SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA-seq to profile cerebellar RNA expression in ATXN1 mice, including lines with ataxia and progressive pathology and lines having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar RNA-seq data revealed two gene networks that significantly correlated with disease, the Magenta (342 genes) and Light Yellow (35 genes) Modules. Features of the Magenta and Light Yellow Modules indicate they reflect distinctive pathways. The Magenta Module provides a description of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects other transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. We also found that up-regulation of cholecystokinin (Cck) blocked progression of Purkinje cell pathology and that loss of Cck function in mice lacking progressive disease enabled Purkinje cell pathology to progress to cell death. Overall design: Cerebellar mRNA expression profiles from ATXN1[82Q], ATXN1[30Q], and ATXN1[30Q]-D776 transgenic mice and wild type/FVB mice at 5 weeks, 12 weeks and 28 weeks of age ---------------------------- cuffnorm_ATXN1.82Q_ATXN1.30Q.D776_WTFVB_genes.fpkm_tracking.txt: CuffNorm normalized values for all samples (snoRNAs and miRNAs removed) cuffdiff_week5_ATXN1.82Q_ATXN1.30Q.D776_WTFVB_gene_exp.diff.txt: Cuffdiff comparison between samples at week 5; pairwise comparisons between ATXN1[82Q], ATXN1[30Q]D776 and FVB cuffdiff_week12_ATXN1.82Q_ATXN1.30Q.D776_WTFVB_gene_exp.diff.txt: Cuffdiff comparison between samples at week 12; pairwise comparisons between ATXN1[82Q], ATXN1[30Q]D776 and FVB cuffdiff_week28_ATXN1.82Q_ATXN1.30Q.D776_WTFVB_gene_exp.diff.txt: Cuffdiff comparison between samples at week 28; pairwise comparisons between ATXN1[82Q], ATXN1[30Q]D776 and FVB cuffdiff_week5_vs_week12_vs_week28_ATXN1.82Q_gene_exp.diff.txt: Cuffdiff comparison between ATXN1[82Q] at week 5, week 12 and week 28 cuffdiff_week5_vs_week12_vs_week28_ATXN1.30Q.D776_gene_exp.diff.txt: Cuffdiff comparison between ATXN1[30Q]D776 at week 5, week 12 and week 28 cuffdiff_week5_vs_week12_vs_week28_FVB_gene_exp.diff.txt: Cuffdiff comparison between wt/FVB at week 5, week 12 and week 28
Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways.
Age, Specimen part, Cell line, Subject
View SamplesMultiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow in order to survive and proliferate. Interactions between the malignant plasma cell and bone marrow mesenchymal stem cell (BMMSC) are thought to be a critical determinant of this requirement, and include both physical and chemical components. There is increasing evidence that the phenotype of the BMMSC is stably altered in patients with MM. More recently, it has been suggested that this phenotypic transformation is also observed in patients with the benign condition known as monoclonal gammopathy of undetermined significance (MGUS), which almost always precedes MM. In this study, we describe a mechanism by which the peptidyl arginine deiminase 2 (PADI2) enzyme plays an key role in the control of malignant plasma cell phenotype by BMMSCs. PADI enzymes deiminate (citrullinate) peptidyl arginine residues, changing the function or interactions made by the target protein. We identified PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through citrullination of arginine residue 26 of histone H3, it induces the upregulation of interleukin-6 (IL-6) expression. This directly leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26.
Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma.
Sex, Age, Specimen part, Disease, Disease stage
View SamplesWe provide here the alterations in gene expression profiles of HepaRG cells, a validated model for cellular steatosis, exposed to three concentration of the polychlorinated biphenyl (PCB) 126, one of the most potent chemical inducing NAFLD. Additionnally, three concentration of the pesticide active ingredient glyphosate were tested. This ultimately suggested sensitive biomarkers of exposure. A gene ontology analysis showed hallmarks of an activation of the AhR receptor by dioxin-like compounds. Our study provides grounds for the development of molecular signatures of fatty liver diseases to rapidly assess toxic effects of chemicals in the HepaRG cell line. Overall design: Differentiated HepaRGTM cells (HPR 116) were purchased from Biopredic International. The cells were kept in the general purpose medium until day 8, when the culture becomes well organized and includes well-delineated trabeculae and many canaliculi-like structures. Three concentrations of the PCB were then tested from day 8 to day 14, in order to cover a wide range of biological effects, starting from low environmental exposures (100 pM) to high concentrations of (1 uM), with an intermediate concentration (10 nM). Three concentrations of glyphosate, or one concentration of the Roundup herbicide (Grand Travaux +) were also tested in the same system.
Comparison of transcriptome responses to glyphosate, isoxaflutole, quizalofop-p-ethyl and mesotrione in the HepaRG cell line.
Specimen part, Cell line, Treatment, Subject
View SamplesWe provide here the alterations in gene expression profiles of HepaRG cells, a validated model for cellular steatosis, exposed to three concentration of quizalofop-p-ethyl, isoxaflutole and mesotrione Overall design: Differentiated HepaRGTM cells (HPR 116) were purchased from Biopredic International. The cells were kept in the general purpose medium until day 8, when the culture becomes well organized and includes well-delineated trabeculae and many canaliculi-like structures. Three concentrations of the different pesticide active ingredients (quizalofop-p-ethyl, isoxaflutole and mesotrione ) were then tested from day 8 to day 14. In order to ensure coverage of a wide range of potential biological effects, three concentrations of each active principle were tested; a concentration representative of low environmental exposure (0.1 uM), an intermediate concentration (10 uM) and a high concentration (1000 uM).
Comparison of transcriptome responses to glyphosate, isoxaflutole, quizalofop-p-ethyl and mesotrione in the HepaRG cell line.
Specimen part, Cell line, Subject
View SamplesWe provide here the alterations in gene expression profiles of 3T3-L1 cells, a validated model for adipogenesis, exposed to quizalofop-p-ethyl for 6h, 24h and 12 days. Overall design: Exposure to endocrine disrupting chemicals is a risk factor for obesity. The most commonly used pesticide active ingredients have never been tested in an adipogenesis assay. We tested for the first time the lipid accumulation induced by glyphosate, 2,4-dichlorophenoxyacetic acid, dicamba, mesotrione, isoxaflutole and quizalofop-p-ethyl (QpE) in 3T3-L1 adipocytes. Only QpE caused triglyceride accumulation from a concentration of 1 µM. We thus conducted an in-depth investigation of molecular mechanisms responsible for the adipogenic effects of quizalopfop-p-ethyl by an RNA-seq analysis.
Quizalofop-p-Ethyl Induces Adipogenesis in 3T3-L1 Adipocytes.
Specimen part, Cell line, Treatment, Subject
View SamplesAngiogenesis is tightly regulated by both soluble growth factors and cellular interactions with the extracellular matrix (ECM). While cell adhesion via integrins has been shown to be required for growth factor signaling and downstream angiogenesis, the effects of quantitative changes in cell adhesion and spreading against the ECM remain less clear.
Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner.
Specimen part
View SamplesAlthough much is known about focal adhesion signaling induced by cell adhesion, how adhesion directs changes in transcription to control cell behavior is far less understood. Here we describe a novel mechanism by which changes in adhesion switch the activities of the mitogen-activated protein kinases (MAPKs) c-Jun N-terminal kinase (JNK) and p38, resulting in the differential activation and promoter occupancy of the SRF cofactors, the ternary complex factors (TCFs) Sap-1 and Net. Adhesion-induced MAPK/TCF switching controls immediate early gene expression and proliferation. This mechanism is of physiological relevance, as proliferative regulation by the TCFs is conserved in an ex ovo model of angiogenesis. Furthermore, microarray analysis identified novel genes and adhesive functions regulated by Sap-1 and Net. Thus our data identify the TCFs as key regulators of adhesion-induced transcription and cell behavior.
Adhesion regulates MAP kinase/ternary complex factor exchange to control a proliferative transcriptional switch.
Cell line
View SamplesThis SuperSeries is composed of the SubSeries listed below.
CSNK1a1 Regulates PRMT1 to Maintain the Progenitor State in Self-Renewing Somatic Tissue.
Specimen part, Treatment
View SamplesHere we determine the target gene sets controlled by PRMT1 or CSNK1a1 in maintaining the undifferentiated state of primary human keratinocytes.
CSNK1a1 Regulates PRMT1 to Maintain the Progenitor State in Self-Renewing Somatic Tissue.
Treatment
View SamplesThe immense molecular diversity of neurons challenges our ability to deconvolve the relationship between the genetic and the cellular underpinnings of neuropsychiatric disorders.
The disruption of Celf6, a gene identified by translational profiling of serotonergic neurons, results in autism-related behaviors.
Sex, Specimen part, Disease
View Samples