Rbfox2 controls autoregulation in RNA-binding protein networks
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Jangi-2014-Rbfox2 controls auto.pdf
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2.49 MB
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Author(s)
Boutz, Paul
Jangi, Mohini
Sharp, Phillip A.
Paul, Prakriti
Date Issued
March 2014
Journal
Genes & Development
Publisher
Cold Spring Harbor Laboratory Press
Citation
Jangi, M., P. L. Boutz, P. Paul, and P. A. Sharp. “Rbfox2 Controls Autoregulation in RNA-Binding Protein Networks.” Genes & Development 28, no. 6 (March 15, 2014): 637–651.
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommerical
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DOI of Published Version
https://doi.org/10.1101/gad.235770.113
