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Genome-Wide Pattern of TCF7L2/TCF4 Chromatin Occupancy in Colorectal Cancer Cells ^,

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,* and Hendrik G. Stunnenberg^2,*

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.

Published ahead of print on 11 February 2008.

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

These authors contributed equally.