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GSE10192
Mus musculus
24 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
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
PPARgamma2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells.
Sample Metadata Fields
Compound, Time
View Samples- Rattus norvegicus
- 12 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Appropriate nutrition during early development is essential for optimal bone mass accretion; however, linkage between early nutrition, childhood bone mass and prevention of bone loss later in life has not been extensively studied. In this report, we have demonstrated several fundamental issues in the field. 1) A significant prevention of ovariectomy (OVX) -induced bone loss from adult rats can occur with only 14 days consumption of a blueberry-containing diet immediately prior to puberty. 2) The molecular mechanisms underlying these effects involve increased myosin production and preserved a shuttle for transcription factors such as Runx2 from cytoplasm to nucleolus which stimulates osteoblast differentiation and reduces mesenchymal stromal cell senescence. 3) The effects of blueberry diet on preserving fidelity of osteoblast differentiation also overcome reduced osteoblast differentiation and activity due to OVX-induced degradation of collagen matrix.
Publication Title
Feeding blueberry diets in early life prevent senescence of osteoblasts and bone loss in ovariectomized adult female rats.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 11 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Substantial evidence implicates IGF-I signaling in the development and progression of breast cancer. To identify transcriptional targets of IGF action in breast cancer cells, we performed gene expression profiling (>22,000 RNA transcripts) of IGF-I-stimulated MCF-7 cells, a well characterized breast cancer cell line that is highly responsive to IGFs. We defined an IGF-I gene signature pattern of hundreds of genes either up-regulated or down-regulated at both 3 and 24 hrs in vitro. After removing genes considered generic to cell proliferation, the signature was examined in four different public profile datasets of clinical breast tumors (representing close to 1000 patients), as well as in profile datasets of experimental models for various oncogenic signaling pathways. Genes with early and sustained regulation by IGF-I were highly enriched for transcriptional targets of the estrogen, Ras, and PI3K/Akt/mTOR pathways. The IGF-I signature appeared activated in most estrogen receptor-negative (ER-) clinical breast tumors and in a substantial subset (~25%) of ER+ breast tumors. Patients with tumors showing activation of the IGF-I signature tended to have a shorter time to disease recurrence (including patients not receiving adjuvant therapy), both when considering all patients and the subset of ER+ patients. We found evidence for cross-talk and common transcriptional endpoints between the IGF-I and estrogen systems. Our results support the idea that the IGF-I pathway is one mechanism by which breast tumors may acquire hormone independence and a more aggressive phenotype.
Publication Title
Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
Illumina HiSeq 2000
Description
Blockades in hematopoiesis deprive the host of vital blood cells and frequently cause leukemia. Here we show that inactivation of mTORC1 in hematopoietic stem cells by deletion of Raptor unmasked a cell type, hereby called myelolymphoblastic innate cell (MLIC) based on unique gene expression signature, cell surface markers, morphology and functions. The MLICs are CD11b(+)Gr-1(-)B7-H1(high)F4/80(low) and have morphology of lymphoblasts with active Ig loci but no gene rearrangement. Within weeks of Raptor deletion, the MLICs account for nearly 50% of bone marrow cells and are found throughout both the lymphoid and non-lymphoid organs. Nevertheless, the MLICs are not malignant as they undergo very limited proliferation in vivo. Importantly, the MLICs broadly express pattern-recognition receptors and produce large amounts of inflammatory cytokines in response to all TLR ligands tested, rendering the host highly susceptible to pathogen-associated molecular patterns. Our data suggest that hematopoietic cell-intrinsic mTORC1 prevents development of self-destructive innate immune attack by suppressing generation of MLICs. Overall design: Raptor F/F mice were crossed with Mx1-Cre mice for more than 2 generations to get Raptor F/F (Ctrl) and Raptor F/F, Mx1-Cre (cKO) mice. Sex-matched 6-8 weeks old Ctrl mice and cKO mice were treated with polyinosinic: polycytidylic acid (pIpC) every other day for consecutive 7 times by intra-peritoneal (i.p.) injection to induce Cre expression and Raptor deletion in mouse hematopoietic system. Raptor mice were sacrificed 2-3 weeks after the last injection of pIpC. Whole BM cells from Raptor Ctrl mice (n=3) and FACS-sorted CD11b(+)Gr-1(-) BM MLICs from Raptor cKO mice (n=3) were used for RNA isolation and subsequent cDNA libraries construction. mRNA profiles of Ctrl-WBM and cKO-MLIC were examined by RNA-sequencing, in triplicate, using Illumina HiSeq 2000.
Publication Title
A population of innate myelolymphoblastoid effector cell expanded by inactivation of mTOR complex 1 in mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 17 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Although estrogen receptor (ER) and insulin-like growth factor (IGF) signaling are important for normal mammary development and breast cancer, cross-talk between these pathways, particularly at the level of gene transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3hr or 24hr. IGF-I regulated mRNA of 5-10-fold more genes than estradiol, and many genes were co-regulated by both ligands. Importantly, expression of these co-regulated genes correlated with poor prognosis of human breast cancer. Closer examination revealed enrichment of repressed transcripts. Interestingly, a number of potential tumor suppressors were down-regulated by IGF-I and estradiol. In fact, BLNK, one of the top repressed genes, is a potential growth suppressor in breast cancer cells. Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ER. However, repression by IGF-I or estradiol required common downstream kinases. In conclusion, E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. There is enrichment of repressed transcripts, and the down-regulation is independent at the receptor level. This may be important clinically, as tumors with active ER and IGF-IR signaling may require co-targeting of both pathways.
Publication Title
Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth.
Sample Metadata Fields
Cell line, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Histone deacetylase 3 (HDAC3) is an epigenome-modifying enzyme that is required for normal mouse development and tissue-specific functions. In vitro, HDAC3 protein itself has minimal enzyme activity, but gains its histone deacetylation function from stable association with the conserved deacetylase activation domain (DAD) contained in nuclear receptor corepressors NCOR1 and SMRT. Here we show that HDAC3 enzyme activity is undetectable in mice bearing point mutations in the DAD of both NCOR1 and SMRT (NS-DADm), despite normal levels of HDAC3 protein. Local histone acetylation is increased, and genomic HDAC3 recruitment is reduced though not abrogated. Remarkably, the NS-DADm mice are born and live to adulthood, whereas genetic deletion of HDAC3 is embryonic lethal. These findings demonstrate that nuclear receptor corepressors are required for HDAC3 enzyme activity in vivo, and suggest that a deacetylase-independent function of HDAC3 may be required for life.
Publication Title
Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
We report the hepatic gene expression changes in NCOR and SMRT DADm-mutated mice.
Publication Title
Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo.
Sample Metadata Fields
Specimen part, Time
View Samples- Drosophila melanogaster
- 8 Downloadable Samples
- Affymetrix Drosophila Genome Array (drosgenome1)
Description
THO2 and HPR1 proteins were co-depleted from Drosophila S2 cells and their role in mRNA export analysed by comparing total RNA and cytoplasmic RNA
Publication Title
The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
The molecular mechanism of how lung sacculation occurs is poorly understood. Loss of epithelial Hdac3 results in defects in the proper expansion of distal lung saccules into primitive alveoli. In this microarray, we seek to investigate the gene profile changes caused by loss of Hdac3 to better understand the molecular pathways that are regulated by Hdac3 during lung sacculation.
Publication Title
HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-β Signaling Regulation.
Sample Metadata Fields
Specimen part
View Samples