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Differentially expressed genes in myotubes derived from MBNL knockouts hiPSCs generated by CRISPR/Cas9.

ABSTRACT: Differentially expressed genes in myotubes derived from MBNL knockouts hiPSCs generated by CRISPR/Cas9.

PROVIDER: PRJNA679805 | ENA |

REPOSITORIES: ENA

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Differentially expressed genes in myotubes derived from MBNL knockouts hiPSCs generated by CRISPR/Cas9

Project description:Differentially expressed genes in myotubes derived from MBNL knockouts hiPSCs generated by CRISPR/Cas9

| PRJNA675134 | ENA

Differentially expressed genes in myotubes derived from MBNL knockouts hiPSCs generated by CRISPR/Cas9.

Project description:Alternative splicing has emerged as a fundamental mechanism not only for the diversification of protein isoforms but also for the spatiotemporal control of development. Therefore, a better understanding of how this mechanism is regulated has the potential not only to elucidate fundamental biological principles, but also to decipher pathological mechanisms implicated in diseases where normal splicing networks are misregulated. Here, we took advantage of human pluripotent stem cells to decipher during human myogenesis the role of MBNL proteins, a family of tissue-specific splicing regulators whose loss of function is associated with Myotonic Dystrophy type 1, an inherited neuromuscular disease. Thanks to the CRISPR/Cas9 technology, we generated human-induced pluripotent stem cells (hiPSCs) depleted in MBNL proteins and evaluated the molecular and functional consequences of this loss on the generation of skeletal muscle cells. Our results indicated that MBNL proteins are specifically required for the late myogenic maturation but not for early myogenic commitment. By a transcriptomic analysis, we further demonstrated that MBNL proteins are not only important for the regulation of alternative splicing but also for the regulation of gene expression. Together, our study reveals the temporal requirement of MBNL proteins in human myogenesis and should facilitate the identification of new therapeutic strategies capable to cope the loss of function of these MBNL proteins.

2021-08-04 | GSE161897 | GEO

Differentially expressed genes in myotubes derived from MBNL knockouts hiPSCs generated by CRISPR/Cas9

2021-08-04 | GSE161029 | GEO

Alternative splicing and gene expression defects in motorneurons derived from DM1 hiPSCs and MBNL knockouts hiPSCs generated by CRISPR/Cas9.

Project description:Myotonic dystrophy type I (DM1) is the most frequent neuromuscular disease (NMD) in adults and only symptomatic treatments have been proposed to patients. DM1 has long been defined by muscular defects but several studies suggested the involvement of the neuromuscular junction (NMJ). In this aim, our purpose raised the question about the pathological contribution of the motoneurons (MNs) in DM1 physiopathology. By using a micropatterned 96-well plate as a co-culture platform, we generated a functional humanized system in 11 days which associates hiPS-derived MNs and human primary skeletal muscle cells. To focus only on DM1 motoneurons-dependent phenotypes, we generated hybrid systems using wild-type skeletal muscle cells combined with mutated hiPS-derived MNs. In this context, we have identified several alterations affecting synaptic vesicular trafficking, AChR clustering and communication between pre- and post-synaptic compartments. More interestingly, hiPS-derived MNs depleted for MBNL1 and MBNL2 reproduced alterations at the pre- and post-synaptic levels. These experiments suggested that the functional defects associated to MNs can be directly attributed to the MBNL family proteins. These findings may be clinically relevant to open new therapeutic approaches taking into account the alterations affecting DM1 motoneurons.

2023-04-26 | GSE171988 | GEO

mbnl mutant zebrafish RNA-Seq experiments

Project description:mbnl knockout Danio rerio were created using CRISPR-Cas9, including single mbnl paralog knockouts, double mbnl paralog knockouts, and a triple mbnl paralog knockout. RNA-Seq was performed using skeletal muscle of three biological replicates of four month old fish.

2021-01-12 | GSE145270 | GEO

Conserved functional antagonism between CELF and MBNL proteins regulates stem cell-specific alternative splicing and regeneration in planarians (dataset 2)

2016-08-01 | GSE75554 | GEO

Conserved functional antagonism between CELF and MBNL proteins regulates stem cell-specific alternative splicing and regeneration in planarians

Project description:Here, we analyze the RNA-binding preferences of the planarian smed-mbnl-like-2, smed-mbnl-1 (isoform X1), smed-bruli, smed-mbnl-1 (isoform Xins), and smed-mbnl-like-1 protein using RNAcompete. In the RNAcompete assay, a purified GST-tagged protein is incubated with an excess of RNA pool and bound RNA from individual pulldown experiments are directly labeled and hybridized to a custom Agilent 244K microarray.

2016-08-01 | E-GEOD-75554 | biostudies-arrayexpress

Loss of MBNL Leads to Disruption of Developmentally Regulated Alternative Polyadenylation in RNA-Mediated Disease

Project description:Mapping MBNL-regulated genome-wide alternative polyadenylation: We report that depletion of Mbnl proteins in mouse embryo fibroblasts (MEFs), DM mouse model quadriceps muscle, and DM-autopsy muscle tissue leads to mis-regulation of alternative polyadenylation

2014-09-05 | GSE60487 | GEO

Proof of concept of blockmiR induced MBNL rescue in Myotonic dystrophy muscle cells

Project description:The symptoms of Myotonic Dystrophy Type 1 (DM1) are multi-systemic and life-threatening. The neuromuscular disorder is rooted in a non-coding CTG microsatellite expansion in the DMPK gene that is correctly transcribed and physically sequesters the MBNL family of proteins. The high-affinity binding occurring between the proteins and the repetitions disallows MBNL proteins from performing their post-transcriptional splicing regulation leading to downstream molecular effects directly related to disease symptoms such as myotonia and muscle weakness. In this study, we build off of previously demonstrated evidence showing that the silencing of miR-23b and miR-218 can increase MBNL1 and 2 protein in DM1 cells. Here we use blockmiR antisense technology to block the binding sites of these miRNAs in order to increase MBNL translation into protein without binding to the microRNAs in DM1 muscle cells. The blockmiRs show therapeutic effects with the rescue of mis-splicing, MBNL subcellular localization, and transcriptomic expression proving that this novel and highly specific strategy could be a potentially viable therapy in Vivo.

2022-07-31 | GSE173359 | GEO

mbnl mutant zebrafish RNA-Seq experiments

Project description:mbnl mutant zebrafish RNA-Seq experiments

| PRJNA606583 | ENA