Exposure to aristolochic acid (AA) is linked to kidney disease and urothelial cancer in humans. The major carcinogenic component of the AA plant extract is aristolochic acid I (AAI). The transcription factor p53 acts as a tumour suppressor and is frequently mutated in AA-induced tumours. Using a mouse model, we previously showed that Trp53 genotype impacts on AAI-induced nephrotoxicity in vivo (i.e. p53 protects from AAI-induced renal proximal tubular injury), but the underlying mechanism(s) involved remain to be further explored. In the present study, we investigated the impact of p53 on AAI-induced gene expression in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with 3.5 mg/kg body weight (bw) AAI daily for 6 days. The Clariom™ S Assay microarray was used to elucidate gene expression profiles in mouse kidneys after AAI treatment in order to identify potential mechanisms by which AAI drives renal injury in Trp53(-/-) kidneys. Principle component analysis and hierarchical clustering in Qlucore Omics Explorer showed that gene expression in AAI-exposed Trp53(+/+), Trp53(+/-) and Trp53(-/-) kidneys is treatment-dependent. However, gene expression profiles did not segregate in a clear-cut manner according to Trp53 genotype, hence further investigations were performed by pathway analysis with MetaCore™. Several pathways, such as those related to epithelial-to-mesenchymal transition, transcription of hypoxia-inducible factor 1 targets, renal injury and secretion of xenobiotics were significantly altered to varying degrees for AAI-exposed kidneys. The top ten up-regulated genes included cyclin-dependent kinase inhibitor 1a (Cdkn1a), a mediator of cell cycle arrest; and neutrophil gelatinase-associated lipocalin (Ngal), which has been shown to play a role in nephritis by promoting inflammation and apoptosis. Members of the solute carrier (Slc) family (i.e. Slc22a2, Slc22a6, Slc22a7, Slc22a8) were amongst the top ten down-regulated genes. Pathway analysis also identified genes that are uniquely affected by AAI treatment in Trp53(+/+), Trp53(+/-) and Trp53(-/-) kidneys. Apoptotic pathways were modulated in Trp53(+/+) kidneys; whereas oncogenic and pro-survival pathways were significantly altered for Trp53(+/-) and Trp53(-/-) kidneys, respectively. Microarray gene expression analysis identified significant toxicogenomic responses to AAI that give novel insights into its mechanism of nephrotoxicity. Alterations of biological processes by AAI in Trp53(+/+), Trp53(+/-) and Trp53(-/-) kidneys could explain the mechanisms by which p53 protects from or p53 loss drives AAI-induced renal injury in vivo.
The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro.
Sex, Specimen part, Treatment
View SamplesWe advance a three gene model of arsenate tolerance in rice based on testing root growth of 108 recombinant inbred lines (RILs) of the Bala x Azucena population. Marker genotype at 3 loci determined arsenate tolerance in 99% of RILs tested. Interestingly, plants must inherit 2, but any two alleles from the tolerant parent (Bala) to have the tolerant phenotype. Challenging the Affymetrix GeneChip Rice Genome array with Azucena and Bala RNA isolated from control and arsenate treated plants revealed 592 genes 2 fold-upregulated by arsenate and 696 downregulated. The array data was also used to identify which genes are expressed within the three target loci.
Rice-arsenate interactions in hydroponics: whole genome transcriptional analysis.
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View SamplesThe aim of this study was to determine the changes in gene expression of rice root tips when they came in to contact with a hard layer (60% wax layer). Three categories of root tips were sampled; tips before the hard layer, tips that had come into contact with the hard layer and root tips which had buckled after coming into contact with the hard layer.
A bioinformatic and transcriptomic approach to identifying positional candidate genes without fine mapping: an example using rice root-growth QTLs.
No sample metadata fields
View SamplesWe used microarrays to establish whether EBF1 and Pax5 repress similar or unique genes. We found that EBF1 uniquely represses the expression of the T-lineage transcription factor Gata3.
Transcriptional repression of Gata3 is essential for early B cell commitment.
Specimen part
View SamplesTCF7L2 regulates multiple metabolic pathways in hepatocytes through a transcriptional network involving HNF4a Overall design: For the identification of Tcf7l2 target genes using a RNA-seq timecourse, and for identifying the binding sites of Tcf7l2 and Hnf4a, Tcf7l2 was silenced in rat H4IIE hepatocytes using siRNA for Tcf7l2 with a scrambled siRNA as control. Treatment times for RNA-seq samples were 3, 6, 9, 12, 15, 18, 48, and 96 hours, and for ChIP-seq samples 15 h. RNA-seq timecourse was performed in duplicate or triplicate, and the ChIP-seq in duplicate for Tcf7l2 and in singlicate for Hnf4a. The H4IIE-specific transcriptome was defined from an independent set of pooled 24 h siRNA treated samples (N=3 for siRNA for Tcf7l2 and N=3 for scrambled siRNA).
The mechanisms of genome-wide target gene regulation by TCF7L2 in liver cells.
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Tumor entrained neutrophils inhibit seeding in the premetastatic lung.
Sex, Specimen part, Disease, Treatment
View SamplesPrimary tumors have been shown to prepare distal organs for later colonization of metastatic cells by stimulating organ-specific infiltration of bone marrow-derived cells. Here we demonstrate that neutrophils accumulate in the lung prior to the arrival of metastatic cells in mouse models of breast cancer. Tumor-entrained neutrophils (TENs) inhibit metastatic seeding in the lungs by generating H2O2, and tumor-secreted CCL2 is a critical mediator of optimal anti-metastatic entrainment of G-CSF-stimulated neutrophils. TENs are present in the peripheral blood of breast cancer patients prior to surgical resection but not in healthy individuals. Thus, while tumor-secreted factors contribute to tumor progression at the primary site, they concomitantly induce a neutrophil-mediated inhibitory process at the metastatic site.
Tumor entrained neutrophils inhibit seeding in the premetastatic lung.
Sex, Specimen part, Disease
View SamplesPrimary tumors have been shown to prepare distal organs for later colonization of metastatic cells by stimulating organ-specific infiltration of bone marrow-derived cells. Here we demonstrate that neutrophils accumulate in the lung prior to the arrival of metastatic cells in mouse models of breast cancer. Tumor-entrained neutrophils (TENs) inhibit metastatic seeding in the lungs by generating H2O2, and tumor-secreted CCL2 is a critical mediator of optimal anti-metastatic entrainment of G-CSF-stimulated neutrophils. TENs are present in the peripheral blood of breast cancer patients prior to surgical resection but not in healthy individuals. Thus, while tumor-secreted factors contribute to tumor progression at the primary site, they concomitantly induce a neutrophil-mediated inhibitory process at the metastatic site.
Tumor entrained neutrophils inhibit seeding in the premetastatic lung.
Sex, Specimen part, Treatment
View SamplesBackground. Differential gene expression in adipose tissue during diet-induced weight loss followed by a weight stability period is not well characterized. Markers of these processes may provide a deeper understanding of the underlying mechanisms. Objective. To identify differentially expressed genes in human adipose tissue during weight loss and weight maintenance after weight loss. Design. RNA from subcutaneous abdominal adipose tissue from nine obese subjects was obtained and analyzed at baseline, after weight reduction on a low calorie diet (LCD), and after a period of group therapy in order to maintain weight stability. Results. Subjects lost 18.8 + 5.4% of their body weight during the LCD and maintained this weight during group therapy. Insulin sensitivity (HOMA) improved after weight loss with no further improvement during weight maintenance. Cyclin-dependent kinase inhibitor 2B (CDKN2B) and JAZF zinc finger 1 (JAZF1), associated with type 2 diabetes, were downregulated. We could also confirm the downregulation of candidates for obesity and related traits, such as tenomodulin (TNMD) and matrix metallopeptidase 9 (MMP9), with weight loss. The expression of other candidates, such as cell death-inducing DFFA-like effector A (CIDEA) and stearoyl-CoA desaturase (SCD) were upregulated during weight loss but returned to baseline levels during weight maintenance. Conclusion. Genes in the adipose tissue are differentially expressed during weight loss and weight maintenance after weight loss. Genes that show sustained regulation may be of potential interest as markers of the beneficial effects of weight loss whereas others seem to be primarily involved in the process of weight loss itself.
Differential gene expression in adipose tissue from obese human subjects during weight loss and weight maintenance.
Sex, Age
View SamplesMenisci play a vital role in load transmission, shock absorption and joint stability. The current dogma is that the menisci simply protects the cartilage and play no role in osteoarthritis (OA) unless they are injured. However, there is increasing evidence suggesting that OA menisci may not merely be bystanders in the disease process of OA. This study sought: 1) to determine the prevalence of meniscal degeneration in OA patients, 2) to examine gene expression in OA meniscal cells compared to normal control meniscal cells, and 3) to test the hypothesis that OA meniscal cells are different from normal meniscal cells.
Analysis of meniscal degeneration and meniscal gene expression.
Specimen part
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