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Updated: May 6, 2026

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges
Michael T Lovci1, Dana Ghanem, Henry Marr
11] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA. [2] Stem Cell Program, University of California, San Diego, La Jolla, California, USA. [3] Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA.
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.
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