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Genome Res. 2015 Nov;25(11):1771-80. doi: 10.1101/gr.192518.115. Epub 2015 Aug 20.

Regulation of alternative splicing in Drosophila by 56 RNA binding proteins.

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Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA; Broad Institute, Cambridge, Massachusetts 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut 06030, USA;
Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA;
Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA; Department of Plant and Microbial Biology, University of California, Berkeley, California 94720, USA.


Alternative splicing is regulated by RNA binding proteins (RBPs) that recognize pre-mRNA sequence elements and activate or repress adjacent exons. Here, we used RNA interference and RNA-seq to identify splicing events regulated by 56 Drosophila proteins, some previously unknown to regulate splicing. Nearly all proteins affected alternative first exons, suggesting that RBPs play important roles in first exon choice. Half of the splicing events were regulated by multiple proteins, demonstrating extensive combinatorial regulation. We observed that SR and hnRNP proteins tend to act coordinately with each other, not antagonistically. We also identified a cross-regulatory network where splicing regulators affected the splicing of pre-mRNAs encoding other splicing regulators. This large-scale study substantially enhances our understanding of recent models of splicing regulation and provides a resource of thousands of exons that are regulated by 56 diverse RBPs.

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