ArgRS, MetRS, and SRRM2 dependent changes in mRNA splicing and exon usage
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA694846 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13529900_1.fastq.gz | Fastqsanger.gz | |||
| SRR13529900_2.fastq.gz | Fastqsanger.gz | |||
| SRR13529901_1.fastq.gz | Fastqsanger.gz | |||
| SRR13529901_2.fastq.gz | Fastqsanger.gz | |||
| SRR13529902_1.fastq.gz | Fastqsanger.gz |
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Project description:Arginine is involved in inflammation and amino acid signaling, in part through the mTORC1 pathway. In cell-based assays and in the mouse, we found that arginine regulates nuclear levels of arginyl-tRNA synthetase (ArgRS) and that nuclear ArgRS interacts and co-localizes with the Serine/Arginine Repetitive Matrix Protein 2 (SRRM2), a spliceosomal protein crucial for the formation of nuclear speckle condensates. Arginine depletion or ArgRS knock down, both of which decreased nuclear ArgRS levels, mobilized SRRM2 for trafficking from nuclear condensates and altered mRNA processing and splice junction usage while minimally affecting expression of other cellular RNAs. These splice junction changes included a subset that were inversely correlated with SRRM2 knock down induced changes and the affected genes encompassed components of the mTORC1 pathway. This inverse correlation suggests that the nuclear ArgRS-SRRM2 interaction regulates SRRM2 nuclear trafficking and alternative splicing in the physiological response to changed arginine levels resulting from inflammation.
2023-04-03 | GSE165513 | GEO
Project description:We reported the joint SRRM1/2 regulation is not the major mechanism of SRRM2-mediated alternative splicing, and that maintenance of splicing condensates by SRRM2 is important for proper alternative splicing. We knocked SRRM1/2 down with three different shRNAs, performed RNA-seq and derived the differential alternative splicing events (DASEs) using rMATS. DASEs of SRRM1/2 were largely different with little overlap, and displayed a different splicing pattern. SRRM2 deficiency induces skipping of cassette exons with short introns and weak 5’ splice. Nearly 25% of the skipped events upon SRRM2 knockdown were unannotated. More than 40% of validated DASEs upon SRRM2 suppression were associated with protein domain change (>50% domain removed by splicing). Domain changes, and especially large region removal by multiple exon skipping is a significant mechanism for protein dysfunction. Thus, alternative splicing is the major mechanism for the maintenance of protein function and cell homeostasis by SRRM2.
2022-08-30 | GSE199720 | GEO
Project description:Srrm2 splicing factor is a novel gene implicated in developmental disorders and diseases. However, the role of Srrm2 in early mammalian development remains unexplored. Here, we show that Srrm2 expression dosage is critical for maintaining embryonic stem cell pluripotency and cell identity. Srrm2 heterozygosity promotes loss of stemness characterized by the coexistence of cells expressing naive and formative markers, together with large gene expression shifts, including in serum-response transcription factor targets and differentiation-related genes. Depletion of Srrm2 by RNA interference in embryonic stem cells identified splicing misregulation of specific genes, often linked to exon skipping. These results show that Srrm2 dosage is key in controlling stemness and cell fate decisions. Our findings unveil Srrm2’s molecular and cellular implications in development, shedding light on the involvement of splicing regulators in early embryogenesis, developmental diseases and tumorigenesis.
2024-04-12 | GSE243431 | GEO
Project description:Srrm2 splicing factor is a novel gene implicated in developmental disorders and diseases. However, the role of Srrm2 in early mammalian development remains unexplored. Here, we show that Srrm2 expression dosage is critical for maintaining embryonic stem cell pluripotency and cell identity. Srrm2 heterozygosity promotes loss of stemness characterized by the coexistence of cells expressing naive and formative markers, together with large gene expression shifts, including in serum-response transcription factor targets and differentiation-related genes. Depletion of Srrm2 by RNA interference in embryonic stem cells identified splicing misregulation of specific genes, often linked to exon skipping. These results show that Srrm2 dosage is key in controlling stemness and cell fate decisions. Our findings unveil Srrm2’s molecular and cellular implications in development, shedding light on the involvement of splicing regulators in early embryogenesis, developmental diseases and tumorigenesis.
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Project description:Srrm2 splicing factor is a novel gene implicated in developmental disorders and diseases. However, the role of Srrm2 in early mammalian development remains unexplored. Here, we show that Srrm2 expression dosage is critical for maintaining embryonic stem cell pluripotency and cell identity. Srrm2 heterozygosity promotes loss of stemness characterized by the coexistence of cells expressing naive and formative markers, together with large gene expression shifts, including in serum-response transcription factor targets and differentiation-related genes. Depletion of Srrm2 by RNA interference in embryonic stem cells identified splicing misregulation of specific genes, often linked to exon skipping. These results show that Srrm2 dosage is key in controlling stemness and cell fate decisions. Our findings unveil Srrm2’s molecular and cellular implications in development, shedding light on the involvement of splicing regulators in early embryogenesis, developmental diseases and tumorigenesis.
2024-04-12 | GSE243432 | GEO
Project description:Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
2024-04-25 | PXD050320 | Pride
Project description:Neuronal activity regulates alternative exon usage
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Project description:Cells respond to perturbations like inflammation by sensing changes in metabolite levels. Especially prominent is arginine, which has known connections to the inflammatory response. Here, we found that depletion of arginine during inflammation decreased levels of a nuclear form of arginyl-tRNA synthetase (ArgRS). Surprisingly, we found that nuclear ArgRS interacts and co-localizes with serine/arginine repetitive matrix protein 2 (SRRM2), a spliceosomal and nuclear speckle protein, and that decreased levels of nuclear ArgRS correlated with changes in condensate-like nuclear trafficking of SRRM2 and splice-site usage in certain genes. These splice-site usage changes cumulated in the synthesis of different protein isoforms that altered cellular metabolism and peptide presentation to immune cells. Our findings uncover a novel mechanism whereby a tRNA synthetase cognate to a key amino acid that is metabolically controlled during inflammation modulates the splicing machinery.
2023-04-14 | PXD036232 | Pride
Project description:Papillary thyroid carcinoma (PTC) displays strong but so far largely uncharacterized heritability. Here we studied genetic predisposition in a family with six affected individuals. We genotyped all available family members and conducted whole exome sequencing of blood DNA from two affected individuals. Haplotype analysis and other genetic criteria narrowed our list of candidates to a germline variant in the serine/arginine repetitive matrix 2 gene (SRRM2). This heterozygous variant, c.1037C>T (Ser346Phe or S346F; rs149019598) cosegregated with PTC in the family. It was not found in 138 other PTC families. It was found in 7/1,170 sporadic PTC cases and in 0/1,404 controls (p=0.004). The encoded protein SRRM2 (also called SRm300) is part of the RNA splicing machinery. To evaluate the possibility that the S346F missense mutation affects alternative splicing, we compared RNA-Seq data in leukocytes from three mutation carriers and three controls. Significant differences in alternative splicing were identified for 1,642 exons, of which a subset of 7 exons was verified experimentally. The results confirmed a higher ratio of inclusion of exons in mutation carriers. These data suggest that the S346F mutation in SRRM2 predisposes to PTC by affecting alternative splicing of unidentified downstream target genes.
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Project description:Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
2024-04-25 | GSE260790 | GEO