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Genome wide analysis of RNA species present in SMN-containing RNPs

ABSTRACT: Several studies indicate that SMN-containing mRNP complexes could be involved in the axonal localization of a large number of mRNAs. We have used murine motor neuron-like NSC-34 cells and RNA Immuno-Precipitation experiments coupled to microarray analyses to perform a genome-wide analysis of RNA species present in mRNP complexes containing the full length SMN protein (flSMN). In situ hybridization and immuno-fluorescence experiments performed on several candidates indicate that these mRNAs colocalize with the SMN protein in neurites and axons of differentiated NSC-34 cells. Moreover, they localize in cell processes in a SMN-dependent manner. Thus, low SMN levels might result in localization deficiencies of mRNAs required for axonogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE40197 | GEO | 2013/11/29

SECONDARY ACCESSION(S): PRJNA173074

REPOSITORIES: GEO

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Genome wide analysis of RNA species present in SMN-containing RNPs

Project description:Several studies indicate that SMN-containing mRNP complexes could be involved in the axonal localization of a large number of mRNAs. We have used murine motor neuron-like NSC-34 cells and RNA Immuno-Precipitation experiments coupled to microarray analyses to perform a genome-wide analysis of RNA species present in mRNP complexes containing the full length SMN protein (flSMN). In situ hybridization and immuno-fluorescence experiments performed on several candidates indicate that these mRNAs colocalize with the SMN protein in neurites and axons of differentiated NSC-34 cells. Moreover, they localize in cell processes in a SMN-dependent manner. Thus, low SMN levels might result in localization deficiencies of mRNAs required for axonogenesis. RNA species coimmunoprecipitated with the SMN protein were used for hybridization of Affymetrix microarrays

2013-11-29 | E-GEOD-40197 | biostudies-arrayexpress

Ribosome profiling of SMN-primed ribosomes and active ribosome profiling from brains of a mouse model of severe SMA

Project description:Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, with an incidence of around 1 in 6,000-10,000 live births. SMA is caused by low levels of full-length survival of motor neuron protein (SMN). We demonstrate that SMN binds to ribosomes and that this interaction is tissue-dependent. We performed ribosome profiling analyses on lysates from P5 wild-type mouse brains exposed to RNase I, from which we isolated SMN-primed ribosomes by immunoprecipitation. SMN-primed ribosomes are preferentially positioned within the first five codons of a set of mRNAs which are enriched for translational enhancer sequences in the 5’UTR and rare codons at the beginning of their coding sequence. These SMN-specific mRNAs are associated with neurogenesis, lipid metabolism, ubiquitination, chromatin regulation and translation. Additionally, we analyzed the positioning of active ribosomes using the Active-RiboSeq method based on RiboLace and compared early symptomatic SMA mouse brains to age-matched controls. We found that loss of SMN induces ribosome depletion, especially at the beginning of the coding sequence of SMN-specific mRNAs, leading to impairment of proteins involved in motor neuron function and stability. Keywords: motor neuron disease, spinal muscular atrophy, SMA, SMN, SMN1, survival of motor neuron, SMN-primed ribosome profiling, translation, RiboLace, Ribo-Seq, active translation, ribosome heterogeneity

2020-08-11 | GSE154106 | GEO

Trancriptional regulation by axonal SMN on motor neuron cells

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

Interaction of 7SK with the Smn complex modulates snRNP production

Project description:Gene expression requires tight coordination of the molecular machineries that mediate transcription and splicing. While the interplay between transcription kinetics and spliceosome fidelity has been investigated before, less is known about mechanisms regulating the assembly of the spliceosomal machinery in response to transcription changes. Here we report an association of the Smn complex, which mediates spliceosomal snRNP biogenesis, with the 7SK complex involved in transcriptional regulation. We found that Smn interacts with the 7SK core components Larp7 and Mepce and specifically associates with 7SK subcomplexes containing hnRNP R. The association between Smn and 7SK complexes is enhanced upon transcriptional inhibition leading to reduced production of snRNPs. Taken together, our findings reveal a functional association of Smn and 7SK complexes that is governed by global changes in transcription. Thus, in addition to its canonical nuclear role in transcriptional regulation, 7SK has cytosolic functions in fine-tuning spliceosome production according to transcriptional demand.

2021-01-26 | PXD021360 | Pride

Transcriptome profiling of untreated and doxycycline-treated HeLa/TO-SmN

Project description:Purpose is to examine the effect of SmN expression to gene expression in HeLa Compare the differences between the transcriptome of untreated and doxycycline-treated HeLa/TO-SmN in which expression of SmN is under doxycycline control

2015-01-16 | E-GEOD-54136 | biostudies-arrayexpress

Transcriptome and translatome profiling from brains of a mouse model of severe SMA

Project description:Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, with an incidence of around 1 in 6,000-10,000 live births. SMA is caused by low levels of full-length survival of motor neuron protein (SMN). Approximately 95% of SMA cases in humans are caused by homozygous deletion of SMN1, with a smaller number caused by discrete mutations within the gene. In concert with other RNA binding proteins, SMN forms complexes both in the nucleus and the cytoplasm of neurons. As such, SMN protein has housekeeping roles in the assembly of ribonucleoprotein (RNP) complexes. In addition, SMN localises to dendrites, synapses and axons in vivo and in vitro, where it is part of messenger RNP (mRNP) complexes with well-known roles in the transport of mRNA. These cellular processes are tightly linked to local translation, suggesting that SMN may play a pivotal role in its regulation. We employed next generation sequencing (NGS) to identify and quantify RNAs associated with polysomes (POL-Seq) in parallel with total cytoplasmic RNA (RNA-Seq) in an established mouse model of severe SMA at both early and late-symptomatic stages. This approach enables the simultaneous identification of variations in RNA populations at both translatome (RNAs engagement with polysomes) and transcriptome (steady state cytoplasmic RNAs) levels. Keywords: motor neuron disease, spinal muscular atrophy, SMA,SMN, translation, polysome profiling, POL-Seq, RNA-Seq

2017-10-24 | GSE102204 | GEO

HITS-CLIP of SMN

Project description:We performed HITS-CLIP to determine cellular RNA targets of the SMN protein. Three replicates were performed in SH-SY5Y cells.

2018-08-01 | GSE110411 | GEO

Multiple Molecular Pathways are influenced by Progranulin in a neuronal cell model

Project description:NSC-34 cells produced by fusing mouse embryonic spinal cord motor neuron with neuroblastoma cells expressing reduced level of PGRN (NSC-34/ShPGRN), NSC-34 cells overexpressing hPGRN(NSC-34-/hPGRN) or vector controls were compared in triplicate

2021-11-25 | MSV000088451 | MassIVE

HITS-CLIP of SMN

Project description:HITS-CLIP of SMN

| PRJNA433653 | ENA

Gain of toxic function by long-term SMN overexpression in the sensory-motor circuit.

Project description:The neurodegenerative disease spinal muscular atrophy (SMA) is a leading genetic cause of infant death caused by deficiency in the survival motor neuron (SMN) protein. Currently approved SMA treatments aim to restore SMN, but the potential for expression of SMN beyond physiological levels is a unique feature of AAV9-SMN gene therapy. Here, we show that long-term AAV9-mediated SMN overexpression in mouse models induces dose-dependent, late-onset motor dysfunction associated with loss of proprioceptive synapses and neurodegeneration. Mechanistically, aggregation of overexpressed SMN in the cytoplasm of motor circuit neurons sequesters components of small nuclear ribonucleoproteins (snRNPs), leading to splicing dysregulation and widespread transcriptome abnormalities with prominent signatures of neuroinflammation and innate immune response. Thus, long-term SMN overexpression can interfere with its normal activity in RNA regulation and trigger SMA-like pathogenic events through toxic gain of function mechanisms. These unanticipated, SMN-dependent and neuron-specific liabilities of AAV9-SMN warrant further evaluation of the long-term safety of gene therapy in SMA.

2021-02-01 | GSE149391 | GEO

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