Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26448352_1.fastq.gz | Fastqsanger.gz |
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Project description:shRNA knockdown against SMN1 in HepG2 cells followed by RNA-seq. (SMN1-BGHLV20) For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODE_Data_Use_Policy_for_External_Users_03-07-14.pdf
2016-11-08 | GSE88018 | GEO
Project description:Alternative splicing diversifies mRNA transcripts in human cells. While the spliceosome pairs exons with a high degree of accuracy, the rates of rare aberrant and non-canonical pre-mRNA splicing have not been evaluated at the nucleotide level to determine the quantity and identity of these events across splice junctions. Using ultra-deep sequencing the frequency of aberrant and non-canonical splicing events for three splice junctions flanking exon 7 of SMN1 were determined at single nucleotide resolution. After correction for background noise introduced by PCR amplification and sequencing steps, pre-mRNA splicing was shown to maintain a low overall rate of aberrant and non-canonically spliced events. Several previously unannotated splicing events across 3 exon|intron junctions in SMN1 were identified. Mutations within SMN exon 7 were shown to affect splicing fidelity by modulating RNA secondary structures, by altering the binding site of regulatory proteins and by changing the 5’ splice site strength. Mutations also create a truncated SMN1 exon 7 through the introduction of a de novo non-canonical 5’ splice site. The results from the ultra-deep sequencing approach highlight the impressive fidelity of pre-mRNA splicing and demonstrate that the immediate sequence context around splice sites is the main driving force behind non-canonical splice site pairing.
2019-09-24 | GSE137883 | GEO
Project description:Although recent advances in gene therapy provide hope for spinal muscular atrophy (SMA) patients, the pathology remains the leading genetic cause of infant mortality. SMA is a monogenic pathology that originates from the loss of the SMN1 gene in most cases or mutations in rare cases. Interestingly, SMN1 mutations occur broadly either within the TUDOR methyl-arginine (Rme) reader domain of SMN or its carboxy terminal oligomerization domain. We hypothesized that in SMN1 mutant cases, SMA may emerge from aberrant protein-protein interactions between SMN and key neuronal factors. Using a proximity-dependent biotinylation proteomic (BioID) approach, we have identified and validated a number of SMN-interacting proteins, including Fragile X mental retardation family members (FMRFM), such as FMRP itself as well as FXR1 and FXR2, some depending on a wild-type version of the TUDOR domain.
2022-10-19 | PXD030970 | Pride
Project description:Spinal muscular atrophy (SMA) genes, SMN1 and SMN2, produce multiple circular RNAs (circRNAs), including C2A-2B-3-4 that encompasses early exons 2A, 2B, 3 and 4. Here we report the transcriptome- and proteome-wide effects of overexpression of C2A-2B-3-4 in inducible HEK293 cells. Our RNA-Seq analysis revealed altered expression of ~15% genes (4,172 genes) by C2A-2B-3-4. About half of the affected genes by C2A-2B-3-4 remained unaffected by L2A-2B-3-4, a linear transcript encompassing exons 2A, 2B, 3 and 4 of SMN1/SMN2. These findings underscore the unique role of the structural context of C2A-2B-3-4 in gene regulation. A surprisingly high number of upregulated genes by C2A-2B-3-4 were located on chromosomes 4 and 7, whereas many of the downregulated genes were located on chromosomes 10 and X. Supporting a cross-regulation of SMN1/SMN2 transcripts, C2A-2B-3-4 and L2A-2B-3-4 upregulated and downregulated SMN1/SMN2 mRNAs, respectively. Proteome analysis revealed 61 upregulated and 57 downregulated proteins by C2A-2B-3-4 with very limited overlap with those affected by L2A-2B-3-4. Independent validations confirmed the effect of C2A-2B-3-4 on expression of genes associated with chromatin remodeling, transcription, spliceosome function, ribosome biogenesis, lipid metabolism, cytoskeletal formation, cell proliferation and neuromuscular junction formation. Our findings reveal a broad role of C2A-2B-3-4, a universally expressed circRNA produced by SMN1/SMN2.
2024-02-14 | GSE255511 | GEO
Project description:Spinal muscular atrophy (SMA) genes SMN1/SMN2 produce multiplecircular RNAs (circRNAs), including C2A-2B-3-4that encompassesearly exons 2A, 2B, 3 and 4. Here we report the transcriptome-and proteome-wide effects of overexpression of C2A-2B-3-4 in inducible HEK293 cells. Our RNA-Seq analysisrevealedaltered expression of ~15% genes (4,172 genes) by C2A-2B-3-4. About half of the affected genes by C2A-2B-3-4 remained unaffected by L2A-2B-3-4, a linear transcript encompassing exons 2A, 2B, 3 and 4 of SMN1/SMN2.These findings underscore theuniquerole of the structural context of C2A-2B-3-4 in gene regulation. A surprisingly high numberof upregulated genes by C2A-2B-3-4 were located on chromosomes 4 and 7, whereas many of the downregulated genes were located on chromosomes 10 and X. Supporting a cross-regulation of SMN1/SMN2transcripts, C2A-2B-3-4 and L2A-2B-3-4upregulated and downregulatedSMN1/SMN2mRNAs, respectively. Proteome analysis revealed 61 upregulated and 57 downregulated proteins by C2A-2B-3-4 with very limited overlap with those affected by L2A-2B-3-4. Independent validations confirmed the effect ofC2A-2B-3-4on expression ofgenesassociated with chromatin remodeling, transcription, spliceosome function, ribosome biogenesis, lipid metabolism, cytoskeletal formation, cell proliferationand neuromuscular junction formation. Our findings reveal a broad role of C2A-2B-3-4, a universally expressed circRNA produced by SMN1/SMN2.
2024-05-23 | PXD048160 | Pride
Project description:Muscular atrophy (SMA) is an autosomal recessive disease causing selective motor neuron death by the loss of telomeric survival motor neuron gene, SMN1. Axonal SMN, a-SMN, is a truncated form of SMN, derived from an alternatively spliced SMN1 gene. (Setola, et. al. 2007 PNAS 104, 1959-1964). The cellular clones expressing a-SMN in a tetracycline-dependent manner were isolated from NSC34 by two-step stable transfection, first with the tetracycline-repressor construct and subsequently with the a-SMN cDNA. To identify novel a-SMN target genes, the transcriptome of several a-SMN clones was analyzed and compared with that of parental cells.
2012-01-07 | E-MEXP-3402 | biostudies-arrayexpress
Project description:The survival motor neuron 1 (SMN1) gene is the causative gene for the spinal muscular atrophy (SMA) disease, the first genetic cause of infant mortality. It affects primarily motor neurons which are the targets of the approved genetic therapies aimed to compensate for the loss of SMN1. However, the limitations of these therapies are now evident since they are not cures, and alternative strategies need to be investigated. Because of the ubiquitous and multifunctional roles of SMN1 in the cell, deeper understanding of the molecular mechanisms underlying intrinsic abnormalities of the different tissues affected by SMA is crucial for the development of new therapeutic approaches. Here we used a muscle specific genetic mouse model for the identification of key cellular processes associated to SMN1 loss, at single myofiber level. We found that mitochondrial dysfunction is a key pathogenetic event in SMA: mitochondria are abnormal with internal degenerated cristae. The ultrastructural changes are coincident with alterations in ROS levels by monoamine oxidase A and Ca2+ homeostasis. Interestingly, the improvements of the myopathic phenotype of the muscle-specific SMA model mice by transplantation of amniotic fluid stem (AFS) cells led to restore mitochondrial function. Our data suggest that a mitochondria-targeting therapy may represent a complementary and broad treatment strategy to further optimize the current treatment.
2023-03-08 | GSE207890 | GEO
Project description:Spinal Muscular Atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) is predominantly skipped cannot compensate for the lack of SMN1. Nusinersen is an antisense oligonucleotide that upregulates E7 inclusion and SMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that, by promoting transcriptional elongation, the histone deacetylase inhibitor VPA cooperates with nusinersen to promote E7 inclusion. Surprisingly, nusinersen promotes the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to PolII elongation that inhibits E7 inclusion. By removing the roadblock, VPA counteracts the undesired chromatin effects of nusinersen, resulting in higher E7 inclusion, without large pleiotropic effects, as assessed by genome-wide analyses. Combined administration of nusinersen and VPA in SMA mice strongly synergized in SMN expression, growth, survival, and neuromuscular function.
2022-06-09 | GSE167762 | GEO