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Molecular and Cellular Biology, April 2008, p. 2732-2744, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.02175-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Genome-Wide Pattern of TCF7L2/TCF4 Chromatin Occupancy in Colorectal Cancer Cells{triangledown} ,{dagger}

Pantelis Hatzis,1 Laurens G. van der Flier,1 Marc A. van Driel,2 Victor Guryev,1 Fiona Nielsen,2 Sergei Denissov,2 Isaäc J. Nijman,1 Jan Koster,3 Evan E. Santo,3 Willem Welboren,2 Rogier Versteeg,3 Edwin Cuppen,1 Marc van de Wetering,1 Hans Clevers,1,{ddagger}* and Hendrik G. Stunnenberg2,{ddagger}*

Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands,1 Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands,2 Department of Human Genetics, M1-134, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands3

Received 7 December 2007/ Returned for modification 17 January 2008/ Accepted 4 February 2008

Wnt signaling activates gene expression through the induced formation of complexes between DNA-binding T-cell factors (TCFs) and the transcriptional coactivator β-catenin. In colorectal cancer, activating Wnt pathway mutations transform epithelial cells through the inappropriate activation of a TCF7L2/TCF4 target gene program. Through a DNA array-based genome-wide analysis of TCF4 chromatin occupancy, we have identified 6,868 high-confidence TCF4-binding sites in the LS174T colorectal cancer cell line. Most TCF4-binding sites are located at large distances from transcription start sites, while target genes are frequently "decorated" by multiple binding sites. Motif discovery algorithms define the in vivo-occupied TCF4-binding site as evolutionarily conserved A-C/G-A/T-T-C-A-A-A-G motifs. The TCF4-binding regions significantly correlate with Wnt-responsive gene expression profiles derived from primary human adenomas and often behave as β-catenin/TCF4-dependent enhancers in transient reporter assays.

* Corresponding author. Mailing address for Hans Clevers: Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands. Phone: 31-302-12-1831. Fax: 31-302-12-1801. E-mail: h.clevers{at}niob.knaw.nl. Mailing address for Hendrik G. Stunnenberg: Nijmegen Center for Molecular Life Sciences, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands. Phone: 31-24-3610524. Fax: 31-243610520. E-mail: h.stunnenberg{at}ncmls.ru.nl

{triangledown} Published ahead of print on 11 February 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally.

Molecular and Cellular Biology, April 2008, p. 2732-2744, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.02175-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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