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The SPN-4 Rbfox RNA-binding protein selects maternal mRNAs for CCR4-NOT-dependent clearance in C. elegans embryos

ABSTRACT: The SPN-4 Rbfox RNA-binding protein selects maternal mRNAs for CCR4-NOT-dependent clearance in C. elegans embryos

PROVIDER: PRJNA1322436 | ENA |

REPOSITORIES: ENA

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The SPN-4 Rbfox RNA-binding protein selects maternal mRNAs for CCR4-NOT-dependent clearance in C. elegans embryos

Project description:The elimination of many maternal mRNAs is an essential feature of the maternal-to-zygotic transition. We report an essential pathway that clears many maternal transcripts from early C. elegans embryos using the RbFox-related SPN-4 RNA-binding protein as a specificity factor and the CCR4-NOT deadenylase complex as an effector. We biochemically identified SPN-4-associated mRNAs from late-stage oocytes and found that the set of SPN-4-associated transcripts is enriched for maternal mRNAs that undergo early decay. Single-molecule fluorescence in situ hybridization experiments established that many SPN-4-associated mRNAs fail to be eliminated in the absence of SPN-4. In the 3’UTRs of two target mRNAs, we identified RbFox motifs that bind SPN-4 in vitro and are required for SPN-4-dependent clearance in vivo. In a genetic screen to identify factors that work with SPN-4, we isolated alleles of CCR4-NOT components. Auxin-induced degradation of the LET-711/NOT1 scaffold and the CCF-1 deadenylase disrupted clearance of two SPN-4-associated transcripts. Our results support a model in which SPN-4 initiates expression in late-stage oocytes, associates with maternal mRNA targets through RNA sequences in their 3’UTRs and promotes CCR4-NOT-mediated decay during early embryogenesis.

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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.

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The CCR4-NOT complex suppresses untimely translational activation of maternal mRNAs.

Project description:Control of mRNA poly(A) tail has central role to regulate mRNA metabolism: translation efficiency and mRNA stability. Gene expression in maturing oocytes largely relies on the regulation of mRNA metabolism as they are transcriptionally silent. The CCR4-NOT complex is a major deadenylase for mammals and regulates poly(A) tails of maternal mRNAs, however their function to translational regulation was not well understood. Here we show that CCR4-NOT suppresses translational activity of maternal mRNAs during oocyte maturation. Oocytes which lack entire deadenylase activity of CCR4-NOT by genetic deletion of its catalytic subunits: CNOT7 and CNOT8 showed increase of both expression of maternal mRNAs and translational activity of them during oocyte maturation.

2023-10-01 | GSE224308 | GEO

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

Project description: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.

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Expression data from wild-type, ccr4∆, and ccr4∆ pbp1∆ yeast cells.

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Project description:Methotrexate Clearance

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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.

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Expression data from wild-type, ccr4∆, and ccr4∆ pbp1∆ yeast cells.

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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

Expression profiling of fission yeast strains: wild-type, erh1∆, and ccr4∆

Project description:We report gene expression profiling in the fission yeast Schizosaccharomyces pombe. We performed high-throughput sequencing of RNA isolated from wild-type, erh1∆, and ccr4∆ strains. We find that many meiotic gene containing degradation sequence DSR are expressed in vegetative erh1∆, while these meiotic mRNAs do not increase in ccr4∆, indicating that Erh1 and Ccr4 target different set of genes during vegetative growth.

2016-06-15 | GSE76112 | GEO

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