TY - JOUR
T1 - Ab initio identification of functionally interacting pairs of cis-regulatory elements
AU - Friedman, Brad A.
AU - Stadler, Michael B.
AU - Shomron, Noam
AU - Ding, Ye
AU - Burge, Christopher B.
PY - 2008/10
Y1 - 2008/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=53549103032&partnerID=8YFLogxK
U2 - 10.1101/gr.080085.108
DO - 10.1101/gr.080085.108
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AN - SCOPUS:53549103032
SN - 1088-9051
VL - 18
SP - 1643
EP - 1651
JO - Genome Research
JF - Genome Research
IS - 10
ER -