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Splicing activation by Rbfox requires self-aggregation through its tyrosine-rich domain

ABSTRACT: To determine how the higher order assembly of Rbfox proteins affect Rbfox-dependent splicing regulation, we expressed Rbfox wildtype and its mutant protein in Flp-In™ T-REx™ 293 Rbfox2-/- cells and extracted RNA from these cells to perform RASL-seq which profiles thousands of alternative splicing event.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89597 | GEO | 2017/07/13

SECONDARY ACCESSION(S): PRJNA352682

REPOSITORIES: GEO

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Concentration-dependent regulation by Rbfox enabled by motifs of intermediate affinity

Project description:The Rbfox family of splicing factors regulate alternative splicing during animal development and in disease, impacting thousands of exons in the maturing brain, heart, and muscle. Rbfox proteins have long been known to bind to the RNA sequence GCAUG with high affinity, but just half of Rbfox CLIP peaks contain a GCAUG motif. We incubated recombinant RBFOX2 with over 60,000 mouse and human transcriptomic sequences to reveal significant binding to several moderate-affinity, non-GCAYG sites at a physiologically relevant range of RBFOX concentrations. We find that many of these “secondary motifs” bind Rbfox robustly in cells and that several together can exert regulation comparable to a GCAUG in a trichromatic splicing reporter assay. Furthermore, secondary motifs regulate RNA splicing in neuronal development and in neuronal subtypes where cellular Rbfox concentrations are highest, enabling a second wave of splicing changes as Rbfox levels increase.

2020-06-16 | GSE152510 | GEO

Co-regulation of splicing by Rbfox1 and hnRNP M [hnRNPM k-d+Rbfox1 RNA-Seq]

Project description:hnRNP M and Rbfox proteins are subunits of the Large Assembly of Splicing Regulators (LASR). The purpose of this study is to investigate how these two splicing factors affect each others' role in regulating splice site choices in pre-mRNA. hnRNP M is knocked down by RNAi in Flp-In T-REx 293 cells (Invitrogen), whereas Rbfox1 is expressed inducibly under tetracycline control from construct integrated into the genome at the FRT site. Using this system, splicing and expression profiles of cells expressing and/or lacking these proteins are compared on a whole genome level by RNA-seq technology.

2016-04-21 | GSE76476 | GEO

Identification of GFP-FIP200-interacting proteins

Project description:GFP or GFP-200 proteins were purified from the corresponding Flp-In™ T REx™ 293 cells using GFP-Trap beads. Purified proteins were analyzed by mass spectrometry.

2021-07-01 | PXD022563 | Pride

Impaired myocardial contractility underlies an Rbfox-mediated zebrafish model of hypoplastic left heart syndrome

Project description:Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, which was previously linked to HLHS in newborns, display cardiovascular defects overlapping those in HLHS patients. In contrast to current models, we demonstrate that co-existing ventricular, valve, and aortic deficiencies in rbfox mutant zebrafish arise secondary to impaired myocardial contractility. On a molecular and cellular level, we find diminished expression and alternative splicing of sarcomere and mitochondrial components that compromise sarcomere assembly and mitochondrial respiration, respectively. Injection of human RBFOX2 rescues ventricular structure and function in rbfox mutant zebrafish, demonstrating conservation of molecular function between humans and zebrafish Rbfox proteins. However, injection of RBFOX2 variants previously identified in newborns with HLHS do not. Taken together, our data suggest that mutations in RBFOX2 are causal for HLHS and challenge the obligate multigenic etiology of the disease. Instead, we provide a complimentary paradigm where HLHS can arise from a single gene mutation where ventricular, valve, and aortic deficiencies manifest secondary to a primary myocardial defect.

2022-07-08 | GSE189934 | GEO

Myocardial-intrinsic defects underlie an Rbfox-mediated zebrafish model of hypoplastic left heart syndrome

Project description:Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of left sided structures including the ventricle, valves, and aorta1. Although the mechanisms of disease pathogenesis remain elusive due to a paucity of candidate genes and animal models, prevailing paradigm suggests that HLHS is a multigenic disease of co-occurring phenotypes2,3. Here, we report that zebrafish lacking two orthologs of the RNA binding protein RBFOX2, a gene previously linked to HLHS in humans4,5, display cardiovascular defects overlapping those in HLHS patients. In contrast to current models, we demonstrate that co-existing ventricular, valve, and aortic deficiencies in rbfox mutant zebrafish arise secondary to impaired myocardial function as all three phenotypes are rescued when Rbfox is expressed specifically in the myocardium. On a molecular and cellular level, we find diminished expression and alternative splicing of sarcomere and mitochondrial components in rbfox-deficient hearts that compromise sarcomere assembly and mitochondrial respiration, respectively. Injection of human RBFOX2 mRNA restores ventricular structure and function in rbfox mutant zebrafish, while HLHS-linked RBFOX2 variants fail to rescue. Taken together, our data suggest that mutations in RBFOX2 are causal for HLHS pathogenesis and provide a complimentary paradigm for HLHS emergence where co-existing ventricular, valve, and aortic deficiencies have a monogenic etiology caused by myocardial dysfunction.

2022-07-12 | MTBLS4176 | MetaboLights

Effects of pan-UPF1 knockdown on RNA abundance

Project description:Flp-In T-REx-293 cells transfected with non-targeting control siRNA or UPF1-specific siRNA as indicated and used for total RNA-seq.

2022-04-07 | GSE176197 | GEO

PP1-NIPP1 wild type and mutant overexpression in Flip-In™ T-Rex Hela cells

Project description:RNAi-seq of stable Flp-In™ T-Rex Hela cells that inducibly expressed PP1-NIPP1 and mutants.

2018-06-28 | GSE104320 | GEO

The Anti-cancer Factor Quinolinone Inhibitors Disrupt Spindles and the Interactions between LSF and Microtubule-associated Proteins

Project description:Identification of mitotic BioLSF-interacting proteins whose association is sensitive to Factor Quinolinone Inhibitor 1 (FQI1): The dataset is comprised of two independent experimental replicates, with each biological replicate consisting of runs of 4 samples. For each set, the four protein samples were generated from cells in mitosis, in which cells lacked, expressed basal levels, or expressed induced levels of a biotinylated, tagged LSF protein (BioLSF). Finally, cells with induced BioLSF levels were treated for one hour in mitosis with either FQI1 or vehicle (DMSO). Proteins purified on streptavidin beads were analyzed by mass spectrometry. More specifically, the four runs in each set derived from: 1) DLD-1 Flp-In™ T-REx™ TIR1 parental cells treated with vehicle (Parent_DMSO) as a negative control, 2) DLD-1 Flp-In™ T-REx™ TIR1 BioLSF cells with only leaky, basal BioLSF expression (BioLSF_DMSO), 3) DLD-1 Flp-In™ T-REx™ TIR1 BioLSF cells with induced BioLSF expression (BioLSF_DOX), and 4) DLD-1 Flp-In™ T-REx™ TIR1 BioLSF cells with induced BioLSF expression that were treated with FQI1 in mitosis (BioLSF_DOX_FQI1).

2022-05-26 | PXD024149 | Pride

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

Rett Syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models

Project description:Rett syndrome (RTT) is a severe neurological disorder which is mainly caused by mutations found in the X-linked gene encoding MeCP2. Despite extensive studies, the molecular functions of MeCP2 remain elusive. Here, we report that MeCP2 is a new subunit of a higher-order multiunit protein complex Rbfox/LASR and acts as a scaffold for this splicing complex. Deletion or mutation of MeCP2 leads to defects in forming MeCP2/Rbfox/LASR complex and aberrant alternative pre-mRNA splicing. Our data link RTT to an impaired function of MeCP2 in splicing control through its role in nucleating Rbfox/LASR macromolecule assembly.

2021-08-28 | GSE142716 | GEO

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