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Nucleic Acids Research, 2000, Vol. 28, No. 8 1808-1818
© 2000 Oxford University Press

Discovering regulatory elements in non-coding sequences by analysis of spaced dyads

Jacques van Helden*, Alma. F. Rios1 and Julio Collado-Vides1

Unité de Conformation des Macromolécules Biologiques, Université Libre de Bruxelles, CP 160/16, 50 av. F. D. Roosevelt, B-1050 Bruxelles, Belgium and 1Centro de Investigación sobre Fijación de Nitrógeno, Universidad Nacional Autónoma de México, AP565A, Cuernavaca 62100, Morelos, Mexico

The application of microarray and related technologies is currently generating a systematic catalog of the transcriptional response of any single gene to a multiplicity of experimental conditions. Clustering genes according to the similarity of their transcriptional response provides a direct hint to the regulons of the different transcription factors, many of which have still not been characterized. We have developed a new method for deciphering the mechanism underlying the common transcriptional response of a set of genes, i.e. discovering cis-acting regulatory elements from a set of unaligned upstream sequences. This method, called dyad analysis, is based on the observation that many regulatory sites consist of a pair of highly conserved trinucleotides, spaced by a non-conserved region of fixed width. The approach is to count the number of occurrences of each possible spaced pair of trinucleotides, and to assess its statistical significance. The method is highly efficient in the detection of sites bound by C6 Zn2 binuclear cluster proteins, as well as other transcription factors. In addition, we show that the dyad and single-word analyses are efficient for the detection of regulatory patterns in gene clusters from DNA chip experiments. In combination, these programs should provide a fast and efficient way to discover new regulatory sites for as yet unknown transcription factors.

* To whom correspondence should be addressed. Tel: +32 2 650 20 13; Fax: +32 2 648 89 54; Email: jvanheld@ucmb.ulb.ac.be


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