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Nucleic Acids Research 2005 33(3):864-872; doi:10.1093/nar/gki230
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Published online 8 February 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

Linking disease-associated genes to regulatory networks via promoter organization

S. Döhr, A. Klingenhoff1, H. Maier, M. Hrabé de Angelis, T. Werner1 and R. Schneider*

Institute of Experimental Genetics, GSF-National Research Center for Environment and Health Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany 1 Genomatix Software GmbH Landsberger Str. 6, D-80339 München, Germany

*To whom correspondence should be addressed. Tel: +49 89 3187 4060; Fax: +49 89 3187 4400; Email: ralf.schneider{at}gsf.de

Received October 14, 2004. Revised November 26, 2004. Accepted January 19, 2005.

Pathway- or disease-associated genes may participate in more than one transcriptional co-regulation network. Such gene groups can be readily obtained by literature analysis or by high-throughput techniques such as microarrays or protein-interaction mapping. We developed a strategy that defines regulatory networks by in silico promoter analysis, finding potentially co-regulated subgroups without a priori knowledge. Pairs of transcription factor binding sites conserved in orthologous genes (vertically) as well as in promoter sequences of co-regulated genes (horizontally) were used as seeds for the development of promoter models representing potential co-regulation. This approach was applied to a Maturity Onset Diabetes of the Young (MODY)-associated gene list, which yielded two models connecting functionally interacting genes within MODY-related insulin/glucose signaling pathways. Additional genes functionally connected to our initial gene list were identified by database searches with these promoter models. Thus, data-driven in silico promoter analysis allowed integrating molecular mechanisms with biological functions of the cell.


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