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GSE40130
Homo sapiens
10 Downloadable Samples
Illumina HumanWG-6 v3.0 expression beadchip
Description
Elevated expression and activity of the epidermal growth factor receptor (EGFR)/protein kinase B (Akt) signaling pathway is associated with development, progression and treatment resistance of head and neck cancer (HNC). Several studies have demonstrated that microRNA-7 (miR-7) regulates EGFR expression and Akt activity in a range of cancer cell types via its specific interaction with the EGFR mRNA 3 untranslated region (3-UTR). In the present study, we found that miR-7 regulated EGFR expression and Akt activity in HNC cell lines, and that this was associated with reduced growth in vitro and in vivo of cells (HN5) that were sensitive to the EGFR tyrosine kinase inhibitor (TKI) erlotinib (Tarceva). miR-7 acted synergistically with erlotinib to inhibit growth of erlotinib-resistant FaDu cells, an effect associated with increased inhibition of Akt activity. Microarray analysis of HN5 and FaDu cell lines transfected with miR-7 identified a common set of downregulated miR-7 target genes, providing insight into the tumor suppressor function of miR-7. Furthermore, we identified several target miR-7 mRNAs with a putative role in the sensitization of FaDu cells to erlotinib. Together, these data support the coordinate regulation of Akt signaling by miR-7 in HNC cells and suggest the therapeutic potential of miR-7 alone or in combination with EGFR TKIs in this disease.
Publication Title
Regulation of epidermal growth factor receptor signaling and erlotinib sensitivity in head and neck cancer cells by miR-7.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 2 Downloadable Samples
Illumina HiSeq 2500
Description
Multiple signaling pathways, structural proteins and transcription factors are involved in regulation of endothelial barrier function. The Forkhead protein FOXF1 is a key transcriptional regulator of lung embryonic development, and we use a conditional knockout approach to examine the role of FOXF1 in adult lung homeostasis and lung injury and repair. Tamoxifen-regulated deletion of both Foxf1 alleles in endothelial cells of adult mice (Pdgfb-iCreER/Foxf1 caused lung inflammation and edema, leading to respiratory insuffency and uniform mortality. Deletion of a single foxf1 allele was sufficient to increase susceptibility of heterozygous mice to acute lung injury. FOXF1 abundance was decreased in pulmonary endothelial cells of human patients with acute lung injury. Gene expression analysis of pulmonary endothelial cells of FOXF1 deletion indicated reduced expression for genes critical for maintance and regulation of adherens junctions. FOXF1 knockdown in vitro and in vivo disrupted adherens junctions, increased lung endothelial permeability, and the abundance of mRNA and protein for sphingosine 1 phosphate receptor 1 (S1PR1), a key regulator of endothelial barrier function. Chromatin immunoprecipitation and luciferase reporter assay demonstrated that FOXF1 directly bound to and induced the tanscriptional activity of the S1pr1 promoter. Pharmacological administratiion of S1P to injured pdgfb-iCreER/Foxf1 mice restored endothelial barrier function, decreased lung edema and improved survival. Thus, FOXF1 promotes normal lung homeostasis and lung repair, at least in part, by enhancing endothelial barrier function through transcriptional activation of the S1P/S1PR1/ signaling pathway. Overall design: RNA was isolated and pooled from the lungs of multiple mice with either the Foxf1 floxed alleles alone or Pdgfb-iCreER Foxf1 floxed mice.
Publication Title
FOXF1 maintains endothelial barrier function and prevents edema after lung injury.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 2 Downloadable Samples
- Illumina HiSeq 2000
Description
Hepatic fibrosis is the common end stage to a variety of chronic liver injuries and is characterized by an excessive deposition of extracellular matrix (ECM), which disrupts the liver architecture and impairs liver function. The fibrous lesions are produced by myofibroblasts, which differentiate from hepatic stellate cells (HSC). The myofibroblasts transcriptional networks remain poorly characterized. Previous studies have shown that the Forkhead box F1 (FOXF1) transcription factor is expressed in HSCs and stimulates their activation during acute liver injury; however, the role of FOXF1 in the progression of hepatic fibrosis is unknown. In the present study, we generated aSMACreER;Foxf1fl/fl mice to conditionally inactivate Foxf1 in myofibroblasts during carbon tetrachloride-mediated liver fibrosis. Foxf1 deletion increased collagen depositions and disrupted liver architecture. Timp2 expression was significantly increased in Foxf1-deficient mice while MMP9 activity was reduced. RNA sequencing of purified liver myofibroblasts demonstrated that FOXF1 inhibits expression of pro-fibrotic genes, Col1a2, Col5a2, and Mmp2 in fibrotic livers and binds to active repressors located in promotors and introns of these genes. Overexpression of FOXF1 inhibits Col1a2, Col5a2, and MMP2 in primary murine HSCs in vitro. Altogether, FOXF1 prevents aberrant ECM depositions during hepatic fibrosis by repressing pro-fibrotic gene transcription in myofibroblasts and HSCs. Overall design: RNAseq on isolated hepatic stromal cells from Foxf1 fl/fl and aSMACreER;Foxf1 fl/fl mice after 5 weeks of carbon tetrachloride-induced liver injury.
Publication Title
The Forkhead box F1 transcription factor inhibits collagen deposition and accumulation of myofibroblasts during liver fibrosis.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 2 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Transcription factor FoxM1 is expressed in proliferating cells, and its expression is critical for cell proliferation in embryos and tumors. FoxM1 regulates a multi-gene transcriptional network for cell cycle regulation.
Publication Title
Forkhead box M1 transcriptional factor is required for smooth muscle cells during embryonic development of blood vessels and esophagus.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 6 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Despite inheritance of hypertension in families, identifying genetic mechanisms predisposing individuals to hypertension has remained challenging. The effects of single genes contributing to the development of hypertension may not be readily detected in individuals whose genomes also contain other genetic factors that resist hypertension. By using a highly permissive rat genome for inherited hypertension, we demonstrate that increased expression of one such gene, Rififylin (Rffl), is a novel inherited risk factor for hypertension and increased mortality. Animals overexpressing Rffl demonstrated delayed endocytic recycling, accumulated polyubiquitinated proteins, increased beats/min of neonatal cardiomyocytes, had shorter QT-intervals and developed salt-insensitive hypertension very early in their life (50-52 days). Thus, the discovery of a physiological link between overexpression of rififylin and the development of hypertension constitutes a novel mechanism that could be targeted for rectifying normal QT-interval and preventing hypertension.
Publication Title
Augmented rififylin is a risk factor linked to aberrant cardiomyocyte function, short-QT interval and hypertension.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 2000
Description
Purpose: The purpose of this study is to compare the transcriptome expression profiles of E13.5 Foxf2-/-;Osr2RFP/+ and control palatal mesenchyme by using RNA-seq analysis. Methods: Foxf2+/- female mice were crossed with Foxf2+/-;Osr2RFP/+ male mice.The embryos were harvested at E13.5. The pair of palatal shelves were dissected from each Osr2-RFP+ embryo. The RFP+ palatal mesenchyme cells were isolated by using fluorescence-activated cell sorting (FACS). RNA-seq analysis was carried out using the FACS-isolated palatal mesenchyme from Foxf2-/-;Osr2RFP/+, Foxf2+/-;Osr2RFP/+ and Osr2RFP/+embryos, respectively. Overall design: The transcriptome expression profiles of E13.5 control and Foxf2-/-Osr2RFP/+ palatal mesenchyme by using RNA-seq analysis, in duplicates, using Illumina HisEq 2000.
Publication Title
A Shh-Foxf-Fgf18-Shh Molecular Circuit Regulating Palate Development.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 50 Downloadable Samples
- Affymetrix Rat Clariom S Assay (clariomsrat), Illumina HiSeq 2000
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Time-course analysis of the effect of embedded metal on skeletal muscle gene expression.
Sample Metadata Fields
Sex, Specimen part, Treatment, Time
View Samples- Rattus norvegicus
- 50 Downloadable Samples
- Illumina HiSeq 2000, Affymetrix Rat Clariom S Assay (clariomsrat)
Description
As a consequence of military operations, many veterans suffer from penetrating wounds and long-term retention of military grade heavy metal fragments. Fragments vary in size and location, and complete surgical removal may not be feasible or beneficial in all cases. Increasing evidence suggests retention of heavy metal fragments may have serious biological implications, including increased risks for malignant transformation. Previous studies assessed the tumorigenic effects of metal alloys in rats, demonstrating combinations of metals are sufficient to induce tumor formation after prolonged retention in skeletal muscle tissue. In this study, we analyzed transcriptional changes in skeletal muscle tissue in response to eight different military-relevant pure metals over 12 months. We found that most transcriptional changes occur at 1 and 3 months after metal pellets are embedded in skeletal muscle and these effects resolve at 6 and 12 months. We also report significant immunogenic effects of nickel and cobalt and suppressive effects of lead and depleted uranium on gene expression. Overall, skeletal muscle exhibits a remarkable capacity to adapt to and recover from internalized metal fragments; however, the cellular response to chronic exposure may be restricted to the metal-tissue interface. This data suggests that unless affected regions are specifically captured by biopsy, it would be difficult to reliably detect changes in muscle gene expression that would be indicative of long-term adverse health outcomes.
Publication Title
Time-course analysis of the effect of embedded metal on skeletal muscle gene expression.
Sample Metadata Fields
Sex, Specimen part, Treatment, Time
View Samples- Caenorhabditis elegans
- 5 Downloadable Samples
- Illumina HiSeq 2000
Description
Germline nuclear RNAi in C. elegans is a transgenerational gene-silencing pathway that leads to the H3K9 trimethylation (H3K9me3) response and transcriptional repression of target genes. The H3K9me3 response induced either by exogenous dsRNA or endogenous siRNA (endo-siRNA) is highly specific to the target loci and transgenerationally heritable. Despite these features, the role of H3K9me3 in transcriptional repression and heritable gene silencing at native target genes has not been tested. To resolve this gap, we first determined that the combined activities of three H3K9 histone methyltransferases (HMTs), MET-2, SET-25, and SET-32, are responsible for virtually all of the detectable level of germline nuclear RNAi-dependent H3K9me3 at native genes, triggered either by exogenous dsRNA or endo-siRNAs. By performing RNA Polymerase II ChIP-seq and pre-mRNA-seq analyses, we found that the loss of the H3K9me3 response at germline nuclear RNAi targets in the met-2;set-25;set-32 mutant does not lead to any defect in transcriptional repression or heritable RNAi. Therefore, H3K9me3 is not required for exogenous dsRNA-induced heritable RNAi or the maintenance of endo siRNA-mediated transcriptional silencing in C. elegans germline. This study provides a unique paradigm in which transcriptional silencing and heterochromatin, triggered by the same upstream pathway, can be decoupled. Overall design: In this study we tested if RNAi-mediated H3K9me3 is required for the heritable RNAi and transcriptional silencing at native endogenous and exogenous RNAi targets. Using genetic approach we generated nearly completely deficient H3K9me3 worm strain (met-2;set-25;set-32). Using Pol II ChIP-seq, pre-mRNA-seq and mRNA-seq we validated transcriptional changes at the endogenous targets in the H3K9me3 deficient condition (met-2;set-25;set-32). We performed oma-1 dsRNA feeding and heritable RNAi experiment and using H3K9me3 ChIP-seq measured level of RNAi-triggered H3K9me3 contribution by set-32 or met-2;set-25 or met-2;set-25;set-32 HMTs at the oma-1 gene. Using oma-1 mRNA and pre-mRNA qRT-PCR we tested heritable RNAi effect at oma-1 genomic locus in these HMT mutants.
Publication Title
Decoupling the downstream effects of germline nuclear RNAi reveals that H3K9me3 is dispensable for heritable RNAi and the maintenance of endogenous siRNA-mediated transcriptional silencing in <i>Caenorhabditis elegans</i>.
Sample Metadata Fields
Subject
View Samples- Caenorhabditis elegans
- 46 Downloadable Samples
- Illumina HiSeq 2000
Description
Environmental stress-induced transgenerational epigenetic effects have been observed in various model organisms and human. The capacity and mechanism of such phenomena, particularly in animals, are poorly understood. In C. elegans, siRNA mediates transgenerational gene silencing through the germline nuclear RNAi pathway. At the organismal level, this pathway plays a transgenerational role in maintaining the germline immortality when C. elegans is under a mild heat stress. However, the underlying molecular mechanism is unknown. In this study, we performed a 12-generation temperature-shift experiment (15°C->23°C->15°C) using the wild type (N2) and a mutant strain that lacks the germline-specific nuclear AGO protein HRDE-1/WAGO-9. We found that the temperature-sensitive mortal germline (Mrt) phenotype of the hrde-1 mutant is reversible, indicating a transgenerational cumulative but also reversible nature of the underlying molecular cause. By taking the whole-genome RNA and chromatin profiling approaches, we revealed an epigenetic role of HRDE-1 in repressing heat stress-induced transcriptional activation of over 280 genes, predominantly in or near LTR retrotransposons. Strikingly, for some of these elements, the heat stress-induced transcription becomes progressively activated in the hrde-1 mutant over several generations under heat stress. Furthermore, the effect of heat stress-induced transcription activation is heritable for at least two generations after the heat stress. Interestingly, the siRNA expression of these genes tend to be heat-inducible in the wild type animals, but not in the hrde-1 mutant, suggesting a role of siRNAs in repressing heat-inducible elements. Our study revealed a novel phenomenon of transgenerational feed-forward transcriptional activation, which is normally repressed in the wild type C. elegans by the germline nuclear RNAi pathway. It also provides a new paradigm to study epigenetic circuitry that connects the environment and gene regulation in the germline. Overall design: In this study, we performed a 12-generation temperature-shift experiment (15°C->23°C->15°C) using the wild type and hrde-1 mutant. mRNA-seq, Pol II ChIP-seq, H3K9me3 ChIP-seq, and small RNA-seq analyses were performed for all or some of the generations. The effects of temperature change in whole-genome mRNA expression, siRNA expression, gene transcription, and H3K9me3 were investigated at the multigenerational time scale in both the WT and hrde-1 mutant animals.
Publication Title
A transgenerational role of the germline nuclear RNAi pathway in repressing heat stress-induced transcriptional activation in C. elegans.
Sample Metadata Fields
Subject
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