E-cadherin downregulation in cancer cells is associated with epithelial-to-mesenchymal transition (EMT) and metastatic prowess, but the underlying mechanisms are incompletely characterized. In this study, we probed E-cadherin expression at the plasma membrane as a functional assay to identify genes involved in E-cadherin downregulation. The assay was based on the E-cadherin-dependent invasion properties of the intracellular pathogen Listeria monocytogenes. On the basis of a functional readout, automated microscopy and computer-assisted image analysis were used to screen siRNAs targeting 7,000 human genes. The validity of the screen was supported by its definion of several known regulators of E-cadherin expression, including ZEB1, HDAC1 and MMP14. We identified three new regulators (FLASH, CASP7 and PCGF1), the silencing of which was sufficient to restore high levels of E-cadherin transcription. Additionally, we identified two new regulators (FBXL5 and CAV2), the silencing of which
Novel strategies to enforce an epithelial phenotype in mesenchymal cells.
Age, Specimen part, Cell line, Treatment
View SamplesWe hypothesize that the observed differences in incidences of pleural and peritoneal malignant mesothelioma (MM) are the result of differences in the direct response of these cell types to asbestos rather than to differences mediated by the in vivo microenvironment. To test this hypothesis, we characterized cellular responses to asbestos in a controlled environment using high-throughput RNA sequence and other assays. Overall design: Examination of asbestos-treated versus untreated mesothelial cells from four cell lines representing two tissue types in culture.
Differential Susceptibility of Human Pleural and Peritoneal Mesothelial Cells to Asbestos Exposure.
No sample metadata fields
View SamplesInterleukin (IL)-17 plays an important and protective role in host defence and has been demonstrated to orchestrate airway inflammation by cooperating with and inducing proinflammatory cytokines. Mircoarrays were used to identify immediate-early/ primary response IL-17A-dependent gene transcripts in primary human bronchial ASM cells from mild asthmatic and healthy individuals.
IL-17A mediates a selective gene expression profile in asthmatic human airway smooth muscle cells.
Sex, Age, Specimen part, Treatment, Subject, Time
View SamplesKLF7 null mice show profound axonal growth defects in the olfactory epithelium. The goal of this study was the identification of potential KLF7 target genes in olfactory sensory neurons.
Identification of genes regulated by transcription factor KLF7 in differentiating olfactory sensory neurons.
No sample metadata fields
View SamplesObjective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38 signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38 in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38-controlled transcripts comprising female- and male-specific gene modules, with greater p38 dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38 in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS
Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells.
Sex, Specimen part
View SamplesGene expression microarrays were used to compare gene alterations induced by exposure to equitoxic doses of crocidolite asbestos and cristobalite silica in an isolate of normal human bronchial epithelial cells.
Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells.
Specimen part
View SamplesWe report the application of high-throughput RNA sequencing to the human prefrontal cortex. The brain dataset was obtained by sequencing total RNAs extracted from the dorsolateral prefrontal cortex of five deceased human patients with no apparent pathology, followed by depletion of ribosomal RNA to obtain all non-rRNA coding and non-coding RNAs in the human brain transcriptome. Overall design: Five samples were sequenced, four coming from frozen brain tissue (frontal cortex) of deceased female human patients with no remarkable pathology, and one from a male patient with no remarkable pathology.
HAMR: high-throughput annotation of modified ribonucleotides.
Sex, Specimen part, Subject
View SamplesThe surprising observation that virtually the entire human genome is transcribed means we know very little about the function of many emerging classes of RNAs, except their astounding diversity. Traditional RNA function prediction methods rely on sequence or alignment information, which are limited in their ability to classify classes of non-coding RNAs (ncRNAs). To address this, we developed CoRAL, a machine learning-based approach for classification of RNA molecules. CoRAL uses biologically interpretable features including fragment length, cleavage specificity, and antisense transcription to distinguish between different ncRNA classes. We evaluated CoRAL using genome-wide small RNA sequencing (smRNA-seq) datasets from two human tissue types (brain and skin [GSE31037]), and were able to classify six different types of RNA transcripts with 79~80% accuracy in cross-validation experiments, and with 71~73% accuracy when CoRAL uses one tissue type for training and the other as validation. Analysis by CoRAL revealed that long intergenic ncRNAs, small cytoplasmic RNAs, and small nuclear RNAs show more tissue specificity, while microRNAs, small nucleolar, and transposon-derived RNAs are highly discernible and consistent across the two tissue types. The ability to consistently annotate loci across tissue types demonstrates the potential of CoRAL to characterize ncRNAs using smRNA-seq data in less characterized organisms. Overall design: Four samples were sequenced, each one coming from frozen brain tissue (frontal cortex) of a deceased female human patient with no remarkable pathology.
HAMR: high-throughput annotation of modified ribonucleotides.
Sex, Specimen part, Disease, Disease stage, Subject
View SamplesDuring Epithelial-Mesenchymal Transition (EMT), apical-basal polarized epithelial cells are converted to front-to-back polarized mesenchymal cells that only form loose cell-cell adhesions. These phenotypic changes are accompanied by acquisition of increased motility and invasiveness. EMT programs are orchestrated by pleiotropic transcription factors (TFs), such as Twist1 and Snail1 and effect morphogenetic steps during embryogenesis, including mesoderm formation and neural crest migration. EMTs have also been implicated in the acquisition of aggressive traits by carcinoma cells, including the ability to complete several steps of the metastatic cascade as well as propagation of the tumor by single cells (clonogenicity), a defining trait of tumor-initiating or cancer stem cells. However, the molecular links between the expression of EMT-TFs, the process of EMT and acquisition of clonogenicity remain obscure.
Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation.
Sex, Specimen part, Cell line
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Copy number variation in Y chromosome multicopy genes is linked to a paternal parent-of-origin effect on CNS autoimmune disease in female offspring.
Sex, Age, Specimen part
View Samples