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Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis

ABSTRACT: Self-renewing hematopoietic stem cells (HSCs) generate all blood cells and give rise to long-term reconstitution of the hematopoietic system after transplantation, but the molecular mechanisms that specifically regulate HSCs remain poorly defined. Here we found that HSCs displayed a distinct mRNA alternative splicing pattern and preferentially expressed Rbfox2, an alternative splicing regulator, compared with multipotent progenitors (MPPs). Deletion of Rbfox2 from the hematopoietic compartment specifically depleted HSCs, but not progenitors in the adult bone marrow. Rbfox1 did not function redundantly with Rbfox2 in HSCs. Mechanistically, Rbfox2 loss led to proteostasis stress, including increased protein synthesis rate and accumulated misfolded/unfolded protein contents, in HSCs, but not in progenitors. Small molecules that restore proteostasis rescued HSC defects in Rbfox2-deficient mice. Our work thus reveals that HSCs, but not progenitors, selectively rely on Rbfox2 for their self-renewal and maintenance.

ORGANISM(S): Mus musculus

PROVIDER: GSE210650 | GEO | 2025/11/01

REPOSITORIES: GEO

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Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis

Project description:Purpose: The goals of this study are to compare transcriptomes using RNA-seq of mouse myoblasts (C2C12 cell line) in undifferentiated and differentiated states and with siRNA-mediated knock down of the RNA binding proteins, Rbfox1 (only expressed in differentiated state) and Rbfox2 (expressed in both undifferentiated and differentiated states). Methods: Differentiated and undifferentiated C2C12 cultures treated with Rbfox1 (differentiated only) or Rbfox2 siRNAs or a mock siRNA transfection were used for RNA-Seq analysis using Illumina HiSeq2000. 101x2 paired-end RNA-seq reads were first uniquely aligned to the mouse genome (mm9) using TopHat 1.4.1. RSEM was used to count the number of reads mapped to genes using UCSC database, followed by edgeR to call differentially expressed genes with false discovery rate less than 0.01. Cufflinks was used to reconstruct isoforms and analyze alternative splicing and percent spliced in (PSI) was calculated. PSI values were validated by RT-PCR. Results: 58-88% of the RNA-seq reads from technical and biological replicates mapped uniquely to the mouse genome. Analysis of gene expression and alternative splicing changes are published in Singh et al. Molecular Cell (2014). Conclusions: Our study has identified gene expression and alternative splicing transitions that occur during myoblast differentiation, demonstrate that 30% of the splicing transitions are regulated by Rbfox2, demonstrated that Rbfox2 is required for a late step of myoblast differentiation and identified two Rbfox2-regulated splicing transitions that are required for differentiation. Undifferentiated and differentiated C2C12 cultures with Rbfox2 depletion or Rbfox1 depletion (differentiated only) in at least duplicate samples analyzed by deep sequencing on Illumina HiSeq2000.

2014-07-15 | E-GEOD-58928 | biostudies-arrayexpress

Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis

2014-07-15 | GSE58928 | GEO

Rbfox2 controls autoregulation in RNA binding protein networks

Project description:We generated a global analysis of Rbfox2 splicing regulation combined with a highly specific, single nucleotide-resolution Rbfox2 RNA binding map. We found that Rbfox2 regulates the splicing and expression of many previously unknown targets, and particularly a number of RNA binding proteins (RBPs), by modulating alternative splicing coupled-NMD. Based on our observations of RBP-Rbfox2 co-regulation with a polarity predicted by Rbfox2 binding, we propose a model whereby Rbfox2 tunes autoregulatory splicing events to control RBP expression levels and in turn alter their respective splicing networks. iCLIP for epitope-tagged Rbfox2 and control untagged Rbfox2; RNAseq of control and Rbfox2 knockdown in mouse embryonic stem cells

2014-03-17 | E-GEOD-54794 | biostudies-arrayexpress

Rbfox2 controls autoregulation in RNA binding protein networks

2014-03-17 | GSE54794 | GEO

Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis

Project description:Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis

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Retinal transcriptome analysis of Rbfox2 deficient animals

Project description:Rbfox proteins regulate alternative splicing, mRNA stability and translation. These proteins are involved in neurogenesis and have been associated with various neurological conditions. We generated expression profile in adult and developing mouse retinas which lacks in Rbfox2 expression by RNA sequencing. The goals of this study is to identify the affected pathways in Rbfox2 KO mouse retina as well as potential splicing targets of Rbfox2.

2020-11-18 | GSE155411 | GEO

RNAseq of livers from WT mice or livers with Rbfox2 knockout fed CD

Project description:Rbfox2 is required for maintaining hepatic metabolic homeostasis, here we carry out RNAseq to of WT and aged matched littermate Rbfox2 knockout mice under high fructose in order to determine changes in alternative splicing and mRNA expression caused by knockout of this splicing factor in this metabolic environment.

2022-09-26 | GSE151748 | GEO

Expression data from human pancreatic cancer cell lines and mouse orthotopic tumors generated using human PDAC cell lines replete and depleted for RBFOX2

Project description:RBFOX2 is an RNA binding protein that directs alternative splicing. In this study, we characterized RBFOX2-mediated alternative splicing in pancreatic cancer (PDAC) In this dataset, we assayed gene-level and exon-level expression differences in pancreatic cancer cell lines replete and depleted for RBFOX2 expression and in 8 pairs of orthotopic pancreas tumors and related liver metastases generated from human 4039 or Panc1 cell lines replete or depleted for RBFOX2.

2023-11-07 | GSE211435 | GEO

RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis

Project description:ABSTRACT 20-30% of patients with nasopharyngeal carcinoma (NPC) develop distant metastasis or recurrence leading to poor survival, of which the underlying key molecular events have yet to be addressed. Here we profiled alternative splicing events in 85 NPC samples using transcriptome analysis and revealed that the long isoform of GOLIM4 (-L) with exon-7 was highly expressed in NPC and associated with poor prognosis. Lines of evidence demonstrated the pro-tumorigenic function of GOLIM4-L in NPC cells. We further revealed that RBFOX2 binds to a GGAA motif in exon-7 and promotes its inclusion forming GOLIM4-L. RBFOX2 knockdown suppressed the tumorigenesis of NPC cells, phenocopying GOLIM4-L knockdown, which was significantly rescued by GOLIM4-L overexpression. Moreover, high expression of RBFOX2 was correlated with the exon-7 inclusion of GOLIM4 in NPC biopsies and associated with worse prognosis. Furthermore, we observed that RBFOX2 and GOLIM4 could influence vesicle-mediated transport through maintaining the organization of Golgi apparatus. Finally, we revealed that RAB26 interacted with GOLIM4 and mediated its tumorigenic potentials in NPC cells. Taken together, our findings provide insights into how alternative splicing contributes to NPC development, by highlighting a functional link between GOLIM4-L and its splicing regulator RBFOX2 activating vesicle-mediated transport involving RAB26. Keywords: GOLIM4, RBFOX2, Nasopharyngeal carcinoma (NPC), Alternative splicing, RAB26

2022-06-01 | GSE178195 | GEO

Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice

Project description:RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein-2 (RBFOX2) in maintaining cholesterol homeostasis in an obesogenic environment in the liver. Using enhanced individual-nucleotide resolution UV-crosslinking and immunoprecipitation (eiCLIP), we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesityinduced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.

2022-11-28 | PXD036976 | Pride

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