Transcriptome profile of ATP7B KO cells and WT cells treated with Copper (Cu) to study Autophagy as a pro-survival mechanism in Wilson disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE107323 | GEO | 2019/02/26
REPOSITORIES: GEO
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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:Purpose：Wilson's disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems. Hepatocyte transplantation showed therapeutic potential, however, this strategy is often hindered by a shortage of quality donor cells and by allogeneic immune rejection. Here we evaluate the function and efficacy of autologous reprogrammed, ATP7B gene-restored hepatocytes using a murine model of WD Mathods and Results: By reprogramming hepatocytes from ATP7B-/- mice with small molecules, sufficient liver progenitor cells (LPCs) are harvested. After lentivirus-mediated miniATP7B gene transfection and re-differentiation, functional LPC-ATP7B-Heps are developed. RNA-seq data show that compared with LPC-GFP-Heps with enrichment of genes mainly in pathways of oxidative stress and cell apoptosis, in LPC-ATP7B-Heps under high copper stress pathways for copper ion binding and cell proliferation are enriched. LPC-ATP7B-Heps transplantation into ATP7B-/- mice alleviates deposition of excess liver copper with its associated inflammation and fibrosis, comparable to those observed using normal primary hepatocytes at four months after transplantation. Conclusion: We establish the autologous reprogrammed, ATP7B gene restored LPC-ATP7B-Heps and further transplantation demonstrate alleviated copper accumulation in WD mice.
2022-03-05 | GSE197948 | GEO
Project description:Wilson disease (WD) is a severe metabolic disorder caused by genetic inactivation of copper-transporting ATPase ATP7B. In WD, copper accumulates in several tissues, particularly in the liver, inducing marked time-dependent pathological changes. To identify initial events in the copper-dependent development of liver pathology we utilized the Atp7b-/- mice, an animal model for WD. Analysis of mRNA from livers of control and Atp7b-/- 6 weeks-old mice using oligonucleotide arrays revealed specific changes of the transcriptome at this stage of copper accumulation. Few messages (29 up-regulated and 46 down-regulated) change their abundance more than 2-fold pointing to the specific effect of copper on gene expression/mRNA stability. The gene ontology analysis revealed copper effects on distinct metabolic pathways. Keywords: comparative genomic hybridization
2006-12-19 | GSE5348 | GEO
Project description:Wilson disease (WD) is a severe metabolic disorder caused by genetic inactivation of copper-transporting ATPase ATP7B. In WD, copper accumulates in several tissues, particularly in the liver, inducing marked time-dependent pathological changes. To identify initial events in the copper-dependent development of liver pathology we utilized the Atp7b-/- mice, an animal model for WD. Analysis of mRNA from livers of control and Atp7b-/- 6 weeks-old mice using oligonucleotide arrays revealed specific changes of the transcriptome at this stage of copper accumulation. Few messages (29 up-regulated and 46 down-regulated) change their abundance more than 2-fold pointing to the specific effect of copper on gene expression/mRNA stability. The gene ontology analysis revealed copper effects on distinct metabolic pathways. Experiment Overall Design: RNA isolation for microarrays: Immediately after removal, what size [mg] the liver pieces for RNA isolation were frozen in liquid nitrogen and stored till further use. The total RNA was isolated from frozen mouse livers using TRIZOL reagent (Invitrogen) according to manufacturerâs recommendations followed by a subsequent sample
2008-06-13 | E-GEOD-5348 | biostudies-arrayexpress
Project description:Wilson’s disease (WD) is a rare genetic disease caused by mutations in the ATP7B gene. These mutations impact the expression and/or function of the copper-transporting ATP7B protein, leading to massive toxic accumulation of copper in the liver and brain. Due to its low incidence and highly variable clinical presentations, WD is challenging to diagnose. Here, we explored the plasma proteome of the Atp7b-/- mouse, a genetic and phenotypic model of WD, to provide new insights into the pathogenic mechanisms of WD and discover potential biomarkers for WD diagnosis. A mass spectrometry (MS)-based proteomics workflow combining unbiased discovery analysis followed by targeted quantification was developed. Analysis of two independent groups of samples (discovery and validation cohorts) highlighted seven plasma proteins for which abundance was significantly modified (more than 2-fold) between Atp7b-/- mice and wild-type littermates. To assess the clinical significance and specificity of these seven proteins as potential biomarkers for WD, we adapted our targeted proteomics assay to allow the quantification of human orthologues in plasma from WD patients (treated with copper chelators), non-alcoholic steatohepatitis patients (disease-control group), and healthy donors. The plasma proteome changes observed in the Atp7b-/- mouse were not confirmed in treated WD patients, with the exception of alpha-1 antichymotrypsin, levels of which were decreased in WD patients compared to healthy individuals. Plasma ceruloplasmin was investigated in both the Atp7b-/- mouse model and human patients, and was found to be significantly decreased in the human form of WD only.
2020-04-14 | PXD011007 | Pride
Project description:Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, leading to copper accumulation in the liver and brain. Excess copper inhibits S-adenosyl-L-homocysteine hydrolase, leading to variable WD phenotypes from widespread alterations in DNA methylation and gene expression. Previously, we demonstrated that maternal choline supplementation in the Jackson toxic milk (tx-j) mouse model of WD corrected higher thioredoxin 1 transcript levels in fetal liver. Here, we investigated the effect of maternal choline supplementation on genome-wide DNA methylation patterns in tx-j fetal liver by whole-genome bisulfite sequencing (WGBS). Tx-j Atp7b genotype-dependent differences in DNA methylation were corrected by choline for genes including, but not exclusive to, oxidative stress pathways. To examine phenotypic effects of postnatal choline supplementation, tx-j mice were randomized to one of six treatment groups: with or without maternal and/or continued choline supplementation, and with or without copper chelation with penicillamine (PCA) treatment. Hepatic transcript levels of thioredoxin 1 and peroxiredoxin 1 were significantly higher in mice receiving maternal and continued choline with or without PCA treatment compared to untreated mice. A comparison of WGBS of human WD liver compared to tx-j mouse liver demonstrated a significant overlap of differentially-methylated genes associated with ATP7B deficiency. Further, eight genes in the thioredoxin pathway were differentially methylated in human WD liver samples. In summary, Atp7b deficiency and choline supplementation have a genome-wide impact, including on thioredoxin system-related genes, in tx-j mice. These findings could explain the variability of WD phenotype and suggest new complementary treatment options for WD.
2018-07-25 | GSE117592 | GEO
Project description:Transcriptome profile of ATP7B KO cells and WT cells treated with Copper (Cu) to study Autophagy as a pro-survival mechanism in Wilson disease
| PRJNA419762 | ENA
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: Not available
| S-EPMC4070386 | biostudies-literature
Project description:Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes. WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9. We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.
2019-02-14 | GSE117593 | GEO