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Bioinformatics 20(Suppl. 1) © Oxford University Press 2004; all rights reserved.

Functional inference from non-random distributions of conserved predicted transcription factor binding sites

Christoph Dieterich *, Sven Rahmann and Martin Vingron

Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, D-14195 Berlin, Germany

Received on January 15, 2004; accepted on March 1, 2004

Motivation: Our understanding of how genes are regulated in a concerted fashion is still limited. Especially, complex phenomena like cell cycle regulation in multicellular organisms are poorly understood. Therefore, we investigated conserved predicted transcription factor binding sites (TFBSs) in man–mouse upstream regions of genes that can be associated to a particular cell cycle phase in HeLa cells. TFBSs were predicted from selected binding site motifs (represented by position weight matrices, PWMs) based on a statistical approach. A regulatory role for a transcription factor is more probable if its predicted TFBSs are enriched in upstream regions of genes, that are associated with a subset of cell cycle phases. We tested for this association by computing exact P-values for the observed phase distributions under the null distribution defined by the relative amount of conserved upstream sequence of genes per cell cycle phase. We considered non-exonic and 5'-untranslated region (5'-UTR) binding sites separately and corrected for multiple testing by taking the false discovery rate into account.

Results: We identified 22 non-exonic and 11 5'-UTR significant PWM phase distributions although expecting one false discovery. Many of the corresponding transcription factors (e.g. members of the thyroid hormone/retinoid receptor subfamily) have already been associated with cell cycle regulation, proliferation and development. It appears that our method is a suitable tool for detecting putative cell cycle regulators in the realm of known human transcription factors.

Availability: Further details and supplementary data can be obtained from http://corg.molgen.mpg.de/cellcycle

Contact: christoph.dieterich{at}molgen.mpg.de

* To whom correspondence should be addressed.


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