Nucleic Acids Research Advance Access originally published online on July 10, 2007
Nucleic Acids Research 2007 35(14):4845-4857; doi:10.1093/nar/gkm485
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Nucleic Acids Research, 2007, Vol. 35, No. 14 4845-4857
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Computational Biology |
A correlation with exon expression approach to identify cis-regulatory elements for tissue-specific alternative splicing
1Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, 2Affymetrix, Inc., Santa Clara, CA, 95051 and 3Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA
*To whom correspondence should be addressed. Tel: +(510) 486 6973; Fax: +1 510 486 6746; Email: jgconboy{at}lbl.gov
Received March 12, 2007. Revised June 4, 2007. Accepted June 5, 2007.
Correlation of motif occurrences with gene expression intensity is an effective strategy for elucidating transcriptional cis-regulatory logic. Here we demonstrate that this approach can also identify cis-regulatory elements for alternative pre-mRNA splicing. Using data from a human exon microarray, we identified 56 cassette exons that exhibited higher transcript-normalized expression in muscle than in other normal adult tissues. Intron sequences flanking these exons were then analyzed to identify candidate regulatory motifs for muscle-specific alternative splicing. Correlation of motif parameters with gene-normalized exon expression levels was examined using linear regression and linear splines on RNA words and degenerate weight matrices, respectively. Our unbiased analysis uncovered multiple candidate regulatory motifs for muscle-specific splicing, many of which are phylogenetically conserved among vertebrate genomes. The most prominent downstream motifs were binding sites for Fox1- and CELF-related splicing factors, and a branchpoint-like element ACUAAC; pyrimidine-rich elements resembling PTB-binding sites were most significant in upstream introns. Intriguingly, our systematic study indicates a paucity of novel muscle-specific elements that are dominant in short proximal intronic regions. We propose that Fox and CELF proteins play major roles in enforcing the muscle-specific alternative splicing program, facilitating expression of unique isoforms of cytoskeletal proteins critical to muscle cell function.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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