Catechol-O-methyltransferase (COMT) is an ubiquitously expressed enzyme that maintains basic biologic functions by inactivating catechol substrates. In humans, polymorphic variance at the COMT locus has been associated with modulation of pain sensitivity (Andersen & Skorpen, 2009) and risk for developing psychiatric disorders (Harrison & Tunbridge, 2008). A functional haplotype associated with increased pain sensitivity was shown to result in decreased COMT activity by altering mRNA secondary structure-dependent protein translation (Nackley et al., 2006). However, the exact mechanisms whereby COMT modulates pain sensitivity and behavior remain unclear and can be further studied in animal models. We have pursued a genome-wide approach to examining gene expression in multiple brain regions in inbred strains of mice and have discovered that Comt1 is differentially expressed. This expression difference was validated with qPCR. A B2-B4 Short Interspersed Element (SINE) was inserted in the 3'UTR of Comt1 in 14 strains that also shared a common haplotype. Experiments using mammalian expression vectors of full-length cDNA clones with and without the SINE element demonstrate that strains with the SINE haplotype (+SINE) have greater Comt1 enzymatic activity. +SINE mice also exhibit behavioral differences in anxiety assays and decreased pain sensitivity. These results suggest that a haplotype, defined by a 3'UTR B2-B4 SINE element, regulates Comt1 expression and mouse behavior.
Comt1 genotype and expression predicts anxiety and nociceptive sensitivity in inbred strains of mice.
Sex, Specimen part
View SamplesOver-activation of the aryl hydrocarbon receptor by TCDD in mice leads among other phenotypes to a severe thymic atrophy accompanied by immunosuppression. TCDD causes a block in thymocyte maturation and a preferential emigration of immature CD4-CD8- DN thymocytes (recent thymic emigrants) into the periphery. As part of this study gene expression profiles from DN thymocytes and thymic emigrants were generated from TCDD and solvent control mice
Role of the aryl hydrocarbon receptor in thymocyte emigration in vivo.
Specimen part, Treatment
View SamplesWe used a reciprocal cross of Mus musculus and M. domesticus in which F1 males are sterile in one direction and fertile in the other direction, in order to associate expression differences with sterility.
Widespread over-expression of the X chromosome in sterile F₁hybrid mice.
Specimen part
View SamplesThis study provides a comprehensive evaluation of changes in gene expression during treatment with Genistein in vitro.
Dose- and Time-Dependent Transcriptional Response of Ishikawa Cells Exposed to Genistein.
Treatment
View SamplesWe have determined the gene expression profile induced by 17 alpha-ethynyl estradiol (EE) in Ishikawa cells, a human uterine-derived estrogen-sensitive cell line, at various doses (1 pM, 100 pM, 10 nM, and 1 microM) and time points (8, 24, and 48 h). The transcript profiles were compared between treatment groups and controls (vehicle-treated) using high-density oligonucleotide arrays to determine the expression level of approximately 38,500 human genes. By trend analysis, we determined that the expression of 2560 genes was modified by exposure to EE in a dose- and time-dependent manner (p </= 0.0001). The annotation available for the genes affected indicates that EE exposure results in changes in multiple molecular pathways affecting various biological processes, particularly associated with development, morphogenesis, organogenesis, cell proliferation, cell organization, and biogenesis. All of these processes are also affected by estrogen exposure in the uterus of the rat. Comparison of the response to EE in both the rat uterus and the Ishikawa cells showed that 71 genes are regulated in a similar manner in vivo as well as in vitro. Further, some of the genes that show a robust response to estrogen exposure in Ishikawa cells are well known to be estrogen responsive, in various in vivo studies, such as PGR, MMP7, IGFBP3, IGFBP5, SOX4, MYC, EGR1, FOS, CKB, and CCND2, among others. These results indicate that transcript profiling can serve as a viable tool to select reliable in vitro systems to evaluate potential estrogenic activities of target chemicals and to identify genes that are relevant for the estrogen response.
The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol.
No sample metadata fields
View SamplesThe rat uterus responds to acute estrogen treatment with a series of well characterized physiological responses; however, the gene expression changes required to elicit these responses have not been fully characterized. In order to understand early events induced by estrogen exposure in vivo, we evaluated the temporal gene expression in the uterus of the immature rat after a single dose of 17 Alpha-ethynyl estradiol (EE) by microarray analysis, evaluating the expression of 15,923 genes. Immature 20 day old rats were exposed to a single dose of EE (10 ug/kg) and the effect on uterine histology, weight and gene expression were determined after 1, 2, 8, 24, 48, 72 and 96 h. EE induced changes in the expression of 3,867 genes, at least at one time point (p¡Ü0.0001), and at least 1.5 fold (up- or down-regulated). Specifically, the expression of 8, 116, 3030, 2076, 381, 445, and 125 genes was modified at 1, 2, 8, 24, 48, 72 or 96 hours after exposure to EE respectively (p¡Ü0.0001, t Test). At the tissue and organ level, a clear uterotrophic response was elicited by EE after only 8 h, reaching a maximum after 24 h and remaining detectable even after 96 h of exposure. The uterine phenotypic changes were induced by sequential changes in the transcriptional status of a large number of genes, in a program that involves multiple molecular pathways. Using the gene ontology to better understand the temporal response to estrogen exposure, we determined that the earliest changes were in the expression of genes whose products are involved in transcriptional regulation and signal transduction, followed by genes implicated in protein synthesis, energy utilization, solute transport, cell proliferation and differentiation, tissue remodeling and immunological responses among other pathways. The compendium of genes here presented represents a comprehensive compilation of estrogen-responsive genes involved in the uterotrophic response.
Uterine temporal response to acute exposure to 17alpha-ethinyl estradiol in the immature rat.
Sex, Age, Specimen part, Compound, Time
View SamplesThis study provides a comprehensive evaluation of changes in gene expression during treatment with Bisphenol A in vitro.
The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent.
Cell line, Treatment
View SamplesZBTB4 is a mammalian transcription factor with Zinc fingers and a BTB/POZ domain, which can bind methylated CpGs, as well as certain unmethylated consensus sequences. ZBTB4 is frequently downregulated in human cancers, but it is unclear whether this is a cause or consequence of transformation. To investigate the role of ZBTB4 in normal and pathological conditions, we generated Zbtb4-/- mice
Loss of the Methyl-CpG-Binding Protein ZBTB4 Alters Mitotic Checkpoint, Increases Aneuploidy, and Promotes Tumorigenesis.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
A novel transcriptomics based in vitro method to compare and predict hepatotoxicity based on mode of action.
Sex, Time
View SamplesThis study provides an evaluation of changes in gene expression associated with dioctyl phthalate treatment of rat hepatocytes in vitro.
A novel transcriptomics based in vitro method to compare and predict hepatotoxicity based on mode of action.
Sex, Time
View Samples