MECP2-related pathways are dysregulated in a cortical organoid model of Myotonic dystrophy [scRNA-Seq]
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PROVIDER: PRJNA833424 | ENA |
REPOSITORIES: ENA
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Project description:MECP2-related pathways are dysregulated in a cortical organoid model of Myotonic dystrophy
| PRJNA833427 | ENA
Project description:MECP2-related pathways are dysregulated in a cortical organoid model of Myotonic dystrophy [eCLIP]
| PRJNA833435 | ENA
Project description:MECP2-related pathways are dysregulated in a cortical organoid model of Myotonic dystrophy [bulk RNA-Seq]
| PRJNA833434 | ENA
Project description:Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci discovered early in maturation of three-dimensional cortical organoids from DM1 patient-derived induced pluripotent stem cells, cause hyperphosphorylation of CUGBP Elav-Like Family Member 2 (CELF2 ) protein. Integrative single-cell RNA-seq and enhanced crosslinking and immunoprecipitation (eCLIP ) analysis revealed reduced CELF2 protein-RNA substrate interactions resulting in mis-regulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the Methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(-/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-Methyl-D-aspartic acid (NMDA ) antagonists as potential treatment avenues for neuronal defects in DM1. To evaluate if the post-translational modification of CELF2 impacts its RNA targets, we generated transcriptome-wide eCLIP maps of CELF2 protein-RNA interactions in mature, 6-month-old control and DM1 cortical organoids. All CELF2 eCLIP libraries per organoid line were performed in biologically independent duplicates, with each replicate experiment consisting of a CELF2 (IP) and a paired size-matched input (SMInput) library . We used CLIPper to identify clusters of reads representing regions in the transcriptome significantly associated with CELF2 binding in both neurotypical lines and compared them to DM1 cortical organoids with 600 and 1200 CUG repeats.
2022-06-30 | GSE201895 | GEO
Project description:Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3’ untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci discovered early in maturation of three-dimensional cortical organoids from DM1 patient-derived induced pluripotent stem cells, cause hyperphosphorylation of CUGBP Elav-Like Family Member 2 (CELF2 ) protein. Integrative single-cell RNA-seq and enhanced crosslinking and immunoprecipitation (eCLIP ) analysis revealed reduced CELF2 protein-RNA substrate interactions resulting in mis-regulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the Methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(-/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-Methyl-D-aspartic acid (NMDA ) antagonists as potential treatment avenues for neuronal defects in DM1. To determine if CUG expansions in DMPK alter cellular RNA composition during differentiation, we performed transcriptomic analyses using RNA-seq at four consecutive developmental stages, ranging from iPSCs to 6-month-old cortical organoids from two independent differentiations. mine We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different time points.
2022-06-30 | GSE201897 | GEO
Project description:Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci found early in the maturation of three-dimensional (3D) cortical organoids from DM1 patient-derived induced pluripotent stem cells (iPSCs) cause hyperphosphorylation of CUGBP Elav-like family member 2 (CELF2) protein. Integrative single-cell RNA sequencing and enhanced cross-linking and immunoprecipitation (eCLIP) analysis revealed that reduced CELF2 protein-RNA substrate interactions results in misregulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2(y/-) cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify N-methyl-d-aspartic acid (NMDA) antagonists as potential treatment avenues for neuronal defects in DM1.
| S-EPMC9645119 | biostudies-literature
Project description:Misregulated alternative splicing appears to be a major factor in the pathogenesis of myotonic dystrophy. The present study was done to further explore alternative splicing in this condition by doing exon-level analysis of mRNA from skeletal muscle of 8 subjects with type 1 myotonic dystrophy, 7 subjects with type 2 myotonic dystrophy, 8 disease controls (subjects with facioscapulohumeral muscular dystrophy), and 8 healthy controls . The ratios of signals from the various exons of a gene provided an index of altered exon inclusion/exclusion that was independent of the overall expression of that gene. There were numerous transcripts for which there was evidence of abnormal alternative splicing in subjects with myotonic dystrophy. For many of these transcripts, the abnormal splicing was confirmed by an independent RT-PCR approach. 31 subjects, one sample per subject, four groups: healthy subjects (n = 8), facioscapulohumeral dystrophy (n = 8), type 1 myotonic dystrophy (n = 8), type 2 myotonic dystrophy (n = 7)
2013-06-15 | E-GEOD-47968 | biostudies-arrayexpress
Project description:Autopsy and biopsy muscle and heart tissue was collected from consented human subjects with and without confirmed myotonic dystrophy type 1, myotonic dystrophy type 2, or Duchenne muscular dystrophy. RNA was isolated for preparation of RNAseq libraries and sequenced on the Illumina platform.
2016-09-29 | GSE86356 | GEO
Project description:Misregulated alternative splicing appears to be a major factor in the pathogenesis of myotonic dystrophy. The present study was done to further explore alternative splicing in this condition by doing exon-level analysis of mRNA from skeletal muscle of 8 subjects with type 1 myotonic dystrophy, 7 subjects with type 2 myotonic dystrophy, 8 disease controls (subjects with facioscapulohumeral muscular dystrophy), and 8 healthy controls . The ratios of signals from the various exons of a gene provided an index of altered exon inclusion/exclusion that was independent of the overall expression of that gene. There were numerous transcripts for which there was evidence of abnormal alternative splicing in subjects with myotonic dystrophy. For many of these transcripts, the abnormal splicing was confirmed by an independent RT-PCR approach.
2013-06-15 | GSE47968 | GEO
Project description:As cortical organoids consist of a heterogeneous population of cell-types, 6-month-old DM1 and Rett syndrome cortical organoids were subjected to single cell RNA-seq (scRNA-seq) analysis to determine which cell type(s) CELF2’s RNA targets are expressed in. Unsupervised clustering was implemented on the combined dataset of 8595 cells from control, DM600, and DM1200 cortical organoids that consisted of ~2865 cells per organoid line and ~17,575 reads per cell to identify genotype-specific clusters at 6-months post-differentiation. Uniform Manifold Approximation and Projection (UMAP) for dimension reduction revealed clear differences between control and DM1 organoids. From the expression of established cell-type specific gene markers, smaller sub-clusters were combined to represent four major cell classes: neural progenitors, intermediate neural progenitors, glutamatergic cortical neurons, and glial cells.
2022-06-30 | GSE201891 | GEO