Rbfox2 controls autoregulation in RNA-binding protein networks.

TitleRbfox2 controls autoregulation in RNA-binding protein networks.
Publication TypeJournal Article
Year of Publication2014
AuthorsJangi, M, Boutz, PL, Paul, P, Sharp, PA
JournalGenes Dev
Date Published2014 Mar 15
KeywordsAlternative Splicing, Amino Acid Motifs, Animals, Binding Sites, Cells, Cultured, Embryonic Stem Cells, Gene Expression Regulation, Developmental, Introns, Mice, Protein Binding, RNA-Binding Proteins

The tight regulation of splicing networks is critical for organismal development. To maintain robust splicing patterns, many splicing factors autoregulate their expression through alternative splicing-coupled nonsense-mediated decay (AS-NMD). However, as negative autoregulation results in a self-limiting window of splicing factor expression, it is unknown how variations in steady-state protein levels can arise in different physiological contexts. Here, we demonstrate that Rbfox2 cross-regulates AS-NMD events within RNA-binding proteins to alter their expression. Using individual nucleotide-resolution cross-linking immunoprecipitation coupled to high-throughput sequencing (iCLIP) and mRNA sequencing, we identified >200 AS-NMD splicing events that are bound by Rbfox2 in mouse embryonic stem cells. These "silent" events are characterized by minimal apparent splicing changes but appreciable changes in gene expression upon Rbfox2 knockdown due to degradation of the NMD-inducing isoform. Nearly 70 of these AS-NMD events fall within genes encoding RNA-binding proteins, many of which are autoregulated. As with the coding splicing events that we found to be regulated by Rbfox2, silent splicing events are evolutionarily conserved and frequently contain the Rbfox2 consensus UGCAUG. Our findings uncover an unexpectedly broad and multilayer regulatory network controlled by Rbfox2 and offer an explanation for how autoregulatory splicing networks are tuned.

Alternate JournalGenes Dev.
PubMed ID24637117
PubMed Central IDPMC3967051
Grant ListP30-CA14051 / CA / NCI NIH HHS / United States
R01-GM34277 / GM / NIGMS NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States