Genome-wide pattern of TCF7L2/TCF4 chromatin occupancy in colorectal cancer cells

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

^* To whom correspondence should be addressed. Email: h.clevers{at}niob.knaw.nl.

	Abstract

Wnt signaling activates gene expression through the induced formation of complexes between DNA-binding TCF factors and the transcriptional co-activator -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 identify 6868 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 evolutionary 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 -catenin/TCF4-dependent enhancers in transient reporter assays.