PrP as a suitable target for reduction of Cu toxicity in WD. Indeed, we found that Cu accumulation in ATP7B-KO cells stimulates expression of PrP, which brings to toxic Cu overload while PrP suppression significantly reduces Cu accumulation and toxicity in ATP7B-deficient cells. In sum our data highlight an important regulatory role of PrP in copper metabolism and as a therapeutic tool for Wilson disease.
2024-12-09 | GSE260454 | GEO
Project description:The amyloidogenic processing of APP to A-beta is known to play a central role in Alzheimer’s disease pathogenesis. Despite this, however, the physiological role of APP and its processing still remains elusive. In the current study we utilzed a transcriptional profiling approach, to determine the pathways that may become dysregulated in the brains of APPswe transgenic mice (Tg2576). As many pathways linked to Alzheimer’s disease are also linked to cholesterol metabolism, we also treated the Tg2576 mice with LXR agonist TO901317, to determine the effects of LXR agonists on the hippocampal transcriptome of Tg2576 mice. We used microarrays to identify gene expression modulated in hippocampus of transgenic TG2576 mice that express human APP containing the Swedish mutation and the transcriptional responses to treatment with an LXR agonist.
2017-08-01 | GSE31624 | GEO
Project description:To understand whether hepatic cells use autophagy to defend against Cu toxicity in WD, we employed ATP7B knockout (ATP7B-KO) HepG2 cell line, by Quant-seq experiments. Transcriptome analysis of the of ATP7B KO cells and WT cells treated with Copper (Cu) compared with untreated cells.
2019-02-26 | GSE107323 | GEO
Project description:We used RNA-sequencing to determine the transcriptional response to liver X receptor (LXR) activation in primary human CD4+ T cells, both at rest and under activation conditions. CD4+ T cells were isolated from 3 healthy donors and treated with the synthetic LXR agonist GW3965 (GW) for 24 hours. Gene expression was compared to control samples (CTRL) treated with the LXR antagonist GSK1440233. To activate the T cell antigen receptor (TCR), cells were pre-treated with CTRL/GW alone for 6 hours then transferred to plates containing anti-CD3 and anti-CD28 for a further 18 hours.
2021-04-30 | E-MTAB-9141 | biostudies-arrayexpress