Regulation of alternative splicing in Drosophila by 56 RNA binding proteins

  1. Steven E. Brenner1,6
  1. 1Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA;
  2. 2Broad Institute, Cambridge, Massachusetts 02142, USA;
  3. 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
  4. 4Department of Genetics and Genome Sciences, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut 06030, USA;
  5. 5Department of Genome Dynamics, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA;
  6. 6Department of Plant and Microbial Biology, University of California, Berkeley, California 94720, USA
  1. Corresponding authors: graveley{at}uchc.edu, brenner{at}compbio.berkeley.edu

Abstract

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.

Footnotes

  • [Supplemental material is available for this article.]

  • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.192518.115.

  • Freely available online through the Genome Research Open Access option.

  • Received March 26, 2015.
  • Accepted August 19, 2015.

This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

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