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Nucleic Acids Research Advance Access originally published online on January 30, 2007
Nucleic Acids Research 2007 35(4):1098-1107; doi:10.1093/nar/gkl1157
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Nucleic Acids Research, 2007, Vol. 35, No. 4 1098-1107
© 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.

Genomics

Identifying synergistic regulation involving c-Myc and sp1 in human tissues

Fabio Parisi1, Pratyaksha Wirapati2 and Felix Naef1–3,*

1Swiss Institute for Experimental Cancer Research (ISREC) and NCCR Molecular Oncology, Lausanne, Switzerland, 2Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland and 3School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland

*To whom correspondence should be addressed. Tel: +1 41 6931621; Fax: +1 41 6931635; Email: felix.naef{at}isrec.ch

Received May 25, 2006. Revised December 18, 2006. Accepted December 20, 2006.

Combinatorial gene regulation largely contributes to phenotypic versatility in higher eukaryotes. Genome-wide chromatin immuno-precipitation (ChIP) combined with expression profiling can dissect regulatory circuits around transcriptional regulators. Here, we integrate tiling array measurements of DNA-binding sites for c-Myc, sp1, TFIID and modified histones with a tissue expression atlas to establish the functional correspondence between physical binding, promoter activity and transcriptional regulation. For this we develop SLM, a methodology to map c-Myc and sp1-binding sites and then classify sites as sp1-only, c-Myc-only or dual. Dual sites show several distinct features compared to the single regulator sites: specifically, they exhibit overall higher degree of conservation between human and rodents, stronger correlation with TFIID-bound promoters, and preference for permissive chromatin state. By applying regression models to an expression atlas we identified a functionally distinct signature for strong dual c-Myc/sp1 sites. Namely, the correlation with c-Myc expression in promoters harboring dual-sites is increased for stronger sp1 sites by strong sp1 binding and the effect is largest in proliferating tissues. Our approach shows how integrated functional analyses can uncover tissue-specific and combinatorial regulatory dependencies in mammals.


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