Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges

MT Lovci, D Ghanem, H Marr, J Arnold, S Gee… - Nature structural & …, 2013 - nature.com
MT Lovci, D Ghanem, H Marr, J Arnold, S Gee, M Parra, TY Liang, TJ Stark, LT Gehman…
Nature structural & molecular biology, 2013nature.com
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 …
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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