Genome-wide pattern of TCF7L2/TCF4 chromatin occupancy in colorectal cancer cells.
Wnt signaling activates gene expression through the induced formation of complexes between DNA-binding T-cell factors (TCFs) and the transcriptional coactivator beta-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 beta-catenin/TCF4-dependent enhancers in transient reporter assays.
Hatzis
Pantelis
P
Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
van der Flier
Laurens G
LG
van Driel
Marc A
MA
Guryev
Victor
V
Nielsen
Fiona
F
Denissov
Sergei
S
Nijman
Isaäc J
IJ
Koster
Jan
J
Santo
Evan E
EE
Welboren
Willem
W
Versteeg
Rogier
R
Cuppen
Edwin
E
van de Wetering
Marc
M
Clevers
Hans
H
Stunnenberg
Hendrik G
HG
D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D011485:Protein Binding; D051820:TCF Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014158:Transcription, Genetic / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism
D002843:Chromatin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D004247:DNA