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GSE18281
Mus musculus
33 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Interaction of hematopoietic progenitors with the thymic stromal microenvironment induces them to proliferate, adopt the T cell fate, and asymmetrically diverge into multiple T lineages. Progenitors at various developmental stages are stratified among different regions of the thymus, implying that the corresponding microenvironments differ from one another, and provide unique sets of signals to progenitors migrating between them. The nature of these differences remains undefined. Here we use novel physical and computational approaches to characterize these stromal subregions, distinguishing gene expression in microdissected tissues from that of their lymphoid constituents. Using this approach, we comprehensively map gene expression in functionally distinct stromal microenvironments, and identify clusters of genes that define each region. Quite unexpectedly, we find that the central cortex lacks distinctive features of its own, and instead appears to function by sequestering unique microenvironments found at the cortical extremities, and modulating the relative proximity of progenitors moving between them.
Publication Title
Spatial mapping of thymic stromal microenvironments reveals unique features influencing T lymphoid differentiation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 37 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Austism spectrum disorder (ASD) is a heterogeneous behavioral disease most commonly characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a common clinical outcome. Transcript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA/lentivirus constructs. Whole genome expression analysis was conducted for each of the knock-down cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing luciferase. Gene set enrichment and a causal reasoning engine were employed to indentify pathway level perturbations generated by the transcript knock-down. Quantitation of the shRNA targets confirmed the successful knock-down at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by transfection and viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity. This work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the broadest efficacy across the diverse population of autism patients.
Publication Title
Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 82 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The role of hypoxia in 2-butoxyethanol-induced hemangiosarcoma.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Mus musculus
- 59 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Mice were treated with either 100mg/kg baclofen or 0.5% methylcellulose alone by oral gavage for 1 or 5 days.
Publication Title
The role of hypoxia in 2-butoxyethanol-induced hemangiosarcoma.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Mus musculus
- 44 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Mice were dosed with 2-BE (900mg/kg) or vehicle by oral gavage and sacrificied either after 4 hours of a single dose or after 7 days of daily dosing.
Publication Title
The role of hypoxia in 2-butoxyethanol-induced hemangiosarcoma.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples- Mus musculus
- 189 Downloadable Samples
Illumina HiSeq 3000
Description
The weekly turnover of the intestinal epithelium is driven by multipotent, Lgr5+, crypt base columnar cells (CBCs). In response to injury, however, Lgr5+ cells are lost but then re-emerge and are required for successful recovery. How these resurgent Lgr5+ stem cells arise is unclear. We transcriptionally profiled single cells from regenerating intestinal epithelia and identified a unique cell type we term the revival stem cell (rSC). rSCs are mutually exclusive to CBCs and are distinguished by elevated expression of cell survival and DNA repair genes. In homeostasis, rSCs are extremely rare, but nevertheless give rise to all the major cell types of the intestine including crypt-villus axes. After damage rSCs display a 20-fold, Yap-dependent, transient expansion, reconstitute the Lgr5+ CBC compartment and are required to regenerate a functional intestine. These studies define a unique stem cell phenotype that is mobilized by damage to reconstitute the intestinal epithelium. Overall design: Examination of regenerating mouse intestinal epithelium.
Publication Title
Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 32 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies. We used gene expression data derived from a genetically defined model of Ewing sarcoma to interrogate the Connectivity Map and identify a class of drugs, iron chelators, that downregulate a significant number of EWS-FLI1 target genes. We then identified ribonucleotide reductase M2 (RRM2), the iron-dependent subunit of ribonucleotide reductase (RNR), as one mediator of iron chelator toxicity in Ewing sarcoma cells. Inhibition of RNR in Ewing sarcoma cells led to apoptosis and cell death in vitro and attenuated tumor growth in vivo in a xenograft model. Additionally, we discovered that the sensitivity of Ewing sarcoma cells to inhibition or suppression of RNR is mediated, in part, by high levels of SLFN11, a protein that sensitizes cells to DNA damage. This work demonstrates a unique dependency of Ewing sarcoma cells on RNR and supports further exploration of clinically used inhibitors of RNR as a therapeutic approach in treating this cancer.
Publication Title
Gene expression signature based screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Saccharomyces cerevisiae
- 6 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
Experiments performed over the past three decades have shown that nucleosomes are transcriptional repressors. In Saccharomyces cerevisiae, depletion of histone H4 results in the genome-wide transcriptional de-repression of hundreds genes. The mechanism of de-repression is hypothesized to be rooted directly in chromatin changes. To test this, we reproduced classical H4 depletion experiments by conditional repression of all histone H3 transcription, which depletes the supply of nucleosomes in vivo. RNA-seq results were consistent with the earlier studies, but much more sensitive, revealing nearly 2500 de-repressed genes. Changes in chromatin organization were determined by MNase-seq. Nucleosomes that were preferentially retained occurred in regions of high DNA-encoded nucleosome affinity, and were marked with H3K36me2, which is linked to transcription elongation. Nucleosomes harboring acetyl marks or that contained the variant histone H2A.z were preferentially lost. Genes that were de-repressed lost or rearranged nucleosomes at their promoter, but not in the gene body. Therefore, a combination of DNA-encoded nucleosome stability and nucleosome composition dictates which nucleosomes will be lost under conditions of limiting histone protein. This, in turn, governs which genes will experience a loss of regulatory fidelity. Overall design: MNase-seq experiments consist of three wildtype (1 single-end and 2 paired-end) and four mutant (DCB200.1/H3 shutoff; 2 single-end, 2 paired-end) replicates. Each replicate contains two timepoints reflecting chromatin immediately after ("O hours") and 3 hours after transition to media containing dextrose. RNA-seq data includes three replicates from wildtype or H3 depleted cells after 3 hours in media containing dextrose.
Publication Title
In vivo effects of histone H3 depletion on nucleosome occupancy and position in Saccharomyces cerevisiae.
Sample Metadata Fields
Cell line, Subject, Time
View Samples- Mus musculus
- 3 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Huntington disease (HD) is associated with increased nuclear accumulation of the repressor element-1 silencing transcription factor (REST) which govens a huge gene network. An alternative REST splicing event (E3) eliminates a motif essential for nuclear targeting of REST.
Publication Title
Modulation of nuclear REST by alternative splicing: a potential therapeutic target for Huntington's disease.
Sample Metadata Fields
Cell line, Treatment
View Samples- Rattus norvegicus
- 51 Downloadable Samples
- Affymetrix Rat Gene 1.0 ST Array (ragene10st)
Description
Mechanical overload in the heart induces pathological remodeling that typcially leads to heart failure. We sought to build an in vitro model of heart failure by applying cyclic stretch to engineered isotropic (iso) and anisotropic (aniso) NRVM tissues.
Publication Title
Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip.
Sample Metadata Fields
Specimen part
View Samples