@article{e5ff23e53c444a4f8a1e5a75905b8b5b,
title = "Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges",
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.",
author = "Lovci, {Michael T.} and Dana Ghanem and Henry Marr and Justin Arnold and Sherry Gee and Marilyn Parra and Liang, {Tiffany Y.} and Stark, {Thomas J.} and Gehman, {Lauren T.} and Shawn Hoon and Massirer, {Katlin B.} and Pratt, {Gabriel A.} and Black, {Douglas L.} and Gray, {Joe W.} and Conboy, {John G.} and Yeo, {Gene W.}",
note = "Funding Information: The authors would like to thank A. Pasquinelli, N. Chi, K. Willert and L. Goldstein and members of the Yeo, Conboy and Goldstein labs for critical reading of the manuscript. M.T.L. is supported as a National Science Foundation GK12 Fellow. This work was supported by grants from the National Institute of Health to G.W.Y. (U54 HG007005, R01 HG004659, R01 GM084317 and R01 NS075449) and to J.G.C. (HL045182 and DK094699) and partially supported by grants to J.W.G. (CA112970 and CA126551). J.G.C. also acknowledges support from DK032094. This work was also supported by the Director, Office of Science, and Office of Biological & Environmental Research of the US Department of Energy under Contract No. DE-AC02-05CH1123. D.L.B. and L.T.G. were supported by US National Institutes of Health grant RO1 GM49662 to D.L.B. D.L.B. is an Investigator of the Howard Hughes Medical Institute. M.T.L. and G.W.Y. are grateful for a gift from P. Yang at Genentech that supported M.T.L. G.W.Y. is supported as an Alfred P. Sloan Research Fellow.",
year = "2013",
month = dec,
doi = "10.1038/nsmb.2699",
language = "English (US)",
volume = "20",
pages = "1434--1442",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "12",
}