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Nat Rev Genet. 2014 Oct;15(10):689-701. doi: 10.1038/nrg3778. Epub 2014 Aug 12.

Context-dependent control of alternative splicing by RNA-binding proteins.

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Department of Cellular and Molecular Medicine and Institute for Genomic Medicine, University of California San Diego, La Jolla, California 92093-0651, USA.
Center for Molecular Biology of RNA, and Department of Molecular, Cell, and Developmental Biology, University of California at Santa Cruz, Santa Cruz, California 95064, USA.


Sequence-specific RNA-binding proteins (RBPs) bind to pre-mRNA to control alternative splicing, but it is not yet possible to read the 'splicing code' that dictates splicing regulation on the basis of genome sequence. Each alternative splicing event is controlled by multiple RBPs, the combined action of which creates a distribution of alternatively spliced products in a given cell type. As each cell type expresses a distinct array of RBPs, the interpretation of regulatory information on a given RNA target is exceedingly dependent on the cell type. RBPs also control each other's functions at many levels, including by mutual modulation of their binding activities on specific regulatory RNA elements. In this Review, we describe some of the emerging rules that govern the highly context-dependent and combinatorial nature of alternative splicing regulation.

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