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

PubMed DOI PMC Full Text

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.

Publication Types

["Journal Article", "Research Support, N.I.H., Extramural", "Research Support, Non-U.S. Gov't", "Research Support, U.S. Gov't, Non-P.H.S."]

Keywords

[]

MeSH Terms

["Alternative Splicing", "Animals", "Base Pairing", "Base Sequence", "Binding Sites", "Cell Line", "Conserved Sequence", "Humans", "Kinesins", "Mice", "Microfilament Proteins", "Models, Genetic", "Nucleic Acid Conformation", "RNA Splicing Factors", "RNA, Messenger", "RNA-Binding Proteins", "Regulatory Sequences, Ribonucleic Acid"]

Funding

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)

Potentially Related Datasets (2)

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SRP030031 SRP SRA

SRP029987 SRP SRA