title: Ab initio identification of functionally interacting pairs of cis-regulatory elements.
abstract: Cooperatively acting pairs of cis-regulatory elements play important roles in many biological processes. Here, we describe a statistical approach, compositionally orthogonalized co-occurrence analysis (coCOA) that detects pairs of oligonucleotides that preferentially co-occur in pairs of sequence regions, controlling for correlations between the compositions of the analyzed regions. coCOA identified three clusters of oligonucleotide pairs that frequently co-occur at 5' and 3' ends of human and mouse introns. The largest cluster involved GC-rich sequences at the 5' ends of introns that co-occur and are co-conserved with specific AU-rich sequences near intron 3' ends. These motifs are preferentially conserved when they occur together, as measured by a new co-conservation measure, supporting common in vivo function. These motif pairs are also enriched in introns flanking alternative "cassette" exons, suggesting a role in silencing of intervening exons, and we showed that these motifs can cooperatively silence splicing of an intervening exon in a splicing reporter assay. This approach can be easily generalized to problems beyond RNA splicing.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. friedm@mcb.harvard.edu
authors.forename: Brad A
authors.initials: BA
authors.lastname: Friedman
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stadler
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Burge
mesh_terms: D000818:Animals; D001483:Base Sequence; D019295:Computational Biology; D017124:Conserved Sequence; D005091:Exons; D020862:GC Rich Sequence / Q000235:genetics; D006801:Humans; D007438:Introns; D051379:Mice; D012326:RNA Splicing; D012045:Regulatory Sequences, Nucleic Acid; D017423:Sequence Analysis, RNA
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