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

Abstract

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.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank members of the Clevers and Stunnenberg laboratories for help and discussions, Tokameh Mahmoudi for critical reading of the manuscript, Thanasis Margaritis for assistance with bioinformatics. and Andrea Haegebarth for help with figure preparation.

P.H. is supported by successive European Molecular Biology Organization and Human Frontier Science Program Organization long-term fellowships. M.A.V.D. is supported by EU-FP6 IP EPITRON and STREP X-TRA-NET. S.D. is supported by EU-FP6 IP HEROIC.