An RNA map predicting Nova-dependent splicing regulation

Jernej Ule, Giovanni Stefani, Aldo Mele, Matteo Ruggiu, Xuning Wang, Bahar Taneri, Terry Gaasterland, Benjamin J. Blencowe and Robert B. Darnell ()
Additional contact information
Jernej Ule: Howard Hughes Medical Institute
Giovanni Stefani: Howard Hughes Medical Institute
Aldo Mele: Howard Hughes Medical Institute
Matteo Ruggiu: Howard Hughes Medical Institute
Xuning Wang: Biocomputing, Information Technology
Bahar Taneri: The Rockefeller University
Terry Gaasterland: The Rockefeller University
Benjamin J. Blencowe: University of Toronto
Robert B. Darnell: Howard Hughes Medical Institute

Nature, 2006, vol. 444, issue 7119, 580-586

Abstract: Abstract Nova proteins are neuron-specific alternative splicing factors. We have combined bioinformatics, biochemistry and genetics to derive an RNA map describing the rules by which Nova proteins regulate alternative splicing. This map revealed that the position of Nova binding sites (YCAY clusters) in a pre-messenger RNA determines the outcome of splicing. The map correctly predicted Nova’s effect to inhibit or enhance exon inclusion, which led us to examine the relationship between the map and Nova’s mechanism of action. Nova binding to an exonic YCAY cluster changed the protein complexes assembled on pre-mRNA, blocking U1 snRNP (small nuclear ribonucleoprotein) binding and exon inclusion, whereas Nova binding to an intronic YCAY cluster enhanced spliceosome assembly and exon inclusion. Assays of splicing intermediates of Nova-regulated transcripts in mouse brain revealed that Nova preferentially regulates removal of introns harbouring (or closest to) YCAY clusters. These results define a genome-wide map relating the position of a cis-acting element to its regulation by an RNA binding protein, namely that Nova binding to YCAY clusters results in a local and asymmetric action to regulate spliceosome assembly and alternative splicing in neurons.

Date: 2006
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DOI: 10.1038/nature05304

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