Dataset Information

Opposite Roles of Tra2? and SRSF9 in the v10 Exon Splicing of CD44.

ABSTRACT: CD44 is a transmembrane glycoprotein involved in cell-cell and cell-matrix interactions. Several CD44 protein isoforms are generated in human through alternative splicing regulation of nine variable exons encoding for the extracellular juxta-membrane region. While the CD44 splicing variants have been described to be involved in cancer progression and development, the regulatory mechanism(s) underlying their production remain unclear. Here, we identify Tra2? and SRSF9 as proteins with opposite roles in regulating CD44 exon v10 splicing. While Tra2? promotes v10 inclusion, SRSF9 inhibits its inclusion. Mechanistically, we found that both proteins are able to target v10 exon, with GAAGAAG sequence being the binding site for Tra2? and AAGAC that for SRSF9. Collectively, our data add a novel layer of complexity to the sequential series of events involved in the regulation of CD44 splicing.

SUBMITTER: Oh J

PROVIDER: S-EPMC7692347 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Opposite Roles of Tra2β and SRSF9 in the v10 Exon Splicing of CD44.

Oh Jagyeong J Liu Yongchao Y Choi Namjeong N Ha Jiyeon J Pradella Davide D Ghigna Claudia C Zheng Xuexiu X Shen Haihong H

Cancers 20201030 11

CD44 is a transmembrane glycoprotein involved in cell-cell and cell-matrix interactions. Several CD44 protein isoforms are generated in human through alternative splicing regulation of nine variable exons encoding for the extracellular juxta-membrane region. While the CD44 splicing variants have been described to be involved in cancer progression and development, the regulatory mechanism(s) underlying their production remain unclear. Here, we identify Tra2β and SRSF9 as proteins with opposite ro ...[more]

PMID: 33143085

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Project description:BackgroundMyogenesis is driven by specific changes in the transcriptome that occur during the different stages of muscle differentiation. In addition to controlled transcriptional transitions, several other post-transcriptional mechanisms direct muscle differentiation. Both alternative splicing and miRNA activity regulate gene expression and production of specialized protein isoforms. Importantly, disruption of either process often results in severe phenotypes as reported for several muscle diseases. Thus, broadening our understanding of the post-transcriptional pathways that operate in muscles will lay the foundation for future therapeutic interventions.MethodsWe employed bioinformatics analysis in concert with the well-established C2C12 cell system for predicting and validating novel miR-1 and miR-206 targets engaged in muscle differentiation. We used reporter gene assays to test direct miRNA targeting and studied C2C12 cells stably expressing one of the cDNA candidates fused to a heterologous, miRNA-resistant 3' UTR. We monitored effects on differentiation by measuring fusion index, myotube area, and myogenic gene expression during time course differentiation experiments.ResultsGene ontology analysis revealed a strongly enriched set of putative miR-1 and miR-206 targets associated with RNA metabolism. Notably, the expression levels of several candidates decreased during C2C12 differentiation. We discovered that the splicing factor Srsf9 is a direct target of both miRNAs during myogenesis. Persistent Srsf9 expression during differentiation impaired myotube formation and blunted induction of the early pro-differentiation factor myogenin as well as the late differentiation marker sarcomeric myosin, Myh8.ConclusionsOur data uncover novel miR-1 and miR-206 cellular targets and establish a functional link between the splicing factor Srsf9 and myoblast differentiation. The finding that miRNA-mediated clearance of Srsf9 is a key myogenic event illustrates the coordinated and sophisticated interplay between the diverse components of the gene regulatory network.

Dataset Information

Opposite Roles of Tra2? and SRSF9 in the v10 Exon Splicing of CD44.

Publications

Opposite Roles of Tra2β and SRSF9 in the v10 Exon Splicing of CD44.

Similar Datasets

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