Proceedings of the National Academy of Sciences of the United States of America 20140203 7
Mediator, an evolutionary conserved large multisubunit protein complex with a central role in regulating RNA polymerase II-transcribed genes, serves as a molecular switchboard at the interface between DNA binding transcription factors and the general transcription machinery. Mediator subunits include the Cdk8 module, which has both positive and negative effects on activator-dependent transcription through the activity of the cyclin-dependent kinase Cdk8, and the tail module, which is required fo ...[more]
Project description:We have established Drosophila melanogaster as a model system for ocular hypertension by expressing wild-type human myocilin (MYOC) in the Drosophila eye. Here, we have created transgenic flies that express four clinically relevant mutant forms of MYOC (R342K, Q368X, D380N and K423E) in their eyes using the gmr-Gal4/UAS binary system. We compare and identify human glaucoma candidate genes based on the transcription profiles of flies that express wt-MYOC or mutant-MYOCs.
Project description:Gene transcription in a set of 49 human primary lung adenocarcinomas and 9 normal lung tissue samples was examined using Affymetrix GeneChip technology. We aimed to investigate differential gene expression between the two tissue types. A total of 3,442 genes, called the set MAD, were found to be either up- or down-regulated by at least two fold between the two phenotypes. Genes assigned to a particular gene ontology term were found, in many cases, to be significantly unevenly distributed between the genes in and outside MAD. Terms that were overrepresented in MAD included functions directly implicated in cancer cell metabolism. Based on their functional roles and expression profiles, genes in MAD were grouped into likely co-regulated gene sets.
Project description:In order to study the physiological consequences of a high-copper diet on hepatic gene expression, 6 mM CuCl2 was added to the drinking water for a period of 1 month. After this period, livers of seven control mice and eight copper-treated mice were isolated and were subjected to microarray analysis and copper measurements. The hepatic gene expression profile of copper-treated mice was compared to non-treated mice using a pooled reference.
Project description:Nine time points for microarray analysis were chosen to study early and late transcriptional responses in copper metabolism upon copper overload in HepG2 cells. Samples of copper-treated cells were hybridized using non-treated samples as a reference.
Project description:The purpose of this study was to determine 1) the transcriptional program elicited by exposure to three estrogen receptor (ER) agonists: 17 a-ethynyl estradiol (EE), genistein (Ges) and bisphenol A (BPA) during fetal development of the rat testis and epididymis; and 2) whether very low dosages of estrogens (evaluated over five orders of magnitude of dosage) produce unexpected changes in gene expression (i.e., a non-monotonic dose-response curve). In three independently conducted experiments, Sprague-Dawley rats were dosed (s.c.) with 0.001-10mg EE/kg/day, 0.001-100 mg Ges/kg/day or 0.002-400mg BPA/kg/day. While morphological changes in the developing reproductive system were not observed, the gene expression profile of target tissues were modified in a dose-responsive manner. Independent dose-response analyses of the three studies identified 56 genes that are significantly modified by EE, 28 genes by Ges and 15 genes by BPA (out of 8740). Even more genes were observed to be significantly changed when only the high dose is compared with all lower doses: 141, 46 and 67 genes, respectively. Global analyses aimed at detecting genes consistently modified by all of the chemicals identified 52 genes whose expression changed in the same direction across the three chemicals. The dose-response curve for gene expression changes was monotonic for each chemical, with both the number of genes significantly changed and the magnitude of change, for each gene, decreasing with decreasing dose. Using the available annotation of the gene expression changes induced by ER-agonist, our data suggest that a variety of cellular pathways are affected by estrogen exposure. These results indicate that gene expression data are diagnostic of mode of action and, if they are evaluated in the context of traditional toxicological end-points, can be used to elucidate dose-response characteristics.
Project description:A gene expression study using microarray analysis was performed to elucidate the underlying mechanism leading to embryonic lethality in homozygous Commd1 null (Commd1-/-) mouse embryos. A gene expression profile of 9.5 dpc Commd1-/- embryos were generated and were compared to a gene expression profile of both 8.5 dpc and 9.5 dpc normal embryos.