Expression profiles of liver tissues from wild-type and AID transgenic mice exposed to thioacetamide hepatotoxicity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE62878 | GEO | 2015/07/10
SECONDARY ACCESSION(S): PRJNA265874
REPOSITORIES: GEO
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Project description:AID is an intrinsic DNA mutator enzyme and contributes to tumorigenesis through the accumulation of genetic aberrations. To examine whether mutagenesis induced by AID during inflammation-associated hepatocarcinogenesis depends on the transcriptional levels of the target genes, we performed the gene expression profiling of liver tissues from AID transgenic mice and wild-type mice with and without thioacetamide treatment. AID transgenic mice and wild-type mice were administered with thioacetamide in drinking water for 6 months, and the gene expression levels of their livers are compared.
2015-07-10 | E-GEOD-62878 | biostudies-arrayexpress
Project description:To clarify the regulatory molecular mechanisms behind cell cycle aberrations related to the early stages of hepatocarcinogenesis. We investigated the early stage of hepatocarcinogenesis using global expression analyses. Livers from rats treated with thioacetamide were subjected to microarray analysis. Results were compared with livers from rats untreated controls (n = 4 animals/group).
2012-12-21 | E-GEOD-43066 | biostudies-arrayexpress
Project description:The Thioacetamide-treated rat was first identified as a model of hepatotoxicity by Gupta in 1956 and is now well-established, not least because the histopathogical output closely mimics that seen in humans with chronic liver disease. Acute treatment of rats with Thioacetamide causes pronounced necrosis and inflammation. Animals received intraperitoneal (ip) doses of vehicle-only (0.9% (v/v) saline) (n=3), or 100 mg/kg Thioacetamide (n=3) and were sacrificed after 24 hours. Blood was withdrawn via the descending vena cava and immediately transferred into potassium/EDTA tubes. Following centrifugation (16,100g, 4M-BM-0C, 5 min) the plasma was collected and stored at -80M-BM-0C. miRNA microarray profiling of RNA extracted from the plasma of rats treated with Thioacetamide revealed that a subset of miRNAs were differentially expressed following treatment. These miRNAs appeared to mediate pathways involved in hepatic fibrosis and stellate cell activation, suggesting that they might function as predictive biomarkers following compound-induced hepatotoxicity. The changes correlated well with increases in ALT levels, which are the current gold standard method for determining the extent of liver injury. Furthermore, it is hypothesised that particular aetiologies of liver damage might cause differing expression profiles of miRNAs, thus certain miRNAs could be implemented in a panel-type expression study to distinguish between different types of hepatic injury. Single channel miRNA microarrays were performed on n= 3 samples, 2 treatment groups; control and test. Control animals received vehicle-only (0.9% (v/v) saline) via the ip route. Test animals received 100 mg/kg Thioacetamide dissolved in 0.9% (v/v) saline, via the ip route. 24 h after dosing animals were sacrificed using decapitation under terminal anaesthesia.
2014-03-14 | E-GEOD-55885 | biostudies-arrayexpress
Project description:The Thioacetamide-treated rat was first identified as a model of hepatotoxicity by Gupta in 1956 and is now well-established, not least because the histopathogical output closely mimics that seen in humans with chronic liver disease. Acute treatment of rats with Thioacetamide causes pronounced necrosis and inflammation. Animals received intraperitoneal (ip) doses of vehicle-only (0.9% (v/v) saline) (n=3), or 100 mg/kg Thioacetamide (n=3) and were sacrificed after 24 hours. Blood was withdrawn via the descending vena cava and immediately transferred into potassium/EDTA tubes. Following centrifugation (16,100g, 4°C, 5 min) the plasma was collected and stored at -80°C. miRNA microarray profiling of RNA extracted from the plasma of rats treated with Thioacetamide revealed that a subset of miRNAs were differentially expressed following treatment. These miRNAs appeared to mediate pathways involved in hepatic fibrosis and stellate cell activation, suggesting that they might function as predictive biomarkers following compound-induced hepatotoxicity. The changes correlated well with increases in ALT levels, which are the current gold standard method for determining the extent of liver injury. Furthermore, it is hypothesised that particular aetiologies of liver damage might cause differing expression profiles of miRNAs, thus certain miRNAs could be implemented in a panel-type expression study to distinguish between different types of hepatic injury.
2014-03-14 | GSE55885 | GEO
Project description:To clarify the regulatory molecular mechanisms behind cell cycle aberrations related to the early stages of hepatocarcinogenesis. We investigated the early stage of hepatocarcinogenesis using global expression analyses.
2012-12-21 | GSE43066 | GEO
Project description:To analyze the organ-specific genetic changes in the tumor-related genes commonly triggerd by the AID-mediated mutagenesis, we compared the gene expression profiles among epitherial tumors developed in AID Tg mouse. Experiment Overall Design: We analyzed the up or down regulated genes in tumor tissues compared with nontumor tissues in AID Tg mouse (see Supplementary table at the foot of the record). We compared each gene expression profile among three epitherial tumors in AID Tg mouse.
2008-06-16 | E-GEOD-9304 | biostudies-arrayexpress
Project description:The antibody gene mutator AID promiscuously damages oncogenes and B cell identity genes leading to chromosomal translocations and tumorigenesis. Why non-immunoglobulin loci are susceptible to AID activity is unknown. Here we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome, but are predominantly clustered within super-enhancers. Unexpectedly, in these domains AID deaminates highly active promoters and eRNA+ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment.
2014-12-04 | GSE62063 | GEO
Project description:The activation-induced cytidine deaminase enzyme (AID) is required in germinal center (GC) B cells for somatic hyper-mutation and class switch recombination at the immunoglobulin locus. In GC-B cells, AID is highly expressed, with inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically, irrespective of mutator activity, by directly deaminating 5-methylcytosine (5mC) in concert with base excision repair glycosylases to exchange unmethylated cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, the range and mechanism by which AID promotes pluripotency is not known. Different studies have suggested either a requirement or a lack of function for promoting pluripotency in somatic nuclei following fusion with embryonic stem cells (ESC). Here we tested directly whether AID regulates epigenetic memory, by comparing the relative ability of cells lacking AID to reprogram from a differentiated cell type to an induced pluripotent stem cell (iPSC). We show that loss of AID impacts two distinct steps of reprogramming: First, AID-null cells are transiently hyper-responsive to the reprogramming process. Second, although they initiate expression of pluripotency genes, they fail to stabilize the pluripotent state. The genome of AID-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably up-regulated. MYC target genes are highly enriched in the set of genes hypermethylated and under-expressed in reprogramming cells lacking AID. Recent studies identified a distinctive late step of reprogramming associated with methylation status. AID appears to regulate this step to stabilize the pluripotent state, removing epigenetic memory to promote expression of secondary pluripotency network genes. Transcriptome sequencing of AID-null tail fibroblasts, wildtype tail fibroblasts, AID-null and wildtype tail fibroblasts reprogrammed for three weeks by ectopic expression of transcription factors Oct4, Sox2, KLf4 and cMyc. Methylation profiling by reduced representation bisulphite seuencing of AID-null tail fibroblasts, wildtype tail fibroblasts, AID-null and wildtype tail fibroblasts reprogrammed for three weeks and AID-null and wildtype clones after three weeks of reprogramming (Picked at two weeks)
2013-05-08 | E-GEOD-46700 | biostudies-arrayexpress
Project description:The activation-induced cytidine deaminase enzyme (AID) is required in germinal center (GC) B cells for somatic hyper-mutation and class switch recombination at the immunoglobulin locus. In GC-B cells, AID is highly expressed, with inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically, irrespective of mutator activity, by directly deaminating 5-methylcytosine (5mC) in concert with base excision repair glycosylases to exchange unmethylated cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, the range and mechanism by which AID promotes pluripotency is not known. Different studies have suggested either a requirement or a lack of function for promoting pluripotency in somatic nuclei following fusion with embryonic stem cells (ESC). Here we tested directly whether AID regulates epigenetic memory, by comparing the relative ability of cells lacking AID to reprogram from a differentiated cell type to an induced pluripotent stem cell (iPSC). We show that loss of AID impacts two distinct steps of reprogramming: First, AID-null cells are transiently hyper-responsive to the reprogramming process. Second, although they initiate expression of pluripotency genes, they fail to stabilize the pluripotent state. The genome of AID-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably up-regulated. MYC target genes are highly enriched in the set of genes hypermethylated and under-expressed in reprogramming cells lacking AID. Recent studies identified a distinctive late step of reprogramming associated with methylation status. AID appears to regulate this step to stabilize the pluripotent state, removing epigenetic memory to promote expression of secondary pluripotency network genes.
2013-05-08 | GSE46700 | GEO
Project description:The literature indicates that retinoids can influence the metabolism and actions of xenobiotics and conversely that xenobiotics can influence the metabolism and actions of retinoids. We were interested in understanding the degree to which hepatic retinoid stores, accumulated over a lifetime, affect xenobiotic metabolism, and actions. To investigate this, we induced liver injury through administration of the hepatotoxin thioacetamide (TAA) to chow fed wild type (WT) mice and lecithin:retinol acyltransferase-deficient (Lrat(-/-)) mice that are genetically unable to accumulate hepatic retinoid stores. Within 48 h of TAA-treatment, WT mice develop liver injury as evidenced by focal necrotic areas and increases in serum ALT activity and myeloperoxidase activity in hepatic parenchyma. Simultaneously, features of hepatic encephalopathy develop, as evidenced by a 25% increase in blood ammonia and a threefold reduction of blood glucose levels. This is accompanied by reduced hepatic glutathione, and increased thiobarbituric acid reactive substances, protein carbonyl and sulfhydryl groups, and increased cytochrome P450-catalyzed hydroxylation activity and flavin-containing monooxygenase activity in microsomes prepared from WT liver. Strikingly, none of these TAA-induced effects were observed for matched Lrat(-/-) mice. To confirm that TAA hepatotoxicity depends on retinoid availability, we administered, over 48 h, four oral doses of 3000 IU retinyl acetate each to the mice. This led to the development of hepatotoxicity in Lrat(-/-) mice that was similar in extent to that observed in WT mice. Our findings establish that endogenous hepatic retinoid stores can modulate the toxicity of TAA in mice.
| S-EPMC4064013 | biostudies-literature