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Nucleic Acids Research 2005 33(10):3154-3164; doi:10.1093/nar/gki624
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Published online 2 June 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes

Shannan J. Ho Sui1,2, James R. Mortimer3, David J. Arenillas1,4, Jochen Brumm1,5, Christopher J. Walsh1,2, Brian P. Kennedy4 and Wyeth W. Wasserman1,3,*

1Centre for Molecular Medicine and Therapeutics, University of British Columbia Vancouver, BC, Canada 2Genetics Graduate Program, University of British Columbia Vancouver, BC, Canada 3Merck Frosst Centre for Therapeutic Research Kirkland QC, Canada 4Department of Medical Genetics, University of British Columbia Vancouver, BC, Canada 5Department of Statistics, University of British Columbia Vancouver, BC, Canada

*To whom correspondence should be addressed. Tel: +1 604 875 3812; Fax: +1 604 875 3819; Email: wyeth{at}cmmt.ubc.ca

Received April 5, 2005. Revised April 22, 2005. Accepted May 12, 2005.

Targeted transcript profiling studies can identify sets of co-expressed genes; however, identification of the underlying functional mechanism(s) is a significant challenge. Established methods for the analysis of gene annotations, particularly those based on the Gene Ontology, can identify functional linkages between genes. Similar methods for the identification of over-represented transcription factor binding sites (TFBSs) have been successful in yeast, but extension to human genomics has largely proved ineffective. Creation of a system for the efficient identification of common regulatory mechanisms in a subset of co-expressed human genes promises to break a roadblock in functional genomics research. We have developed an integrated system that searches for evidence of co-regulation by one or more transcription factors (TFs). oPOSSUM combines a pre-computed database of conserved TFBSs in human and mouse promoters with statistical methods for identification of sites over-represented in a set of co-expressed genes. The algorithm successfully identified mediating TFs in control sets of tissue-specific genes and in sets of co-expressed genes from three transcript profiling studies. Simulation studies indicate that oPOSSUM produces few false positives using empirically defined thresholds and can tolerate up to 50% noise in a set of co-expressed genes.


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