Genome-wide maps of polyadenylation sites in OPMD-model and control mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE32302 | GEO | 2012/04/15
SECONDARY ACCESSION(S): PRJNA154499
REPOSITORIES: GEO
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Project description:We applied deep-sequencing based technique, 3'-Seq, to obtain comprehansive maps of poly-A sites in OPMD-model mice expressing trePABPN1(A17) mutant and control mice Examination of poly-A sites in control and OPMD-model mice (in two ages: 20 weeks and 12 months)
2012-04-15 | E-GEOD-32302 | biostudies-arrayexpress
Project description:We applied deep-sequencing based technique, 3'-Seq, to obtain comprehansive maps of poly-A sites in human cells. 3'-Seq was applied to two cell lines (U2OS and RPE-1), in control and PABPN1 knockdown cells
2012-04-15 | GSE27452 | GEO
Project description:We applied deep-sequencing based technique, 3'-Seq, to obtain comprehansive maps of poly-A sites in human cells. 3'-Seq was applied to two cell lines (U2OS and RPE-1), in control and PABPN1 knockdown cells Examination of poly-A sites in control and PABPN1kd cells (in two different cell lines)
2012-04-15 | E-GEOD-27452 | biostudies-arrayexpress
Project description:Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by short GCN repeat expansions within the gene encoding the nuclear poly(A)-binding protein 1 (PABPN1) that extend an N-terminal polyalanine tract in the protein. Mutant PABPN1 aggregates as nuclear inclusions in OMPD patient muscles. We have used the transgenic mouse A17.1 OPMD model that recapitulates the features of the human disorder: progressive muscle weakness, atrophy and formation of PABPN1 nuclear inclusions. Wild-type human PABPN1 contains a stretch of 10 alanines following the initial methionine, which is expanded to 11–18 alanines in OPMD patients. Transgenic A17.1 mouse overexpress an 17 alanine expanded PABPN1 under the control of the HSA promoter. To evaluate a gene therapy approach based on AAV delivery of a ‘suppress and replace’ strategy in OPMD we performed a transcriptomic analysis in treated muscles 18 weeks after injection. Using microarrays, tibialis anterior gene expression was compared between control muscles (FvB), OPMD muscles (A17), AAV-shRNA3x treated muscles (A17 shRNA3X), AAVoptPABPN1 treated muscles (A17 optPABPN1), and AAV-shRNA3x+AAV-optPABPN1 treated muscles (A17 dual).
2017-06-12 | GSE89996 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE27452: Genome-wide maps of polyadenylation sites in control and PABPN1kd cells GSE32302: Genome-wide maps of polyadenylation sites in OPMD-model and control mice Refer to individual Series
2012-04-14 | E-GEOD-32303 | biostudies-arrayexpress
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Project description:Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)8–13 expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets.
2011-01-14 | GSE26604 | GEO
Project description:Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by ptosis, dysphagia and proximal limb weakness. Autosomal-dominant OPMD is caused by a short (GCG)8–13 expansions within the first exon of the poly(A)-binding protein nuclear 1 gene (PABPN1), leading to an expanded polyalanine tract in the mutated protein. Expanded PABPN1 forms insoluble aggregates in the nuclei of skeletal muscle fibres. In order to gain insight into the different physiological processes affected in OPMD muscles, we have used a transgenic mouse model of OPMD (A17.1) and performed transcriptomic studies combined with a detailed phenotypic characterization of this model at three time points. The transcriptomic analysis revealed a massive gene deregulation in the A17.1 mice, among which we identified a significant deregulation of pathways associated with muscle atrophy. Using a mathematical model for progression, we have identified that one-third of the progressive genes were also associated with muscle atrophy. Functional and histological analysis of the skeletal muscle of this mouse model confirmed a severe and progressive muscular atrophy associated with a reduction in muscle strength. Moreover, muscle atrophy in the A17.1 mice was restricted to fast glycolytic fibres, containing a large number of intranuclear inclusions (INIs). The soleus muscle and, in particular, oxidative fibres were spared, even though they contained INIs albeit to a lesser degree. These results demonstrate a fibre-type specificity of muscle atrophy in this OPMD model. This study improves our understanding of the biological pathways modified in OPMD to identify potential biomarkers and new therapeutic targets. A17.1 transgenic mice have previously been described. Male A17.1 mice and WT controls were generated by crossing the heterozygous carrier strain A17.1 obtained from Rubinsztein's group with the FvB background mice. The mice were genotyped by PCR 3–4 weeks after birth. Wild type FvB and A17.1 mice were housed in minimal disease facilities (Royal Holloway, University of London) with food and water ad libitum. Total RNA was extracted from skeletal muscles using RNA Bee (Amsbio) according to the manufacturer's instructions. RNA integration number (RIN) was determined with RNA 6000 Nano (Agilent Technologies). RNA with RIN >7 were used for subsequent steps. RNA labelling was performed with the Illumina® TotalPrep RNA Amplification kit (Ambion) according to the manufacturer's protocol, and subsequently was hybridized to Illumina Mouse v1.1 Bead arrays.
2011-01-14 | E-GEOD-26604 | biostudies-arrayexpress
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2018-08-21 | GSE79468 | GEO
Project description:Oculopharyngeal muscular dystrophy (OPMD) is a late-onset progressive muscle disorder caused by a poly-alanine expansion mutation in PABPN1. The hallmark of OPMD is the accumulation of the mutant protein in insoluble nuclear inclusions. The molecular mechanisms associated with disease onset and progression are unknown. We performed a high-throughput cross-species transcriptome study of affected muscles from two OPMD animal models and from patients at pre-symptomatic and symptomatic stages. The most consistently and significantly OPMD-deregulated pathway across species is the ubiquitin-proteasome system (UPS). By analyzing expression profiles, we found that the majority of OPMD-deregulated genes are age-associated. Based on expression trends, disease onset can be separated from progression; the expression profiles of the proteasome-encoding genes are associated with onset but not with progression. In a muscle cell model, proteasome inhibition and the stimulation of immunoproteasome specifically affect the accumulation and aggregation of mutant PABPN1. We suggest that proteasome down-regulation during muscle aging triggers the accumulation of expPABPN1 that in turn enhances proteasome deregulation and leads to intranuclear inclusions (INI) formation.
2011-04-19 | GSE26605 | GEO