Nucleic Acids Research Advance Access originally published online on July 26, 2007
Nucleic Acids Research 2007 35(15):5120-5129; doi:10.1093/nar/gkm535
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Nucleic Acids Research, 2007, Vol. 35, No. 15 5120-5129
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Computational Biology |
Dissecting the action of an evolutionary conserved non-coding region on renin promoter activity
1Institute for Physiology, Systems Biology - Computational Physiology, Charité Universitätsmedizin, 2Institute for Theoretical Biology, Humboldt University, Berlin and 3Manchester Interdisciplinary Biocentre, School of Chemical Engineering and Analytical Sciences, University of Manchester, UK
*To whom correspondence should be addressed. Tel: +49 30 450 528218; Fax: +49 30 450 528972; Email: ralf.mrowka{at}charite.de
Received February 5, 2007. Revised June 27, 2007. Accepted July 2, 2007.
Elucidating the mechanisms of the human transcriptional regulatory network is a major challenge of the post-genomic era. One important aspect is the identification and functional analysis of regulatory elements in non-coding DNA. Genomic sequence comparisons between related species can guide the discovery of cis-regulatory sequences. Using this technique, we identify a conserved region CNSmd of 
775 bp in size, 14 kb upstream of the renin gene. Renin plays a pivotal role for mammalian blood pressure regulation and electrolyte balance. To analyse the cis-regulatory role of this region in detail, we perform 132 combinatorial reporter gene assays in an in vitro Calu-6 cell line model. To dissect the role of individual subregions, we fit several mathematical models to the experimental data. We show that a multiplicative switch model fits best the experimental data and that one subregion has a dominant effect on promoter activity. Mapping of the sub-sequences on phylogenetic conservation data reveals that the dominant regulatory region is the one with the highest multi-species conservation score.
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