RNPS1 inhibits excessive TNF/TNFR signaling to support hematopoiesis in mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA649939 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14243922_1.fastq.gz | Fastqsanger.gz | |||
| SRR14243922_2.fastq.gz | Fastqsanger.gz | |||
| SRR14243923_1.fastq.gz | Fastqsanger.gz | |||
| SRR14243923_2.fastq.gz | Fastqsanger.gz | |||
| SRR14243924_1.fastq.gz | Fastqsanger.gz |
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Project description:Null mutations of spliceosome components or cofactors are homozygous lethal in eukaryotes, but viable hypomorphic mutations provide an opportunity to understand the physiological impact of individual splicing proteins. We describe a viable missense allele of Rnps1, encoding an essential regulator of splicing and nonsense-mediated decay, identified in a mouse genetic screen for altered immune cell development. Homozygous mice displayed a stem cell-intrinsic defect in hematopoiesis of all lineages due to excessive apoptosis induced by TNF-dependent death signaling. Numerous splicing variants were observed in Rnps1 mutant splenic CD8+ T and HSC cells, potentially driven by dysregulated splicing, characterized by magnification of both intron retention and exon skipping. Strikingly, Tnf knockout rescued all hematopoietic cells to normal or near-normal levels in Rnps1 mutant mice. Thus, RNPS1 is necessary for accurate splicing, without which disinhibited TNF signaling triggers hematopoietic cell death.
2022-03-31 | GSE155492 | GEO
Project description:Null mutations of spliceosome components or cofactors are homozygous lethal in eukaryotes, but viable hypomorphic mutations provide an opportunity to understand the physiological impact of individual splicing proteins. We describe a viable missense allele (F181I) of Rnps1 encoding an essential regulator of splicing and nonsense-mediated decay (NMD), identified in a mouse genetic screen for altered immune cell development. Homozygous mice displayed a stem cell–intrinsic defect in hematopoiesis of all lineages due to excessive apoptosis induced by tumor necrosis factor (TNF)–dependent death signaling. Numerous transcript splice variants containing retained introns and skipped exons were detected at elevated frequencies in Rnps1F181I/F181I splenic CD8+ T cells and hematopoietic stem cells (HSCs), but NMD appeared normal. Strikingly, Tnf knockout rescued all hematopoietic cells to normal or near-normal levels in Rnps1F181I/F181I mice and dramatically reduced intron retention in Rnps1F181I/F181I CD8+ T cells and HSCs. Thus, RNPS1 is necessary for accurate splicing, without which disinhibited TNF signaling triggers hematopoietic cell death.
| S-EPMC9170173 | biostudies-literature
Project description:RNPS1 is a splicing regulatory protein and a component of the ASAP/PSAP complex, which is associated with the exon junction complex and modulates alternative splicing. It was previously postulated that the isolated RRM domain of RNPS1 in complex with ASAP/PSAP is able to regulate certain alternative splicing events. We aimed to investigate in Flp-In T-REx 293 cells which alternative splicing events are rescued by the expression of the wild type RNPS1 or the isolated RRM domain of RNPS1 in a RNPS1 knockdown background by using RNA-Seq analyses. The rescue construct was stably integrated into the genome using the PiggyBac transposon system. As controls, either Luciferase (Luc) siRNA was used or RNPS1 was knocked down without rescue.
2022-05-06 | E-MTAB-10770 | biostudies-arrayexpress
Project description:RNPS1 is a component of the EJC-associated ASAP and PSAP complex. We used full-length RNPS1, RNPS1 with a C-terminal deletion and the RNPS1 RRM in a proximity labeling approach. We aimed to confirm interaction partners of RNPS1 previously identified by MS of RNPS1 IPs using the same RNPS1 deletion mutants (Project 2209 and 2236). By identifying RNPS1 interaction partners we want to uncover how RNPS1 is able to fulfill its splicing regulatory functions.
2022-05-16 | PXD032952 | Pride
Project description:RNPS1 is a splicing regulatory protein and a component of the ASAP/PSAP complex, which is associated with the exon junction complex and modulates alternative splicing. It was previously postulated that the isolated RRM domain of RNPS1 in complex with ASAP/PSAP is able to regulate certain alternative splicing events. We aimed to investigate in HeLa Tet-Off cells which alternative splicing events are rescued by the expression of the isolated RRM domain of RNPS1 in a RNPS1 knockdown background by using RNA-Seq analyses. The rescue construct was stably integrated into the genome using the PiggyBac transposon system. As controls, either Luciferase (Luc) siRNA was used or RNPS1 was knocked down without rescue.
2022-05-06 | E-MTAB-10768 | biostudies-arrayexpress
Project description:Alternative splicing of pre-mRNAs increases the potential for regulation and complexity of gene expression. The exon junction complex (EJC) and its associated splicing factor RNPS1 were recently shown to suppress mis-splicing resulting from the usage of cryptic and reconstituted 5’ and 3’ splice sites in the vicinity of the EJC. Here, we aimed to further investigate the mechanisms underlying splicing regulation by RNPS1. A transcriptome-wide analysis identified hundreds of splice events affected by the knockdown (KD) of RNPS1 in HeLa cells. These included alternative splice site usage as well as intron retention, exon skipping and inclusion. However, only a fraction of these RNPS1-dependent splice events was fully or partially rescued by the expression of the RNPS1 RRM. These results indicated that another domain of RNPS1 is involved in the regulation of the majority of splicing events. Deletion experiments revealed that the N-terminus and S-domain, and in particular the C-terminus of RNPS1 strongly regulate these events. Several splicing factors, including SR proteins and U1 snRNP components, were strongly reduced in the interactome of RNPS1 lacking the C terminus. We conclude that RNPS1 interacts with many splicing factors to direct the assembly of EJC-dependent and-independent splicing complexes.
2022-05-31 | PXD027251 | Pride
Project description:Background: Ozone (O3) is the predominant oxidant air pollutant associated with respiratory inflammation, lung dysfunction, and worsening preexisting airway diseases. We determined that TNFR signlaing pathway plays a key role in lung injury and inflammation caused by O3 in mice. However, downstream molecular mechanisms underlying TNFR pathway have not been investigated. Methods: To investigate the role of TNFR pathway in gene expression changes, Tnfr1/2-deficient (Tnfr-/-) and wild-type (Tnfr+/+, C57BL/6J) mice were exposed to air or 0.3-ppm O3. Total RNAs were isolated from lung homogenates and cDNA microarray analyses were performed to elucidate TNFR-directed transcriptomics in basal lungs (air-exposed) as well as in the lung exposed to time course of O3 (24, 48, and 72 hr). Results: O3 caused time-dependent changes in lung gene expressions with the greatest transcriptome changes at 48-72 hr of exposure in Tnfr+/+ mice. At early time of exposure (24 hr), acute phase and inflammatory responses gene as well as redox and lipid metabolism genes were increased by O3 while cell cycle and DNA damage repair genes were markedly increased by O3 at later time points (48-72 hr). Compared to Tnfr+/+ mice, Tnfr-/- mice had lowered expression of inflammatory response and vascular disorder-related genes at baseline (air). After O3 exposure, Tnfr-/- had enhanced expression of immune and inflammatory genes at 24 hr, indicating compensatory or adpative poentiation of immunity in Tnfr-/- mice. At 48 hr of O3 exposure, Tnfr-/- mice showed suppressed expression of genes involved in epithelial proliferation, inflammatory cell influxes and epithelial injury, compared to Tnfr+/+ mice. At 72 hr of O3 exposure, neurodegeneration and neurotransmitter transport genes were suppressed in Tnfr-/- than in Tnfr+/+. Conclusion: Overall, deficiency of TNFR-mediated signaling in mouse lungs altered transcriptomes to protect lungs from O3-induced inflammation, cell proliferation, oxidative stress, and neuronal disorders.
2021-09-29 | GSE166399 | GEO
Project description:We report the knockdown and rescue of RNPS1, a component of the ASAP and PSAP complexes and, hence, an auxiliary component of the exon junction complex. The studied conditions show an extensive change in alternative splicing and the cell's transcriptome. For the knockdown, HeLa cells were transfected with siRNAs targeting RNPS1 or the Luciferase control. Total RNA was extracted with peqGOLD TriFast, underwent ribosomal depletion and strand-specific library preparation (TruSeq R Stranded Total RNA LT). Sequencing occurred in an Illumina HiSeq4000 sequencer with 2×75bp, producing roughly 35 million read-pair per sample.
2018-11-01 | E-MTAB-6564 | biostudies-arrayexpress
Project description:RNA-Seq of control and RNPS1 knockdown with or without RNPS1 wildtype or RNPS1-RRM domain rescue in Flp-In T-REx 293 cells
| PRJEB46521 | ENA
Project description:The specific contribution of the two TNF-receptors Tnfr1 and Tnfr2 to TNF-induced inflammation in the glomerulus is unknown. In mice, TNF exposure induces glomerular expression of inflammatory mediators like adhesion molecules and chemokines in vivo, and glomerular accumulation of leukocytes. To examine Tnfr-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wild-type and Tnfr-deficient mice following TNF exposure in vitro. Glomeruli were isolated from male C57BL/6J wild-type and Tnfr-deficient mice applying a magnetic bead-based isolation technique. Isolated intact glomeruli were stimulated with TNF for 12 hours in vitro for subsequent RNA extraction and hybridization on Affymetrix microarrays.
2013-09-11 | E-GEOD-43928 | biostudies-arrayexpress