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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kindly provided reagents, samples, or unpublished information as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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