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

Pantelis Hatzis, Laurens G. Van Der Flier, Marc A. Van Driel, Victor Guryev, Fiona Nielsen, Sergei Denissov, Isaäc J. Nijman, Jan Koster, Evan E. Santo, Willem Welboren, Rogier Versteeg, Edwin Cuppen, Marc Van De Wetering, Hans Clevers, Hendrik G. Stunnenberg

Research output: Contribution to journalArticlepeer-review

199 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2732-2744
Number of pages13
JournalMolecular and Cellular Biology
Volume28
Issue number8
DOIs
Publication statusPublished - Apr 2008
Externally publishedYes

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