Ae. Kel et al., Computer-assisted identification of cell cycle-related genes: new targets for E2F transcription factors, J MOL BIOL, 309(1), 2001, pp. 99-120
The processes that take place during development and differentiation are di
rected through coordinated regulation of expression of a large number of ge
nes. One such gene regulatory network provides cell cycle control in eukary
otic organisms. Ln this work, we have studied the structural features of th
e 5' regulatory regions of cell cycle-related genes. We developed a new met
hod for identifying composite substructures (modules) in regulatory regions
of genes consisting of a binding site for a key transcription factor and a
dditional contextual motifs: potential targets for other transcription fact
ors that may synergistically regulate gene transcription. Applying this met
hod to cell cycle-related promoters, we created a program for context-speci
fic identification of binding sites for transcription factors of the E2F fa
mily which are key regulators of the cell cycle. We found that E2F composit
e modules are found at a high frequency and in close proximity to the start
of transcription in cell cycle-related promoters in comparison with other
promoters. Using this information, we then searched for E2F sites in genomi
c sequences with the goal of identifying new genes which play important rol
es in controlling cell proliferation, differentiation and apoptosis. Using
a chromatin immunoprecipitation assay, we then experimentally verified the
binding of E2F in vivo to the promoters predicted by the computer-assisted
methods. Our identification of new E2F target genes provides new insight in
to gene regulatory networks and provides a framework for continued analysis
of the role of contextual promoter features in transcriptional regulation.
The tools described are available at http:// compel.bionet.nsc.ru/FunSite/
SiteScan.html. (C) 2001 Academic Press.