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GSE10493
Mus musculus
144 Downloadable Samples
Description
High-fat diets are associated with increased obesity and metabolic disease in mice and humans. Here we used analysis of variance (ANOVA) to scrutinize a microarray data set consisting of 10 inbred strains of mice from both sexes fed atherogenic high-fat and control chow diets. An overall F-test was applied to the 40 unique groups of strain-diet-sex to identify 15,288 genes with altered transcription. Bootstrapping k-means clustering separated these changes into four strain-dependent expression patterns, including two sex-related profiles and two diet-related profiles. Sex-induced effects correspond to secretion (males) or fat and energy metabolism (females), whereas diet-induced changes relate to neurological processes (chow) or immune response (high-fat). The full set of pairwise contrasts for differences between strains within sex (90 different statistical tests) uncovered 32,379 total changes. These differences were unevenly distributed across strains and between sexes, indicating that strain-specific responses to high-fat diet differ between sexes. Correlations between expression levels and 8 obesity-related traits identified 5,274 associations between transcript abundance and measured phenotypic endpoints. From this number, 2,678 genes are positively correlated with total cholesterol levels and associate with immune-related categories while 2,596 genes are negatively correlated with cholesterol and connect to cholesterol synthesis.
Publication Title
Practical applications of the bioinformatics toolbox for narrowing quantitative trait loci.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 107 Downloadable Samples
Description
In this study that was specifically designed to identify early stages of glaucoma in DBA/2J mice, we used genome-wide expression profiling and a series of computational methods. Our methods successfully subdivided eyes with no detectable glaucoma by conventional assays into molecularly defined stages of disease. These stages represent a temporally ordered sequence of glaucoma states. Using an array of tools, we then determined networks and biological processes that are altered at these early stages. Our strategy proved very sensitive, suggesting that similar approaches will be valuable for uncovering early processes in other complex, later-onset diseases. Early changes included upregulation of both the complement cascade and endothelin system, and so we tested the therapeutic value of separately inhibiting them. Mice with a mutation in the complement component 1a gene (C1qa) were robustly protected from glaucoma with the protection being among the greatest reported. Similarly, inhibition of the endothelin system was strongly protective. Since EDN2 is potently vasoconstrictive and was produced by microglial/macrophages, our data provide a novel link between these cell types and vascular dysfunction in glaucoma. Targeting early events such as the upregulation of the complement and endothelin pathways may provide effective new treatments for human glaucoma.
Publication Title
Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 27 Downloadable Samples
Description
We used a novel probe-level microarray analysis, revealing connections between mRNA processing and lymphoid neoplasia, in a mouse leukemia model. Characteristic differences in mRNA processing, primarily in the 3-untranslated region, distinguished histologically similar tumor subtypes with different survival characteristics. Gene sets with specific processing in each tumor subtype defined signatures useful for tumor subclassification, as demonstrated by internal cross-validation with up to 80% discrimination accuracy. A combination of mRNA expression and sequence analysis suggested that differences in isoform abundance likely arose from both alternative polyadenylation and differential degradation.
Publication Title
Global changes in processing of mRNA 3' untranslated regions characterize clinically distinct cancer subtypes.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
Description
Rosiglitazone (Rosi), a member of the thiazolidinedione class of drugs used to treat type 2 diabetes, activates the adipocyte-specific transcription factor peroxisome proliferator-activated receptor gamma (PPARg). This activation causes bone loss in animals and humans, at least in part due to suppression of osteoblast differentiation from marrow mesenchymal stem cells (MSC). In order to identify mechanisms by which PPARg2 suppresses osteoblastogenesis and promotes adipogenesis in MSC, we have analyzed the PPARg2 transcriptome in response to Rosi. A total of 4,252 transcriptional changes resulted when Rosi (1 uM) was applied to the U-33 marrow stromal cell line, stably transfected with PPARg2 (U-33/g2), as compared to non-induced U-33/g2 cells. Differences between U-33/g2 and U-33 cells stably transfected with empty vector (U-33/c) comprised 7,928 transcriptional changes, independent of Rosi. Cell type-, time- and treatment-specific gene clustering uncovered distinct patterns of PPARg2 transcriptional control of MSC lineage commitment. The earliest changes accompanying Rosi activation of PPARg2 included adjustments in morphogenesis, Wnt signaling, and immune responses, as well as sustained induction of lipid metabolism. Expression signatures influenced by longer exposure to Rosi provided evidence for distinct mechanisms governing the repression of osteogenesis and stimulation of adipogenesis. Our results suggest interactions that could lead to the identification of a master regulatory scheme controlling osteoblast differentiation.
Publication Title
No associated publication
Sample Metadata Fields
Compound, Time
View Samples- Mus musculus
- 14 Downloadable Samples
Description
The recent identification of cancer stem cells (CSCs) in multiple human cancers provides a new inroad to understanding tumorigenesis at the cellular level. CSCs are defined by their characteristics of self-renewal, multipotentiality, and tumor initiation upon transplantation. By testing for these defining characteristics, we provide evidence for the existence of CSCs in a transgenic mouse model of glioma, S100-verbB;Trp53. In this glioma model, CSCs are enriched in the side-population (SP) cells. These SP cells have enhanced tumor-initiating capacity, self-renewal, and multipotentiality compared to non-SP cells from the same tumors. Furthermore, gene expression analysis comparing FACS-sorted cancer SP cells to non-SP cancer cells and normal neural SP cells identified 45 candidate genes that are differentially expressed in glioma stem cells. We validated the expression of two genes from this list (S100a4 and S100a6) in primary mouse gliomas and human glioma samples. Analyses of xenografted human GBM (glioblatoma multiforme) cell lines and primary human glioma tissues show that S100A4 and S100A6 are expressed in a small subset of cancer cells and that their abundance is positively correlated to tumor grade. In conclusion, this study shows that CSCs exist in a mouse glioma model, suggesting that this model can be used to study the molecular and cellular characteristics of CSCs in vivo and to further test the cancer stem cell hypothesis.
Publication Title
Cancer stem cells are enriched in the side population cells in a mouse model of glioma.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
Description
Mutations in the membrane frizzled-related gene (Mfrp) are linked to posterior microphthalmia, retinitis pigmentosa and nanophthalmia in humans. In homozygous Mfrprd6 mice, a splice site mutation causes a slow photoreceptor degeneration characterized by shortening and disorganization of outer segments with eventual photoreceptor loss. To better understand the function of MFRP in the retina, microarray analysis was carried out in mutant and control mice at postnatal day14 (P14), prior to the loss of photoreceptors. Analysis of the data revealed differentially expressed RPE and neuroretina transcripts. Although the analysis of the microarray data from Mfrprd6 mutant mice compared to age-matched wild-type controls identified some transcripts with relative fold change > 5.0, most of the differentially expressed genes showed a relative fold change between1.5 - 2.0. Global gene expression analysis using Ingenuity Pathway Analysis software identified decreased levels of transcripts in phototransduction and visual pathways in Mfrprd6 mutants. Select candidate transcripts were validated by quantitative real-time PCR analyses. The expression of RPE-specific visual transduction protein, RPE65, was significantly decreased in Mfrprd6 mutants. As an indirect consequence of the primary RPE cell defect due to the Mfrprd6 mutation, retinal specific transcripts Rgr, Pde6a, GuCa1b, and Rgs9 were also significantly decreased. We also confirmed the significantly elevated levels of Prss56, a gene previously associated with myopia and open angle glaucoma. In the Mfrprd6 mutant, a progressive increase in Prss56 mRNA levels from 14- to 70-fold was observed from P7 to P21, respectively. In situ hybridization and glutamine synthetase staining of mutant eyes indirectly identified Mller glia in the inner nuclear layer of retina as the cell type expressing the Prss56 transcript.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Description
The BCR-ABL oncogene, generated by Philadelphia chromosome, is present in about 95% human Chronic myeloid leukemia (CML) and 20~30% acute lymphoblastic leukemia (ALL). One of BCR-ABL isoforms, P210, is more often detected in CML and ALL patients. Although BCR-ABL kinase inhibitors are effective in controlling the diseases, they do not provide cure due to the development of drug resistance and the insensitivity of leukemia stem cells to these drugs. Identification of new therapeutic targets is critical. To identify potential target against leukemia stem cells, we studied gene expression in leukemia stem cells, which were identified in mice in our lab (Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S. 2006. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia. Proc Natl Acad Sci USA 103(45):16870-16875.). The sorted leukemia stem cells that expressed BCR-ABL were used for isolation of RNA, followed by the analysis of gene expression using the DNA microarray. The same lineage of non-BCR-ABL-expressing normal hematopoietic stem cells was used as control. We have identified some interesting genes that are up- or down-regulated by BCR-ABL in these leukemia stem cells. We are currently studying the functions of these identified genes.
Publication Title
Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 3 Downloadable Samples
Description
Hoxc13 has been shown to be essential for proper hair shaft differentiation as Hoxc13 gene-targeted (Hoxc13tm1Mrc) mice completely lack external hair. Because of the phenotypic parallels to the Foxn1nu (nude) mutant mice, we tested whether Hoxc13 and Foxn1 act in a common pathway of hair follicle (HF) differentiation. We show that the alopecia exhibited by both the Hoxc13tm1Mrc and Foxn1nu mice is due to strikingly similar defects in hair shaft differentiation and that both mutants suffer from a severe nail dystrophy. These similarities are consistent with the overlap of Hoxc13 and Foxn1 expression patterns in the HF and nail matrix. DNA microarray analysis of scapular skin from Hoxc13tm1Mrc mutant (mut) compared to wild type (wt) mice identified Foxn1 as significantly down-regulated along with numerous hair keratin genes. This Foxn1 down-regulation apparently reflects the loss of direct transcriptional control by HOXC13 as indicated by our results obtained through co-tranfection and chromatin immunoprecipitation (ChIP) assays.
Publication Title
No associated publication
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 5 Downloadable Samples
Description
Several studies have shown that bone mineral density (BMD), a clinically measurable predictor of osteoporotic fracture, is the sum of genetic and environmental influences. In addition, serum IGF-1 levels have been correlated to both BMD and fracture risk. We previously identified a Quantitative Trait Locus (QTL) for Bone Mineral Density (BMD) on mouse Chromosome (Chr) 6 that overlaps a QTL for serum IGF-1. The B6.C3H-6T (6T) congenic mouse is homozygous for C57BL/6J (B6) alleles across the genome except for a 30 cM region on Chr 6 that is homozygous for C3H/HeJ (C3H) alleles. This mouse was created to study biology behind both the BMD and the serum IGF-1 QTLs and to identify the gene(s) underlying these QTLs. Female 6T mice have lower BMD and lower serum IGF-1 levels at all ages measured. As the liver is the major source of serum IGF-1, we examined differential expression in the livers of fasted female B6 and 6T mice by microarray.
Publication Title
A chromosomal inversion within a quantitative trait locus has a major effect on adipogenesis and osteoblastogenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
Description
There is massive destruction of transcripts during maturation of mouse oocytes. The objective of this project was to identify and characterize the transcripts that are degraded versus those that are stable during the transcriptionally silent germinal vesicle (GV)-stage to metaphase II (MII)-stage transition using the microarray approach. A system for oocyte transcript amplification using both internal and 3-poly(A) priming was utilized to minimize the impact of complex variations in transcript polyadenylation prevalent during this transition. Transcripts were identified and quantified using Affymetrix Mouse Genome 430 v2.0 GeneChip. The significantly changed and stable transcripts were analyzed using Ingenuity Pathways Analysis and GenMAPP/MAPPFinder to characterize the biological themes underlying global changes in oocyte transcripts during maturation. It was concluded that the destruction of transcripts during the GV to MII transition is a selective rather than promiscuous process in mouse oocytes. In general, transcripts involved in processes that are associated with meiotic arrest at the GV-stage and the progression of oocyte maturation, such as oxidative phosphorylation, energy production, and protein synthesis and metabolism, were dramatically degraded. In contrast, transcripts encoding participants in signaling pathways essential for maintaining the unique characteristics of the MII-arrested oocyte, such as those involved in protein kinase pathways, were the most prominent among those stables.
Publication Title
Selective degradation of transcripts during meiotic maturation of mouse oocytes.
Sample Metadata Fields
No sample metadata fields
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