Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges

Michael T. Lovci, Dana Ghanem, Henry Marr, Justin Arnold, Sherry Gee, Marilyn Parra, Tiffany Y. Liang, Thomas J. Stark, Lauren T. Gehman, Shawn Hoon, Katlin B. Massirer, Gabriel A. Pratt, Douglas L. Black, Joe W. Gray, John G. Conboy, Gene W. Yeo

Research output: Contribution to journalArticle

130 Scopus citations

Abstract

Alternative splicing (AS) enables programmed diversity of gene expression across tissues and development. We show here that binding in distal intronic regions (>500 nucleotides (nt) from any exon) by Rbfox splicing factors important in development is extensive and is an active mode of splicing regulation. Similarly to exon-proximal sites, distal sites contain evolutionarily conserved GCATG sequences and are associated with AS activation and repression upon modulation of Rbfox abundance in human and mouse experimental systems. As a proof of principle, we validated the activity of two specific Rbfox enhancers in KIF21A and ENAH distal introns and showed that a conserved long-range RNA-RNA base-pairing interaction (an RNA bridge) is necessary for Rbfox-mediated exon inclusion in the ENAH gene. Thus we demonstrate a previously unknown RNA-mediated mechanism for AS control by distally bound RNA-binding proteins.

Original languageEnglish (US)
Pages (from-to)1434-1442
Number of pages9
JournalNature Structural and Molecular Biology
Volume20
Issue number12
DOIs
StatePublished - Dec 1 2013

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Lovci, M. T., Ghanem, D., Marr, H., Arnold, J., Gee, S., Parra, M., Liang, T. Y., Stark, T. J., Gehman, L. T., Hoon, S., Massirer, K. B., Pratt, G. A., Black, D. L., Gray, J. W., Conboy, J. G., & Yeo, G. W. (2013). Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges. Nature Structural and Molecular Biology, 20(12), 1434-1442. https://doi.org/10.1038/nsmb.2699