Ab initio identification of functionally interacting pairs of cis-regulatory elements

Brad A. Friedman; Michael B. Stadler; Noam Shomron; Ye Ding; Christopher B. Burge

doi:10.1101/gr.080085.108

Ab initio identification of functionally interacting pairs of cis-regulatory elements

¹ Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
² Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
³ Division of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

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.

Footnotes

↵4 Present address:

↵4 Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA;
↵5 Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
↵6 Corresponding authors.

↵6 E-mail friedm{at}mcb.harvard.edu; fax (617) 495-3537.

↵6 E-mail cburge{at}mit.edu; fax (617) 452-2936.
[Supplemental material is available online at www.genome.org.]
Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.080085.108.
- Received April 25, 2008.
- Accepted July 21, 2008.