Ontology highlight
ABSTRACT:
PROVIDER: PRJNA421770 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6364170.fastq.gz | Fastqsanger.gz | |||
| SRR6364165.fastq.gz | Fastqsanger.gz | |||
| SRR6364166.fastq.gz | Fastqsanger.gz | |||
| SRR6364167.fastq.gz | Fastqsanger.gz | |||
| SRR6364168.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Small molecule splicing modifiers have been extensively described which target the generic splicing machinery and thus have low target specificity. We have identified potent splicing modifiers with unprecedented high selectively, correcting the splicing deficit of the SMN2 (survival motor neuron 2) gene in Spinal Muscular Atrophy (SMA). Here we show that they directly bind to two sites of the SMN2 pre-mRNA, thereby stabilizing a novel ribonucleoprotein (RNP) complex in the SMN2 gene that is critical for the high target specificity of these small molecules over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work may have wide-ranging consequences for further research to identify small molecules that target splicing correction of specific genes by interacting with tertiary RNA structures.
2017-08-11 | GSE86001 | GEO
Project description:Binding to SMN2 pre-mRNA-Protein complex elicits specificity for small molecule splicing modifiers
| PRJNA339972 | ENA
Project description:Spinal muscular atrophy (SMA) is an autosomal recessive, pediatric-onset disorder caused by the loss of spinal motor neurons thereby leading to generalized muscle atrophy. SMA is caused by the loss of or mutations in the survival motor neuron 1 (SMN1) gene. SMN1 is duplicated only in human to give rise to the paralogous SMN2 gene. These paralogs are nearly identical except for a cytosine to thymine (C-to-T) transition within an exonic splicing enhancer (ESE) element within exon 7. As a result, the majority of SMN2 transcripts lack exon 7 (SMNΔ7) which produces a truncated and unstable SMN protein. Since SMN2 copy number is inversely related to disease severity, it is a well-established target for SMA therapeutics development. 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of sodium/proton exchangers (NHEs), has previously been shown to increase exon 7 inclusion and SMN protein levels in SMA cells. In this study several different types of NHE inhibitors were evaluated for their ability to modulate SMN2 expression. EIPA as well as 5-(N,N-hexamethylene)amiloride (HMA) increase exon 7 inclusion in SMN2 splicing reporter lines as well as in SMA fibroblasts. The EIPA-induced exon 7 inclusion occurs via a mechanism unique from that used by RG7800, another SMN2 splicing modulator, and does not involve previously identified splicing factors. Transcriptome analysis identified novel targets, including TIA1 and FABP3, for further characterization. EIPA and HMA are more selective at inhibiting the NHE5 isoform, which is expressed in fibroblasts as well as in neuronal cells. These results show that NHE5 inhibition increases SMN2 expression and may be a novel target for therapeutics development.
2022-06-16 | GSE179861 | GEO
Project description:Motoneuron cell bodies were isolated by laser capture microdissection from severe SMA mice at postnatal day 3. The comparison was between heterozygote carriers, SMA disease mice and SMA mice rescued by a U7 snRNA correcting the splicing of human SMN2.
2015-03-05 | E-MTAB-3170 | biostudies-arrayexpress
Project description:Proline- and glutamine-rich (PSF) has been identified as an important driver of aggressive cancers, in which PSF-RNA interactions promotes the expression of numerous oncogenic transcripts by modulating epigenetic and splicing systems. To develop small compounds targeting PSF as next generation therapeutic agents for hormone therapy refractory cancers, we performed small molecule library screen and identified the compound designated as No.10-3 as a potent PSF inhibitor. We further describe another small molecule C-30, an improved analog of No.10-3. PSF inhibits p53 epression in prostate cancer cells by epigenetic regulation. We then performed ChIP-seq analysis to determined PSF and p53 binding regions.
2024-09-01 | GSE244040 | GEO
Project description:Small RNAs are implicated in chromatin modification and transcriptional gene silencing across the eukaryotic kingdom. Although well understood, fundamental mechanistic aspects of RNA-mediated chromatin regulation have remained obscure. It has not been possible to unambiguously distinguish whether small RNA loaded Argonaute proteins target the nascent transcript or the underlying DNA sequence. Here, we demonstrate that transcription of the target locus is indispensable for the formation of heterochromatin in fission yeast. Yet, high transcriptional activity opposes RNA-directed chromatin silencing. We further find that pre-mRNA splicing is compatible with RNA-directed heterochromatin formation. Small RNAs complementary to promoter distal introns trigger the formation of stable heterochromatin irrespective of pre-mRNA splicing. However, targeting a functional intron close to the 5’ end of a transcript results in a bistable chromatin state. Together, our results disprove siRNA-DNA base-pairing and provide mechanistic insights that will inform the experimental design of small RNA-directed chromatin silencing studies in multicellular organisms.
2017-02-13 | GSE87672 | GEO
Project description:The nuclear matrix associated hnRNP U/SAF-A protein has been implicated in diverse pathways from transcriptional regulation to telomere length control to X inactivation, but the precise mechanism underlying each of these processes has remained elusive. Here, we report hnRNP U as a regulator of SMN2 splicing from a custom RNAi screen. Genome-wide analysis by CLIP-seq reveals that hnRNP U binds virtually to all classes of regulatory non-coding RNAs, including all snRNAs required for splicing of both major and minor classes of introns, leading to the discovery that hnRNP U regulates U2 snRNP maturation and Cajal body morphology in the nucleus. Global analysis of hnRNP U-dependent splicing by RNA-seq coupled with bioinformatic analysis of associated splicing signals suggests a general rule for splice site selection through modulating the core splicing machinery. These findings exemplify hnRNP U/SAF-A as a potent regulator of nuclear ribonucleoprotein particles in diverse gene expression pathways. Examination of hnRNP U regulated splicing in Hela cells with CLIP-seq (two biological replicates) and paired-end RNA-seq (control and hnRNP U knockdown)
2012-02-16 | E-GEOD-34491 | biostudies-arrayexpress
Project description:RNA secondary structures have been increasingly reported to serve critical regulatory roles in post-transcriptional gene regulation. RNA G-quadruplex secondary structures can serve as cis-elements to recruit splicing factors and regulate alternative RNA splicing. We recently showed that RNA G-quadruplexes play a critical regulatory role in regulating alternative splicing during the epithelial mesenchymal transition. Due to the critical role alternative splicing plays in human health and disease, an unmet need exists to identify small molecule modulators of alternative splicing. In this study, we performed high-throughput screening using a dual-output splicing reporter to identify small molecules capable of regulating alternative splicing by interacting with RNA secondary structure G-quadruplexes. We identify emetine and its analog cephaeline as small molecules that denature RNA G-quadruplexes in a sequence and location independent manner to modify alternative splicing. Transcriptome analysis reveals that treatment with emetine globally regulates alternative splicing, including events associated with exon-proximal G-quadruplexes. These data suggest a critical role for emetine and cephealine as splicing regulators with the selective ability to disrupt RNA G-quadruplex-associated alternative splicing in vivo.
2019-02-01 | GSE113505 | GEO
Project description:Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and is the second most common genetic disorder leading to death in childhood. Motoneurons derived from induced pluripotent stem cells (iPSC) obtained by reprogramming SMA patient and his healthy father fibroblasts, and genetically corrected SMA-iPSC obtained converting SMN2 into SMN1 with target gene correction (TGC), were used to study gene expression and splicing events linked to pathogenetic mechanisms. Microarray technology was used to assess the global gene expression profile as well as splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells. The microarray data derived from three different groups: SMA patient, healty father and treated SMA patient's cells. Each population consists of three RNA profiling cell samples.
2013-01-04 | E-GEOD-27205 | biostudies-arrayexpress