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GSE19793
Mus musculus
31 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Inflammation has pleiotropic effects on carcinogenesis and tumor progression. Signaling through the adaptor protein MyD88 promotes carcinogenesis in several chemically induced cancer models. Interestingly, we observed a protective role for MyD88 in the development of AOM/DSS colitis-associated cancer. The inability of Myd88-/- mice to heal ulcers generated upon injury creates an inflammatory environment that increases the frequency of mutations and results in a dramatic increase in adenoma formation and cancer progression. Susceptibility to colitis development and enhanced polyp formation were also observed in Il18-/- mice upon AOM/DSS treatment, suggesting that the phenotype of MyD88 knockouts is in part due to their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that differentially impact tissue homeostasis and carcinogenesis.
Publication Title
MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Drosophila melanogaster
- 28 Downloadable Samples
Illumina HiSeq 2000, Illumina HiSeq 2500
Description
Muscles organise a pseudo-crystalline array of actin, myosin and titin filaments to build force-producing sarcomeres. To study how sarcomeres are built, we performed mRNA-sequencing of developing Drosophila flight muscles and identified 40 distinct expression profile clusters. Strikingly, two clusters are strongly enriched for sarcomeric components. Temporal gene expression together with detailed morphological analysis enabled us to define two distinct phases of sarcomere development, both of which require the transcriptional regulator Spalt major. During the first sarcomere formation phase, 2.0 µm long immature sarcomeres assemble myofibrils that spontaneously contract. In the second sarcomere maturation phase, sarcomeres grow to their final 3.2 µm length and 1.5 µm diameter and acquire stretch-sensitivity. Interestingly, the final number of myofibrils per flight muscle fiber is determined at the onset of the first phase and remains constant. Together, this defines a biphasic mode of sarcomere and myofibril morphogenesis – a new concept which may also apply to vertebrate muscle or heart development. Overall design: Part I: An 8-point timecourse of wild-type flight muscle development in Drosophila melanogaster was analyzed with duplicates/triplicates for each timepoint Part II: A Mef2-Gal4 x salmIR timecourse in duplicate at 4 timepoints was compared to wild-type flight muscle
Publication Title
A transcriptomics resource reveals a transcriptional transition during ordered sarcomere morphogenesis in flight muscle.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 23 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Caspases, proteolytic enzymes involved in cell death could play a role independent of cell death in the developing heart
Publication Title
Executioner Caspase-3 and 7 Deficiency Reduces Myocyte Number in the Developing Mouse Heart.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina Genome Analyzer
Description
Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, resulting in the death of 200-300 children each year in the United States. Recently it was discovered that approximately 25% of all DIPG cases harbor activating mutations in ACVR1, a gene that encodes Activin A receptor (ALK2), a receptor in the bone morphogenetic protein (BMP) pathway, and that DIPGs with ALK2 mutations commonly harbor an H3.1K27M mutation. Herein, we used the RCAS/TVA retroviral system to study the effects of ACVR1 mutations and H3.1K27M on DIPG pathogenesis. In vitro expression of R206H ACVR1 with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and gene set enrichment analysis (GSEA) revealed Stat3 pathway activation. Neonatal expression of ACVR1 R206H or G328V in combination with H3.1K27M and p53 deletion in nestin-expressing brainstem progenitors induced glioma-like lesions expressing mesenchymal markers with Stat3 activation but was not sufficient for full gliomagenesis. In combination with platelet-derived growth factor A (PDGFA) signaling, ACVR1 R206H and H3.1K27M significantly decreased survival and increased tumor incidence. We demonstrate that targeting the BMP signaling pathway may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs. Exogenous Noggin expression at tumor initiation significantly increased tumor latency and treatment of ACVR1 R206H mutant murine DIPGs with LDN212854, an ACVR1 inhibitor, significantly prolonged their survival. We confirm relevance of our model to the human disease as human DIPG models with ACVR1 mutations were also sensitive to treatment with LDN212854 in vitro. Altogether, our studies demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile in part due to Stat3 activation, and identify LDN212854 as a promising compound to treat children with DIPG. Overall design: We use RNAseq to study the transcriptomal effects of ACVR1 WT or R206H ACVR1 mutation alone and in combination with H3.1K27M mutation on murine nestin-expressing brainstem progenitors at P3-5 (using RCAS/TVA). Key findings were validated by Real-Time PCR.
Publication Title
ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates and redox potential required for the generation of biomass. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. SIRT3 loss promotes a metabolic profile consistent with high glycolysis required for anabolic processes in vivo and in vitro. Mechanistically, SIRT3 mediates metabolic reprogramming independently of mitochondrial oxidative metabolism and through HIF1a, a transcription factor that controls expression of key glycolytic enzymes. SIRT3 loss increases reactive oxygen species production, resulting in enhanced HIF1a stabilization. Strikingly, SIRT3 is deleted in 40% of human breast cancers, and its loss correlates with the upregulation of HIF1a target genes. Finally, we find that SIRT3 overexpression directly represses the Warburg effect in breast cancer cells. In sum, we identify SIRT3 as a regulator of HIF1a and a suppressor of the Warburg effect.
Publication Title
SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization.
Sample Metadata Fields
Specimen part
View Samples- Sus scrofa
- 9 Downloadable Samples
- Porcine Gene 1.0 ST Array (porgene10st)
Description
Microarray analysis was used to compare the transcriptome of esophageal submucosal gland (ESMG) derived spheroids in culture relative to squamous epithelium and fresh ESMGs.
Publication Title
Porcine Esophageal Submucosal Gland Culture Model Shows Capacity for Proliferation and Differentiation.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
TGF is one of most intensively studied regulators of extracellular matrix formation, and has been implicated in the development of pulmonary fibrosis in different models. However, little is know about the role of miRNAs in TGF mediated fibrogenic gene regulation. By using miRNA qRT-PCR array, we have identified miRNAs whose expression are regulated by TGF in IMR-90 cells. Among those down-regulated miRNAs are miR-29 family members. Knockdown miR-29 in IMR-90 cells results in up-regulation of a large number of extracellular matrix and fibrogenic genes including family members of collagen, laminin, integrin, ADAM and MMP, many of them are predicted or confirmed miR-29 targets. Hierarchichal clustering analysis of mRNA array data revealed that many extracellular matrix and fibrogenic genes up-regulated by TGF in IMR-90 cells, are also up-regulated in miR-29 KD cells. Moreover, the similar set of extracellular matrix and fibrogenic genes is also significantly up-regulated in bleomycin treated mouse lungs. Together, our data strongly suggest that downstream of the TGF, miR-29 is a master modulator of genes involved in extracellular matrix formation and might play a significant role in pulmonary fibrosis.
Publication Title
miR-29 is a major regulator of genes associated with pulmonary fibrosis.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
GW182 (Tnrc6a) is a key component of RISC (miRNA-Induced Silencing Complex) that plays a critical role in miRNA-mediated gene silencing. Here, we show that GW182 is expressed in the yolk sac endoderm, and that gene-trap disruption of GW182 leads to growth arrest of yolk sac endoderm, impaired hematopoiesis and embryonic lethality.
Publication Title
Trinucleotide repeat containing 6a (Tnrc6a)-mediated microRNA function is required for development of yolk sac endoderm.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- NextSeq 500
Description
Monocytes are derived from hematopoietic stem cells through a series of intermediate progenitor stages, but the factors that regulate this process are incompletely defined. Using a Ccr2/Cx3cr1 dual-reporter system to model murine monocyte ontogeny, we conducted a small molecule screen that identified an essential role of mechanistic target of rapamycin complex 1 (mTORC1) in the development of monocytes and other myeloid cells. Overall design: Examination of gene expression in 1) Granulocyte-Monocyte Progenitors from Raptor KO mice, Tsc2 KO mice and controls; and 2) DR-ER-Hoxb8 cells differentiated in the presence of DMSO, rapamycin or SL0101-01
Publication Title
The metabolic regulator mTORC1 controls terminal myeloid differentiation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Multiciliated cells are crucial for fluid and ion transport in epithelia of a variety of organs and their impaired development and function are seen in human diseases affecting the brain, respiratory, and reproductive tracts. Multiciliogenesis requires activation of a specialized transcription program coupled to complex cytoplasmic events that lead to large-scale centriole amplification to generate multicilia. Yet, it remains unclear how these events are coordinated to initiate multiciliogenesis in epithelial progenitors. Here we identify an unsuspected mechanism orchestrated by the transcription factor E2f4 essential to integrate these processes. We show that after inducing a transcriptional program of centriole biogenesis, E2f4 translocates to the cytoplasm to become a core component of structures classically identified as fibrous granules (FG), acting as organizing centers for deuterosome assembly and centriole amplification. Remarkably, loss of cytoplasmic E2f4 prevents FG aggregation, deuterosome assembly and multicilia formation even when E2f4s transcriptional function is preserved. Moreover, in E2f4-deficient cells multiciliogenesis is rescued only if both nuclear and cytoplasmic E2f4 activities are restored. Thus, E2f4 integrates previously unrelated nuclear and cytoplasmic events of the multiciliated cell program.
Publication Title
Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis.
Sample Metadata Fields
Specimen part
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