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Vol. 12, Issue 7, 1019-1028, July 2002

Computation-Based Discovery of Related Transcriptional Regulatory Modules and Motifs Using an Experimentally Validated Combinatorial Model

Marc S. Halfon,1,4 Yonatan Grad,2,4 George M. Church,2 and Alan M. Michelson1,3

1 Howard Hughes Medical Institute and Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA; 2 Department of Genetics and Lipper Center for Computational Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

Gene expression is regulated by transcription factors that interact with cis-regulatory elements. Predicting these elements from sequence data has proven difficult. We describe here a successful computational search for elements that direct expression in a particular temporal-spatial pattern in the Drosophila embryo, based on a single well characterized enhancer model. The fly genome was searched to identify sequence elements containing the same combination of transcription factors as those found in the model. Experimental evaluation of the search results demonstrates that our method can correctly predict regulatory elements and highlights the importance of functional testing as a means of identifying false-positive results. We also show that the search results enable the identification of additional relevant sequence motifs whose functions can be empirically validated. This approach, combined with gene expression and phylogenetic sequence data, allows for genome-wide identification of related regulatory elements, an important step toward understanding the genetic regulatory networks involved in development.

[Sequence data reported in this paper have been deposited in GenBank with accession nos. AF513981 (Eve MHE) and AF513982 (Hbr DME). Supplementary material is available online at http://www.genome.org. The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper: R. Blackman]


3 Corresponding author.

4 These authors contributed equally to this work.


12:1019-1028 ©2002 by Cold Spring Harbor Laboratory Press  ISSN 1088-9051/02 $5.00

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