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Title: Regulation of alternative splicing in Drosophila by 56 RNA binding proteins

Alternative splicing is regulated by RNA binding proteins (RBPs) that recognize pre-mRNA sequence elements and activate or repress adjacent exons. 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. In conclusion, 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.
Authors:
 [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [3] ;  [3] ;  [3] ;  [3] ;  [3] ;  [2] ;  [4]
  1. Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Broad Inst. Cambridge, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States). Dept. of Medical Oncology
  2. Univ. of Connecticut Health Center, Farmington, CT (United States). Dept. of Genetics and Genome Sciences and Inst. for Systems Genomics
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Dept. of Genome Dynamics
  4. Univ. of California, Berkeley, CA (United States). Dept. of Plant and Microbial Biology
Publication Date:
Grant/Contract Number:
AC02-05CH11231; DRG-2138-12; U01 HG004271
Type:
Accepted Manuscript
Journal Name:
Genome Research
Additional Journal Information:
Journal Volume: 25; Journal Issue: 11; Journal ID: ISSN 1088-9051
Publisher:
Cold Spring Harbor Laboratory Press
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE; National Science Foundation (NSF); Damon Runyon Cancer Research Foundation, New York City, NY (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1257380
Alternate Identifier(s):
OSTI ID: 1474888

Brooks, Angela N., Duff, Michael O., May, Gemma, Yang, Li, Bolisetty, Mohan, Landolin, Jane, Wan, Ken, Sandler, Jeremy, Booth, Benjamin W., Celniker, Susan E., Graveley, Brenton R., and Brenner, Steven E.. Regulation of alternative splicing in Drosophila by 56 RNA binding proteins. United States: N. p., Web. doi:10.1101/gr.192518.115.
Brooks, Angela N., Duff, Michael O., May, Gemma, Yang, Li, Bolisetty, Mohan, Landolin, Jane, Wan, Ken, Sandler, Jeremy, Booth, Benjamin W., Celniker, Susan E., Graveley, Brenton R., & Brenner, Steven E.. Regulation of alternative splicing in Drosophila by 56 RNA binding proteins. United States. doi:10.1101/gr.192518.115.
Brooks, Angela N., Duff, Michael O., May, Gemma, Yang, Li, Bolisetty, Mohan, Landolin, Jane, Wan, Ken, Sandler, Jeremy, Booth, Benjamin W., Celniker, Susan E., Graveley, Brenton R., and Brenner, Steven E.. 2015. "Regulation of alternative splicing in Drosophila by 56 RNA binding proteins". United States. doi:10.1101/gr.192518.115. https://www.osti.gov/servlets/purl/1257380.
@article{osti_1257380,
title = {Regulation of alternative splicing in Drosophila by 56 RNA binding proteins},
author = {Brooks, Angela N. and Duff, Michael O. and May, Gemma and Yang, Li and Bolisetty, Mohan and Landolin, Jane and Wan, Ken and Sandler, Jeremy and Booth, Benjamin W. and Celniker, Susan E. and Graveley, Brenton R. and Brenner, Steven E.},
abstractNote = {Alternative splicing is regulated by RNA binding proteins (RBPs) that recognize pre-mRNA sequence elements and activate or repress adjacent exons. 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. In conclusion, 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.},
doi = {10.1101/gr.192518.115},
journal = {Genome Research},
number = 11,
volume = 25,
place = {United States},
year = {2015},
month = {8}
}