Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges

Nat Struct Mol Biol. 2013 Dec;20(12):1434-42. doi: 10.1038/nsmb.2699. Epub 2013 Nov 10.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing / physiology*
  • Animals
  • Base Pairing
  • Base Sequence
  • Binding Sites
  • Cell Line
  • Conserved Sequence
  • Humans
  • Kinesins / genetics
  • Kinesins / metabolism
  • Mice
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Models, Genetic
  • Nucleic Acid Conformation
  • RNA Splicing Factors
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism
  • RNA-Binding Proteins / physiology*
  • Regulatory Sequences, Ribonucleic Acid

Substances

  • Enah protein, human
  • KIF21A protein, human
  • Microfilament Proteins
  • RBFOX1 protein, human
  • RNA Splicing Factors
  • RNA, Messenger
  • RNA-Binding Proteins
  • Regulatory Sequences, Ribonucleic Acid
  • Kinesins

Associated data

  • SRA/SRP029987
  • SRA/SRP030031