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Modulation of insulin secretion through RBFOX2-mediated alternative splicing

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE221277 | GEO | 2023/09/25

REPOSITORIES: GEO

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Modulation of insulin secretion by RBFOX2-mediated alternative splicing.

Project description:Insulin secretion is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Although the molecular components of insulin granule trafficking and secretion are well established, how they are regulated to rapidly fine-tune secretion in response to changing environmental conditions is not well characterized. Recent studies have determined that dysregulation of RNA-binding proteins (RBPs) and aberrant mRNA splicing occurs at the onset of diabetes. We demonstrate that the RBP, RBFOX2, is a critical regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis. Conditional mutation of Rbfox2 in the mouse pancreas results in decreased insulin secretion and impaired blood glucose homeostasis. Consistent with defects in secretion, we observe reduced insulin granule docking and corresponding splicing defects in the SNARE complex components. These findings identify an additional mechanism for modulating insulin secretion in both healthy and dysfunctional pancreatic β cells.

| S-EPMC10676425 | biostudies-literature

Modulation of insulin secretion through RBFOX2-mediated alternative splicing [eCLIP-Seq MIN6]

Project description:Recent studies have identified dysregulation of RNA-binding proteins (RBPs) and aberrant mRNA splicing in the onset of diseases including diabetes. Here we investigated the role of RBFOX2 in the pancreatic β cell through the conditional mutation of Rbfox2 in the mouse pancreas (Pdx1:Cre; Rbfox2fl/lf) and RNAi experiments in the mouse insulinoma cell line, MIN6. We then identified the direct targets of RBFOX2 in the mouse β cell transcriptome my eCLIP-Seq in MIN6 cells.

2023-09-25 | GSE221276 | GEO

Modulation of insulin secretion through RBFOX2-mediated alternative splicing [RNA-seq MIN6]

2023-09-25 | GSE221274 | GEO

Modulation of insulin secretion through RBFOX2-mediated alternative splicing

Project description:Modulation of insulin secretion through RBFOX2-mediated alternative splicing

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Modulation of insulin secretion through RBFOX2-mediated alternative splicing [RNA-seq Mouse Iselt]

2023-09-25 | GSE221275 | GEO

Modulation of insulin secretion through RBFOX2-mediated alternative splicing [eCLIP-Seq MIN6]

Project description:Modulation of insulin secretion through RBFOX2-mediated alternative splicing [eCLIP-Seq MIN6]

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Modulation of insulin secretion through RBFOX2-mediated alternative splicing [RNA-seq MIN6]

Project description:Modulation of insulin secretion through RBFOX2-mediated alternative splicing [RNA-seq MIN6]

| PRJNA913812 | ENA

Modulation of insulin secretion through RBFOX2-mediated alternative splicing [RNA-seq Mouse Iselt]

Project description:Modulation of insulin secretion through RBFOX2-mediated alternative splicing [RNA-seq Mouse Iselt]

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RBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing.

Project description:RNA splicing is an important biological process associated with cancer initiation and progression. However, the contribution of alternative splicing to pancreatic cancer (PDAC) development is not well understood. Here, we identify an enrichment of RNA binding proteins (RBPs) involved in splicing regulation linked to PDAC progression from a forward genetic screen using Sleeping Beauty insertional mutagenesis in a mouse model of pancreatic cancer. We demonstrate downregulation of RBFOX2, an RBP of the FOX family, promotes pancreatic cancer progression and liver metastasis. Specifically, we show RBFOX2 regulates exon splicing events in transcripts encoding proteins involved in cytoskeletal remodeling programs. These exons are differentially spliced in PDAC patients, with enhanced exon skipping in the classical subtype for several RBFOX2 targets. RBFOX2 mediated splicing of ABI1, encoding the Abelson-interactor 1 adapter protein, controls the abundance and localization of ABI1 protein isoforms in pancreatic cancer cells and promotes the relocalization of ABI1 from the cytoplasm to the periphery of migrating cells. Using splice-switching antisense oligonucleotides (AONs) we demonstrate the ABI1 ∆Ex9 isoform enhances cell migration. Together, our data identify a role for RBFOX2 in promoting PDAC progression through alternative splicing regulation.

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FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2-Mediated Alternative Splicing.

Project description:Mesenchymal glioblastoma (GBM) is highly resistant to radio-and chemotherapy and correlates with worse survival outcomes in GBM patients; however, the underlying mechanism determining the mesenchymal phenotype remains largely unclear. Herein, it is revealed that FBXO7, a substrate-recognition component of the SCF complex implicated in the pathogenesis of Parkinson's disease, confers mesenchymal properties and chemoresistance in GBM by controlling Rbfox2-mediated alternative splicing. Specifically, FBXO7 ubiquitinates Rbfox2 Lys249 through K63-linked ubiquitin chains upon arginine dimethylation at Arg341 and Arg441 by PRMT5, leading to Rbfox2 stabilization. FBXO7 controls Rbfox2-mediated splicing of mesenchymal genes, including FoxM1, Mta1, and Postn. FBXO7-induced exon Va inclusion of FoxM1 promotes FoxM1 phosphorylation by MEK1 and nuclear translocation, thereby upregulates CD44, CD9, and ID1 levels, resulting in GBM stem cell self-renewal and mesenchymal transformation. Moreover, FBXO7 is stabilized by temozolomide, and FBXO7 depletion sensitizes tumor xenografts in mice to chemotherapy. The findings demonstrate that the FBXO7-Rbfox2 axis-mediated splicing contributes to mesenchymal transformation and tumorigenesis, and targeting FBXO7 represents a potential strategy for GBM treatment.

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