Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 20, Issue 12, Pages 1434-1442Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2699
Keywords
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Funding
- National Science Foundation
- National Institute of Health [U54 HG007005, R01 HG004659, R01 GM084317, R01 NS075449, HL045182, DK094699, CA112970, CA126551]
- Office of Science, and Office of Biological & Environmental Research of the US Department of Energy [DE-AC02-05CH1123]
- US National Institutes of Health [RO1 GM49662]
- [DK032094]
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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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