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Published August 1, 2010 | Published + Supplemental Material
Journal Article Open

Functional selection and systematic analysis of intronic splicing elements identify active sequence motifs and associated splicing factors


Despite the critical role of pre-mRNA splicing in generating proteomic diversity and regulating gene expression, the sequence composition and function of intronic splicing regulatory elements (ISREs) have not been well elucidated. Here, we employed a high-throughput in vivo Screening PLatform for Intronic Control Elements (SPLICE) to identify 125 unique ISRE sequences from a random nucleotide library in human cells. Bioinformatic analyses reveal consensus motifs that resemble splicing regulatory elements and binding sites for characterized splicing factors and that are enriched in the introns of naturally occurring spliced genes, supporting their biological relevance. In vivo characterization, including an RNAi silencing study, demonstrate that ISRE sequences can exhibit combinatorial regulatory activity and that multiple trans -acting factors are involved in the regulatory effect of a single ISRE. Our work provides an initial examination into the sequence characteristics and function of ISREs, providing an important contribution to the splicing code.

Additional Information

© The Author(s) 2010. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received November 27, 2009; Revised March 7, 2010; Accepted March 24, 2010. We thank R. Diamond and D. Perez for FACS assistance and expert technical advice, A. Krainer for the pCISMNxΔ6-wt construct. The Caltech Joseph Jacobs Institute for Molecular Engineering for Medicine (grant to C.D.S.); National Science Foundation (grant MCB-0616264, J.A.B.); National Institutes of Health (fellowship to K.G.H., grant to C.D.S.). Funding for open access charge: National Institutes of Health. Conflict of interest statement . None declared.

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Supplemental Material - gkq248_Supplementary_Data.zip


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