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GSE46532
Mus musculus
18 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Wnt signaling is intrinsic to mouse embryonic stem cell self-renewal. Therefore it is surprising that reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is not strongly enhanced by Wnt signaling. Here, we demonstrate that active Wnt signaling inhibits the early stage of reprogramming to iPSCs, while it is required and even stimulating during the late stage. Mechanistically, this biphasic effect of Wnt signaling is accompanied by a change in the requirement of all four of its transcriptional effectors: Tcf1, Lef1, Tcf3, and Tcf4. For example, Tcf3 and Tcf4 are stimulatory early but inhibitory late in the reprogramming process. Accordingly, ectopic expression of Tcf3 early in reprogramming combined with its loss-of-function late enables efficient reprogramming in the absence of ectopic Sox2. Together, our data indicate that the step-wise process of reprogramming to iPSCs is critically dependent on the stage-specific control and action of all four Tcfs and Wnt signaling.
Publication Title
Stage-specific regulation of reprogramming to induced pluripotent stem cells by Wnt signaling and T cell factor proteins.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The observation that Tcf3 (MGI name: Tcf7l1) bound the same genes as core stem cell transcription factors, Oct4 (MGI name:Pou5f1), Sox2 and Nanog, revealed a potentially important aspect of the poorly understood mechanism whereby Wnts stimulate self renewal of pluripotent mouse embryonic stem (ES) cells. Although the conventional view of Tcf proteins as the -catenin-binding effectors of Wnt signaling suggested Tcf3 should activate target genes in response to Wnts, here we show that Wnt3a and Tcf3 effectively antagonize each others effects on gene expression. Genetic ablation of Tcf3 caused similar effects as treating cells with recombinant Wnt3a.
Publication Title
Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal.
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Metabolically active cells require robust mechanisms to combat oxidative stress. The cytoplasmic thioredoxin reductase/thioredoxin (Txnrd1/Txn1) system maintains reduced protein dithiols and provides electrons to some cellular reductases, including peroxiredoxins.
Publication Title
Cytoprotective Nrf2 pathway is induced in chronically txnrd 1-deficient hepatocytes.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Great interest has been shown in understanding the pathology of Gaucher disease (GD) due to the recently-discovered genetic relationship with Parkinsons disease. For such studies, suitable animal models of GD are required. Chemical induction of GD by inhibition of acid -glucosidase (GCase) using the irreversible inhibitor, conduritol-B-epoxide (CBE), is particularly attractive, although few systematic studies examining the effect of CBE on development of symptoms associated with neurological forms of GD have been performed. We now demonstrate a correlation between the amount of CBE injected into mice and levels of accumulation of the GD substrates, glucosylceramide and glucosylsphingosine, and show that disease pathology, indicated by altered levels of pathological markers, depends on the dose of CBE and its time of injection. Gene array analysis shows a remarkable similarly in the gene expression profile of CBE-treated mice and a genetic GD mouse model, the Gbaflox/flox;nestin-Cre mouse, with 120 of the 144 genes up-regulated in CBE-treated mice also up regulated in Gbaflox/flox;nestin-Cre mice. Finally, we demonstrate that some aspects neuropathology and some behavioral abnormalities can be arrested upon cessation of CBE treatment during a specific time window. Together, our data demonstrate that injection of mice with CBE provides a rapid and relatively easy way to induce symptoms typical of neuronal forms of GD, which will prove particularly useful when examining the role of specific biochemical pathways in GD pathology, since CBE can be injected into mice defective in components of putative pathological pathways, alleviating the need for time consuming crossing of mice.
Publication Title
Identification of Modifier Genes in a Mouse Model of Gaucher Disease.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
We used microarray analysis to profile the function of TCF7L1 in human embryonic stem cells.
Publication Title
TCF7L1 suppresses primitive streak gene expression to support human embryonic stem cell pluripotency.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
We used microarray analysis to profile the function of TCF7L1 in human embryonic stem cells.
Publication Title
TCF7L1 suppresses primitive streak gene expression to support human embryonic stem cell pluripotency.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Rattus norvegicus
- 6 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs).
Publication Title
Inhibitory role of Notch1 in calcific aortic valve disease.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U95 Version 2 Array (hgu95av2)
Description
OBJECTIVE: Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate.
Publication Title
Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation.
Sample Metadata Fields
Sex, Age, Disease
View Samples- Mus musculus
- 12 Downloadable Samples
NextSeq 500
Description
The role of sphingolipids (SLs) in the immune system has come under increasing scrutiny recently due to the emerging contributions that these important membrane components play in regulating a variety of immunological processes. The acyl chain length of SLs appears particularly critical in determining SL function. Here we show a role for very-long acyl chain SLs (VLC-SLs) in invariant natural killer T (iNKT) cell maturation in the thymus and homeostasis in the liver. Ceramide synthase 2 (CerS2) null mice, which lack VLC-SLs, were susceptible to a hepatotropic strain of lymphocytic choriomeningitis virus, which is due to a reduction in the number of iNKT cells. Bone marrow chimera experiments indicated that hematopoietic-derived VLC-SLs are essential for maturation of iNKT cells in the thymus, whereas parenchymal-derived VLC-SLs are crucial for iNKT cell survival and maintenance in the liver. Our findings suggest a critical role for VLC-SL in iNKT cell physiology. Overall design: Liver mRNA profiles of 3-4 month old wild type (WT), WT iNKT cell transfered and CerS2-/-mice, infected or not with LCMV were generated by deep sequencing. Several replicateswere included and pocessed using the MARS-seq protocol (Jaitin et al. 2014 Science.343:776-9) and sequencing in the Illumina NextSeq 500 instrument
Publication Title
Critical Role for Very-Long Chain Sphingolipids in Invariant Natural Killer T Cell Development and Homeostasis.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 1820 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
Objective: Systemic lupus erythematosus (SLE) has substantial unmet medical need and its pathogenesis is incompletely understood. This study characterized baseline gene expression and pharmacodynamic (PD)-induced changes in whole blood gene expression from two phase III, 52-week (W), randomized, placebo-controlled, double-blind studies of 1,760 SLE patients treated with the B cell activating factor (BAFF)-blocking IgG4 monoclonal antibody, tabalumab. Methods: Patient samples were obtained from ILLUMINATE-1 and -2 while control samples were from healthy donors. Blood was collected in TempusTM tubes at baseline, W16 and W52. RNA was analyzed using the Affymetrix Human Transcriptome Array 2.0 and NanoStringTM. Results: At baseline there was elevation of interferon responsive genes (IRG) in patients compared to controls, with 75% positive for this IRG signature. There was, however, substantial heterogeneity of IRG expression and complex relationships among gene networks. The interferon signature was a predictor of future time to flare, independent of anti-double stranded DNA antibody (dsDNA), C3 and C4 levels, and overall disease activity. PD changes in gene expression following tabalumab treatment were extensive, occurring predominantly in B cell-related and immunoglobulin (Ig) genes, and were consistent with other PD-induced changes including dsDNA, C3, and Ig levels. Conclusions: SLE patients demonstrated elevated expression of an IRG signature, detected in 75% of the patients at baseline in ILLUMINATE-1 and -2. There was substantial heterogeneity of gene expression detected among individual patients and in gene networks. The interferon signature was an independent risk factor for future flares. PD changes in gene expression were consistent with the mechanism of BAFF blockade by tabalumab.
Publication Title
Gene Expression and Pharmacodynamic Changes in 1,760 Systemic Lupus Erythematosus Patients From Two Phase III Trials of BAFF Blockade With Tabalumab.
Sample Metadata Fields
Sex, Specimen part, Race, Subject, Time
View Samples