Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE299937 | GEO | 2026/04/14
REPOSITORIES: GEO
Similar Datasets
Project description:Srrm2 haploinsufficiency drives SynGAP-γ reduction, Agap3 mis-splicing, and oligodendrocyte deficits in a genetic mouse model of schizophrenia
| PRJNA1277574 | ENA
Project description:Nuclear speckles (NSs) are nuclear biomolecular condensates that are postulated to arise through liquid-liquid phase separation (LLPS), although the detailed underlying forces driving NS formation remain elusive. SRRM2 and SON are 2 non-redundant scaffold proteins for NSs. How each individual protein governs assembly of NS protein network and the functional relationship between SRRM2 and SON are largely unknown. Here, we uncover immiscible multiphase of SRRM2 and SON within NSs. SRRM2 and SON are functionally independent, specifically regulating alternative splicing of subsets of mRNA targets, respectively. We further uncover that SRRM2 forms multicomponent liquid phase in cells to drive NS subcompartmentalization, which is reliant on homotypic interaction and heterotypic non-selective protein-RNA complex coacervation-driven multicomponent LLPS. SRRM2 RS domains form high-order oligomers, and can be replaced by oligomerizable synthetic modules, the serine residues within the RS domains, however, play an irreplaceable role in fine-tuning the liquidity of NSs.
2024-01-31 | GSE242898 | 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 | GSE243429 | 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.
2024-04-12 | GSE243432 | 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: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:Vaccinia-related kinase 1 (VRK1) is a nuclear serine/threonine kinase that contributes to genome stability through the phosphorylation of diverse substrates. This study investigated whether VRK1 regulates pre-messenger RNA splicing through serine/arginine repetitive matrix protein 2 (SRRM2), a nuclear speckle-associated splicing scaffold. Messenger RNA sequencing was performed in control HEK293T cells, VRK1-knockout HEK293T cells, and SRRM2-depleted HEK293T cells. Alternative splicing events were analyzed using replicate Multivariate Analysis of Transcript Splicing. Most differential alternative splicing events detected following VRK1 knockout or SRRM2 depletion were skipped-exon events. A subset of skipped-exon events was shared between VRK1-knockout and SRRM2-depleted cells, and the corresponding genes were enriched in DNA repair-related pathways. These data support a role for the VRK1-SRRM2 regulatory axis in maintaining the efficient alternative splicing of DNA damage response-related transcripts.
2026-07-22 | GSE338004 | GEO
Project description:In order to investigate the role of SR protein assemblies on GA-multivalent mRNA regions and their relationship to the nuclear speckle. We performed iCLIP of Tra2b, Son-GFP and Srrm2-GFP in mESCs. The GFP-tagged proteins are endogenously tagged and immunoprecipitated using an anti-GFP antibody, while Tra2b was immunoprecipitated using an antibody against the endogenous protein. Srrm2 and Son are very large proteins, but signal was observed at a variety of molecular weights along the membrane, suggesting indirect interactions. We isolated two fractions for each Srrm2 or Son sample: one 'high MW', cut at ~300kDa upwards, and one 'low MW' cut from 40 kDa to 300 kDa. These samples were prepared and sequenced separately. The data provided here has been demultiplexed and trimmed, and therefore should not contain adapter sequences or barcodes. UMI sequences have been moved to the fastq header. Also included are transcriptomic coordinates of deduplicated crosslinks for each sample, using one transcript per gene, as used to plot transcriptomic metaprofiles around multivalent sites.
2025-09-12 | E-MTAB-13331 | biostudies-arrayexpress
Project description:Cells need to sense and respond adequately to environmental stimuli. Metabolites provide information on systemic changes, for example during inflammation. We show that depletion of the amino acid arginine during inflammation reduced nuclear levels of its cognate aminoacyl tRNA synthetase, Arginyl-tRNA synthetase (ArgRS). In the nucleus, ArgRS interacted with serine/arginine repetitive matrix protein 2 (SRRM2), a spliceosomal protein and nuclear speckle organizer, in distinct condensate-like structures. ArgRS’ presence in the nucleus impeded SRRM2 mobility. Differences in SRRM2 speckle trafficking were directly reflected in alternative mRNA splicing: splice site usage was regulated in the opposite direction by ArgRS as by SRRM2, suggesting sequestration of SRRM2 by ArgRS as a regulatory mechanism. ArgRS- and SRRM2-dependent mRNA processing changes cumulated in altered metabolism and peptide presentation to immune cells. Our findings indicate a general mechanism in which ArgRS and SRRM2 act together as upstream regulators during the physiological response to inflammatory injury.
2025-06-12 | PXD027531 | Pride