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GSE80608
Homo sapiens
30 Downloadable Samples
Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Multiple 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.
Publication Title
Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Mus musculus
- 69 Downloadable Samples
Illumina Genome Analyzer IIx, Illumina HiSeq 2000
Description
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
Publication Title
Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples