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
Nature structural & molecular biology · 2013 · Vol. 20 (12) · pp. 1434-42
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.
Potentially related datasets 2
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Funding 20 grants
| Grant | Funder |
|---|---|
| R01 HG004659 | NHGRI NIH HHS (United States) |
| P30 CA023100 | NCI NIH HHS (United States) |
| Howard Hughes Medical Institute (United States) | |
| T32 GM008666 | NIGMS NIH HHS (United States) |
| U54 HG007005 | NHGRI NIH HHS (United States) |
| R01 NS075449 | NINDS NIH HHS (United States) |
| R01 DK094699 | NIDDK NIH HHS (United States) |
| R01 GM084317 | NIGMS NIH HHS (United States) |
| U24 CA126551 | NCI NIH HHS (United States) |
| HL045182 | NHLBI NIH HHS (United States) |
| R01 HL045182 | NHLBI NIH HHS (United States) |
| CA126551 | NCI NIH HHS (United States) |
| R56 HL045182 | NHLBI NIH HHS (United States) |
| R01 GM049662 | NIGMS NIH HHS (United States) |
| P01 DK032094 | NIDDK NIH HHS (United States) |
| DK032094 | NIDDK NIH HHS (United States) |
| CA112970 | NCI NIH HHS (United States) |
| R01 GM49662 | NIGMS NIH HHS (United States) |
| U54 CA112970 | NCI NIH HHS (United States) |
| DK094699 | NIDDK NIH HHS (United States) |