Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges.

TitleRbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges.
Publication TypeJournal Article
Year of Publication2013
AuthorsLovci MT, Ghanem D, Marr H, Arnold J, Gee S, Parra M, Liang TY, Stark TJ, Gehman LT, Hoon S, Massirer KB, Pratt GA, Black DL, Gray JW, Conboy JG, Yeo GW
JournalNat Struct Mol Biol
Volume20
Issue12
Pagination1434-42
Date Published2013 Dec
ISSN1545-9985
KeywordsAlternative Splicing, Animals, Base Pairing, Base Sequence, Binding Sites, Cell Line, Conserved Sequence, Humans, Kinesin, Mice, Microfilament Proteins, Models, Genetic, Nucleic Acid Conformation, Regulatory Sequences, Ribonucleic Acid, RNA, Messenger, RNA-Binding Proteins
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.

DOI10.1038/nsmb.2699
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/24213538?dopt=Abstract
Alternate JournalNat. Struct. Mol. Biol.
PubMed ID24213538
PubMed Central IDPMC3918504
Grant ListCA112970 / CA / NCI NIH HHS / United States
CA126551 / CA / NCI NIH HHS / United States
DK032094 / DK / NIDDK NIH HHS / United States
DK094699 / DK / NIDDK NIH HHS / United States
HL045182 / HL / NHLBI NIH HHS / United States
P30 CA023100 / CA / NCI NIH HHS / United States
R01 DK094699 / DK / NIDDK NIH HHS / United States
R01 GM084317 / GM / NIGMS NIH HHS / United States
R01 GM084317 / GM / NIGMS NIH HHS / United States
R01 GM49662 / GM / NIGMS NIH HHS / United States
R01 HG004659 / HG / NHGRI NIH HHS / United States
R01 HG004659 / HG / NHGRI NIH HHS / United States
R01 HL045182 / HL / NHLBI NIH HHS / United States
R01 NS075449 / NS / NINDS NIH HHS / United States
R01 NS075449 / NS / NINDS NIH HHS / United States
T32 GM008666 / GM / NIGMS NIH HHS / United States
U54 HG007005 / HG / NHGRI NIH HHS / United States
U54 HG007005 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
Track(s): 
Bioinformatics and Systems Biology