Cell type-specific gene expression profiles in CNS of patients with DM1
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PROVIDER: PRJNA814628 | ENA |
REPOSITORIES: ENA
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Project description:Myotonic dystrophy type 1 (DM1) is a multisystem genetic disorder involving the muscle, heart, and central nervous system (CNS). The pathogenesis of CNS symptoms prevalent in patients with DM1 remains unelucidated. To elucidate the CNS pathogenesis in DM1, we investigated cell type-specific abnormalities in cortical neurons, white matter glial cells, and spinal motor neurons of patients with DM1 via laser-capture microdissection(LCM).
2022-07-07 | GSE198321 | GEO
Project description:Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a non-coding CTG repeat expansion in the DMPK gene. This mutation generates a toxic CUG RNA that interferes with the RNA processing of target genes in multiple tissues. Despite debilitating neurological impairment, the pathophysiological cascade of molecular and cellular events in the central nervous system has been less extensively characterized than the molecular pathogenesis of muscle/cardiac dysfunction. Particularly, the contribution of different cell types to DM1 brain disease is not clearly understood. We first used transcriptomics to compare the impact of expanded CUG RNA on the transcriptome of primary neurons, astrocytes and oligodendrocytes derived from DMSXL mice, a transgenic model of DM1. RNA sequencing revealed more frequent expression and splicing changes in glia than neuronal cells. In particular, primary DMSXL oligodendrocytes showed the highest number of transcripts differentially expressed, while DMSXL astrocytes displayed the most severe splicing dysregulation. Interestingly, the expression and splicing defects of DMSXL glia recreated molecular signatures suggestive of impaired cell differentiation: while DMSXL oligodendrocytes failed to upregulate a subset of genes that are naturally activated during the oligodendroglia differentiation, a significant proportion of missplicing events in DMSXL oligodendrocytes and astrocytes increased the expression of RNA isoforms typical of precursor cell stages. Together these data suggest that expanded CUG RNA in glial cells affects preferentially differentiation-regulated molecular events. This hypothesis was corroborated by gene ontology (GO) analyses, which revealed an enrichment for biological processes and cellular components with critical roles during cell differentiation. Finally, we combined exon ontology with phosphoproteomics and cell imaging to explore the functional impact of CUG-associated spliceopathy on downstream protein metabolism. Changes in phosphorylation, protein isoform expression and intracellular localization in DMSXL astrocytes demonstrate the far-reaching impact of the DM1 repeat expansion on cell metabolism. Our multi-omics approaches provide insight into the mechanisms of CUG RNA toxicity in the CNS with cell type resolution, and support the priority for future research on non-neuronal mechanisms and proteomic changes in DM1 brain disease.
2021-03-26 | PXD025011 | Pride
Project description:Analysis of alternative splicing in heart (left ventricles) samples of 3 adult DM1 patients versus 3 adult controls PolyA RNA from left ventricles (heart) of 3 controls and 3 DM1 patients were analysed by massive parrallel sequencing
2015-04-14 | E-GEOD-67812 | biostudies-arrayexpress
Project description:Myotonic dystrophy type 1 (DM1) is a dominantly inherited disease that affects multiple organ systems. Cardiac dysfunction is the second leading cause of death in DM1. We quantified gene expression in heart tissue from a heart-specific DM1 mouse model (EpA960/MCM) which inducibly expresses human DMPK exon 15 containing 960 CUG expanded repeats and that reproduced Celf1 up regulation. To assess if, in addition to splicing and miRNA defects, CUGexp RNA also perturbed the steady state mRNA levels of genes, we carried out a microarray study on wildtype E14, adult, MCM controls and DM1 mouse hearts. As anticipated we noted a large number of genes to be developmentally regulated in wildtype hearts, however, within 72h of induction of CUGexp RNA there appeared to be a coordinate adult-to-embryonic shift in steady state levels of many genes. We identified transcripts over-expressed or under-expressed in hearts of wildtype adult mice, wildtype embryonic day 14 (E14), and DM1 mice induced to express CUGexp RNA for 72h and 1wk, when compared to MCM controls. Multiple group comparison.
2014-01-24 | E-GEOD-48991 | biostudies-arrayexpress
Project description:Introduction: Myotonic dystrophy of type 1 (DM1), the most common dystrophy in adults, is an autosomal dominant inherited disease, affecting around 1 in 8000 person. Patients suffering from DM1 develop essentially muscle disorders such as myotonia, muscle weakness, muscle loss and atrophy. The disease is caused by the mutation of the DMPK "Dystrophia Myotonica Protein Kinase" gene. The mutation correspond to an abnormally large expansion of CTG tri-nucleotides repeats located in the 3'-untranslated region of this gene. Expanded CTG repeats are normally transcribed, but accumulates in RNA aggregates that sequester RNA-binding proteins such as the splicing regulator MBNL1. Consequently, due to MBNL1 sequestration, DM1 is characterized by aberrant splicing of a wide number of mRNA, which are themselves responsible for the symptoms observed in the disease. Purpose: To determine as much as possible novel splicing misregulations taking place in DM1 skeletal muscle, we performed a paired-end RNA sequencing (RNA-seq) using muscles samples of normal individuals (CTRL, n=3) versus muscles of DM1 patients (DM1, n=3). The data was analyzed by a bioinformatical software, called MISO, in order to map the alternative splicing changes between normal and DM1 muscle. The aim of this study was to get a broad and precise view of the splicing changes occurring in DM1 muscle.
2017-08-24 | GSE85984 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE7177: Comparison of gene expression data between wild-type and DM1-affected Mesodermal Precursors Cells (MPC) GSE7178: Comparison of gene expression data between wild-type and DM1-affected Neural Precursors Cells (NPC) GSE7179: Comparison of gene expression data between wild-type and DM1-affected undifferentiated hES cells. Keywords: SuperSeries Refer to individual Series
2010-03-09 | E-GEOD-7214 | biostudies-arrayexpress
Project description:Myotonic dystrophy type 1 (DM1) is a dominantly inherited disease that affects multiple organ systems. Cardiac dysfunction is the second leading cause of death in DM1. We quantified gene expression in heart tissue from a heart-specific DM1 mouse model (EpA960/MCM) which inducibly expresses human DMPK exon 15 containing 960 CUG expanded repeats and that reproduced Celf1 up regulation. To assess if, in addition to splicing and miRNA defects, CUGexp RNA also perturbed the steady state mRNA levels of genes, we carried out a microarray study on wildtype E14, adult, MCM controls and DM1 mouse hearts. As anticipated we noted a large number of genes to be developmentally regulated in wildtype hearts, however, within 72h of induction of CUGexp RNA there appeared to be a coordinate adult-to-embryonic shift in steady state levels of many genes.
2014-01-24 | GSE48991 | GEO
Project description:We are investigating the transcriptional response of changes in RNA steady-state levels between normal and DM1. We used microarrays to detail the global programme of gene expression differences in normal or DM1 myoblasts. Keywords: comparison Two types of cells were analyzed, normal or DM1 deficient. The expression differences were compared to each other and we have deciphered a gene expression profile that is representative of DM1 deficiency.
2010-10-01 | E-GEOD-22498 | biostudies-arrayexpress
Project description:Analysis of alternative splicing in heart (left ventricles) samples of 3 adult DM1 patients versus 3 adult controls
2015-04-14 | GSE67812 | GEO