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.
authors.affiliation: 1] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA. [2] Stem Cell Program, University of California, San Diego, La Jolla, California, USA. [3] Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lovci
authors.forename: Dana
authors.initials: D
authors.lastname: Ghanem
authors.forename: Henry
authors.initials: H
authors.lastname: Marr
authors.forename: Justin
authors.initials: J
authors.lastname: Arnold
authors.forename: Sherry
authors.initials: S
authors.lastname: Gee
authors.forename: Marilyn
authors.initials: M
authors.lastname: Parra
authors.forename: Tiffany Y
authors.initials: TY
authors.lastname: Liang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Stark
authors.forename: Lauren T
authors.initials: LT
authors.lastname: Gehman
authors.forename: Shawn
authors.initials: S
authors.lastname: Hoon
authors.forename: Katlin B
authors.initials: KB
authors.lastname: Massirer
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Pratt
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Black
authors.forename: Joe W
authors.identifier: 0000000192256756
authors.initials: JW
authors.lastname: Gray
authors.forename: John G
authors.initials: JG
authors.lastname: Conboy
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D009690:Nucleic Acid Conformation; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D038621:Regulatory Sequences, Ribonucleic Acid
chemical_list: C511939:Enah protein, human; C119023:KIF21A protein, human; D008840:Microfilament Proteins; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D038621:Regulatory Sequences, Ribonucleic Acid; D016547:Kinesins