Transcriptome analysis of the TA muscles from WT and Dmd Exon 51 Knockout mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA658118 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12478073.fastq.gz | Fastqsanger.gz | |||
| SRR12478074.fastq.gz | Fastqsanger.gz | |||
| SRR12478075.fastq.gz | Fastqsanger.gz | |||
| SRR12478076.fastq.gz | Fastqsanger.gz | |||
| SRR12478077.fastq.gz | Fastqsanger.gz |
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Project description:Duchenne muscular dystrophy (DMD) is a fatal muscle disorder characterized by cycles of degeneration and regeneration of multinucleated myofibers and pathological activation of a variety of other associated cell types. Here, we describe the creation of a new mouse model of DMD caused by deletion of exon 51 of the dystrophin gene, which represents a prevalent mutation in humans. To understand the transcriptional abnormalities and heterogeneity associated with the nuclei of myofibers, as well as other mononucleated cell types that contribute to DMD disease pathogenesis, we performed single nucleus transcriptomics of skeletal muscle of mice with exon 51 deletion. Our results reveal distinctive and previously unrecognized myonuclear subtypes within dystrophic myofibers and uncover degenerative and regenerative transcriptional pathways underlying DMD pathogenesis. Our findings provide new insights into the molecular underpinnings of DMD, controlled by the transcriptional activity of different types of muscle and nonmuscle nuclei.
2020-11-05 | GSE156496 | GEO
Project description:Duchenne muscular dystrophy (DMD) is a fatal muscle disorder characterized by cycles of degeneration and regeneration of multinucleated myofibers and pathological activation of a variety of other associated cell types. Here, we describe the creation of a new mouse model of DMD caused by deletion of exon 51 of the dystrophin gene, which represents a prevalent mutation in humans. To understand the transcriptional abnormalities and heterogeneity associated with the nuclei of myofibers, as well as other mononucleated cell types that contribute to DMD disease pathogenesis, we performed single nucleus transcriptomics of skeletal muscle of mice with exon 51 deletion. Our results reveal distinctive and previously unrecognized myonuclear subtypes within dystrophic myofibers and uncover degenerative and regenerative transcriptional pathways underlying DMD pathogenesis. Our findings provide new insights into the molecular underpinnings of DMD, controlled by the transcriptional activity of different types of muscle and nonmuscle nuclei.
2020-11-05 | GSE156497 | GEO
Project description:Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the dystrophin (DMD) gene, leading to the complete absence of DMD and progressive degeneration of skeletal and heart muscles. Expression of an internally shortened dystrophin in DMD subjects (DMDΔ52) can be achieved by skipping DMD exon 51 to reframe the transcript. To predict the best possible outcome of this therapeutic strategy, we generated transgenic pigs lacking DMD exon 51 and 52, additionally representing a new model for Becker muscular dystrophy (BMD). To inspect the proteome alterations caused by the different dystrophin mutations in an unbiased and comprehensive manner, we performed a label-free liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) of myocardial and skeletal muscle samples from wild-type (WT), DMDΔ52 and DMDΔ51-52 pigs.
2023-07-11 | PXD039533 | Pride
Project description:Single nucleus RNA-seq analysis of the TA muscles from WT and Dmd Exon 51 Knockout mice
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Project description:Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness, and a maximum life span of 3 months due to respiratory impairment. To address the accelerated development of muscular dystrophy in DMD pigs as compared to human patients, we performed a genome-wide transcriptome study of M. biceps femoris samples from 2-day-old and 3-month-old DMD and age-matched wild-type pigs. The transcriptome changes in 3-month-old DMD pigs were in good accordance with the findings of gene expression profiles in human DMD, reflecting the processes of degeneration, regeneration, inflammation, fibrosis, and impaired metabolic activity. The transcriptome profile of 2-day-old DMD pigs pointed towards increased protein and DNA catabolism, reduced extracellular matrix formation and cell proliferation and showed similarities with transcriptome changes induced by exercise injury in muscle. Our transcriptome studies provide new insights into congenital changes associated with dystrophin deficiency and secondary complications arising during postnatal development. Thus the DMD pig is a useful model to determine the hierarchy of physiological derangements in dystrophin-deficient muscle. 13 samples, two conditions, two age-groups, 3-4 biological replicates
2013-08-06 | E-GEOD-44096 | biostudies-arrayexpress
Project description:Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness, and a maximum life span of 3 months due to respiratory impairment. To address the accelerated development of muscular dystrophy in DMD pigs as compared to human patients, we performed a genome-wide transcriptome study of M. biceps femoris samples from 2-day-old and 3-month-old DMD and age-matched wild-type pigs. The transcriptome changes in 3-month-old DMD pigs were in good accordance with the findings of gene expression profiles in human DMD, reflecting the processes of degeneration, regeneration, inflammation, fibrosis, and impaired metabolic activity. The transcriptome profile of 2-day-old DMD pigs pointed towards increased protein and DNA catabolism, reduced extracellular matrix formation and cell proliferation and showed similarities with transcriptome changes induced by exercise injury in muscle. Our transcriptome studies provide new insights into congenital changes associated with dystrophin deficiency and secondary complications arising during postnatal development. Thus the DMD pig is a useful model to determine the hierarchy of physiological derangements in dystrophin-deficient muscle.
2013-08-06 | GSE44096 | GEO
Project description:scRNAseq RAT TA and EOMs WT and DMD 12months
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Project description:Duchenne muscular dystrophy is an X-linked monogenic disease caused by mutations in the dystrophin gene (DMD) and characterized by progressive muscle weakness leading to loss of ambulation and significantly decreased life expectancy. Since the current standard of care for Duchenne muscular dystrophy is to merely treat symptoms, there is a dire need for novel treatment modalities that can correct the underlying genetic mutations. While several gene replacement therapies are being explored in clinical trials, one emerging approach that can directly correct mutations in genomic DNA is base editing. We have recently developed CRISPR-SKIP, a base editing strategy to induce permanent exon skipping by introducing C>T or A>G mutations at splice acceptors in genomic DNA, which can be utilized therapeutically to recover dystrophin expression when a genomic deletion leads to an out-of-frame DMD transcript. We now demonstrate that CRISPR-SKIP can be adapted to correct some forms of Duchenne muscular dystrophy by disrupting the splice acceptor in human DMD exon 45 with high efficiency, which enables open reading frame recovery and restoration of dystrophin expression. We also demonstrate that AAV-delivered split-intein base editors edit the splice acceptor of DMD exon 45 in cultured human cells and in vivo, highlighting the therapeutic potential of this strategy.
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Project description:To investigate the role of the circadian clock gene Bmal1 in skeletal muscle, we compared the circadian transcriptomes of fast tibialis anterior (TA) and slow soleus (SOL) skeletal muscles from muscle-specific Bmal1 KO (mKO) and their control Cre- littermates (Ctrl). Keyword: Circadian Transcriptome, time course 72 samples were analyzed, comprised of 4 experimental groups (Ctrl SOL, mKO SOL, Ctrl TA, mKO TA), with 3 biological replicates for each time point sampled every 4 hours for 24 hours. SOL and TA muscles were collected from the same animals, as indicated by Source Animal ID data column
2014-01-01 | E-GEOD-43071 | biostudies-arrayexpress
Project description:Duchenne Muscular dystrophy (DMD), a yet-incurable X-linked recessive disorder that results in muscle wasting and loss of ambulation is due to mutations in the dystrophin gene. Exonic duplications of dystrophin gene are a common type of mutations found in DMD patients. In this study, we utilized a single guide RNA CRISPR strategy targeting intronic regions to delete the extra duplicated regions in patient myogenic cells carrying duplication of exon 2, exons 2 to 9, and exons 8 to 9 in the DMD gene. Immunostaining on CRISPR-corrected derived myotubes demonstrated the rescue of dystrophin protein. Subsequent RNA sequencing of the corrected myotubes indicated rescue of dystrophin related molecular pathways. Examination of predicted close-match off-targets evidenced no aberrant gene editing at these loci. Here, we further demonstrate the efficiency of a single guide CRISPR strategy capable of deleting multi-exon duplications in the DMD gene without significant off target effect. This resulted in the restoration of dystrophin expression and reversal of transcriptome pathological signatures in the corrected patient-derived cells. Our study contributes valuable insights into the safety and efficacy about the application of the single guide CRISPR strategy as a potential therapeutic approach for DMD patients with duplications of variable size.
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