Discovery of novel transcription factor binding sites by statistical overrepresentation

• Published in: Nucleic acids research Vol. 30; no. 24; pp. 5549 - 5560
• Main Authors: Sinha, Saurabh, Tompa, Martin
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.12.2002
• Subjects: Algorithms; Binding Sites - genetics; Computational Biology - methods; Computational Biology - statistics & numerical data; DNA, Fungal - genetics; DNA, Fungal - metabolism; Genes, Fungal - genetics; Phenotype; Promoter Regions, Genetic - genetics; Protein Binding; Regulon - genetics; Reproducibility of Results; Saccharomyces cerevisiae - genetics; Transcription Factors - metabolism
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkf669

Understanding the complex and varied mechanisms that regulate gene expression is an important and challenging problem. A fundamental sub‐problem is to identify DNA binding sites for unknown regulatory factors, given a collection of genes believed to be co‐regulated. We discuss a computational method that identifies good candidates for such binding sites. Unlike local search techniques such as expectation maximization and Gibbs samplers that may not reach a global optimum, the method discussed enumerates all motifs in the search space, and is guaranteed to produce the motifs with greatest z‐scores. We discuss the results of validation experiments in which this algorithm was used to identify candidate binding sites in several well studied regulons of Saccharomyces cerevisiae, where the most prominent transcription factor binding sites are largely known. We then discuss the results on gene families in the functional and mutant phenotype catalogs of S.cerevisiae, where the algorithm suggests many promising novel transcription factor binding sites. The program is available at http://bio.cs.washington.edu/software.html.