A computational approach for genome-wide mapping of splicing factor binding sites

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Abstract

A computational method is presented for genome-wide mapping of splicing factor binding sites that considers both the genomic environment and evolutionary conservation.

Abstract

Alternative splicing is regulated by splicing factors that serve as positive or negative effectors, interacting with regulatory elements along exons and introns. Here we present a novel computational method for genome-wide mapping of splicing factor binding sites that considers both the genomic environment and the evolutionary conservation of the regulatory elements. The method was applied to study the regulation of different alternative splicing events, uncovering an interesting network of interactions among splicing factors.

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Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.

Xiaohui Xie, Jun Lu, E J Kulbokas … (2005)

Comprehensive identification of all functional elements encoded in the human genome is a fundamental need in biomedical research. Here, we present a comparative analysis of the human, mouse, rat and dog genomes to create a systematic catalogue of common regulatory motifs in promoters and 3' untranslated regions (3' UTRs). The promoter analysis yields 174 candidate motifs, including most previously known transcription-factor binding sites and 105 new motifs. The 3'-UTR analysis yields 106 motifs likely to be involved in post-transcriptional regulation. Nearly one-half are associated with microRNAs (miRNAs), leading to the discovery of many new miRNA genes and their likely target genes. Our results suggest that previous estimates of the number of human miRNA genes were low, and that miRNAs regulate at least 20% of human genes. The overall results provide a systematic view of gene regulation in the human, which will be refined as additional mammalian genomes become available.

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Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification.

Itai Yanai, Hila Benjamin, Michael Shmoish … (2005)

Genes are often characterized dichotomously as either housekeeping or single-tissue specific. We conjectured that crucial functional information resides in genes with midrange profiles of expression. To obtain such novel information genome-wide, we have determined the mRNA expression levels for one of the largest hitherto analyzed set of 62 839 probesets in 12 representative normal human tissues. Indeed, when using a newly defined graded tissue specificity index tau, valued between 0 for housekeeping genes and 1 for tissue-specific genes, genes with midrange profiles having 0.15 50% of all expression patterns. We developed a binary classification, indicating for every gene the I(B) tissues in which it is overly expressed, and the 12-I(B) tissues in which it shows low expression. The 85 dominant midrange patterns with I(B)=2-11 were found to be bimodally distributed, and to contribute most significantly to the definition of tissue specification dendrograms. Our analyses provide a novel route to infer expression profiles for presumed ancestral nodes in the tissue dendrogram. Such definition has uncovered an unsuspected correlation, whereby de novo enhancement and diminution of gene expression go hand in hand. These findings highlight the importance of gene suppression events, with implications to the course of tissue specification in ontogeny and phylogeny. All data and analyses are publically available at the GeneNote website, http://genecards.weizmann.ac.il/genenote/ and, GEO accession GSE803. doron.lancet@weizmann.ac.il Four tables available at the above site.

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Systematic identification and analysis of exonic splicing silencers.

Zefeng Wang, Michael E Rolish, Gene Yeo … (2004)

Exonic splicing silencers (ESSs) are cis-regulatory elements that inhibit the use of adjacent splice sites, often contributing to alternative splicing (AS). To systematically identify ESSs, an in vivo splicing reporter system was developed to screen a library of random decanucleotides. The screen yielded 141 ESS decamers, 133 of which were unique. The silencer activity of over a dozen of these sequences was also confirmed in a heterologous exon/intron context and in a second cell type. Of the unique ESS decamers, most could be clustered into groups to yield seven putative ESS motifs, some resembling known motifs bound by hnRNPs H and A1. Potential roles of ESSs in constitutive splicing were explored using an algorithm, ExonScan, which simulates splicing based on known or putative splicing-related motifs. ExonScan and related bioinformatic analyses suggest that these ESS motifs play important roles in suppression of pseudoexons, in splice site definition, and in AS.

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Author and article information

Journal

Journal ID (nlm-ta): Genome Biol

Title: Genome Biology

Publisher: BioMed Central

ISSN (Print): 1465-6906

ISSN (Electronic): 1465-6914

Publication date (Print): 2009

Publication date (Electronic): 18 March 2009

Volume: 10

Issue: 3

Page: R30

Affiliations

[1 ]Department of Biology, the Technion - Israel Institute of Technology, Haifa 32000, Israel

[2 ]Department of Computer Science, Technion - Israel Institute of Technology, Haifa 32000, Israel

Article

Publisher ID: gb-2009-10-3-r30

DOI: 10.1186/gb-2009-10-3-r30

PMC ID: 2691001

PubMed ID: 19296853

SO-VID: 20378d89-005e-44d8-967f-a3583f103aeb

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 18 December 2008

Date revision received : 26 February 2009

Date accepted : 18 March 2009

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A computational approach for genome-wide mapping of splicing factor binding sites

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Genome Integrity

Most cited references 64

Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.

Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification.

Systematic identification and analysis of exonic splicing silencers.

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