Verzi, M. P.Hatzis, Phillip EvangelosSulahian, R.Philips, J.Schuijers, J.Shin, H.Freed, E.Lynch, J. P.Dang, D. T.Brown, MylesClevers, H.Liu, XiaoleShivdasani, Ramesh2018-03-272010Verzi, M. P., P. Hatzis, R. Sulahian, J. Philips, J. Schuijers, H. Shin, E. Freed, et al. 2010. TCF4 and CDX2, Major Transcription Factors for Intestinal Function, Converge on the Same Cis-Regulatory Regions. Proceedings of the National Academy of Sciences 107, no. 34: 15157–15162. doi:10.1073/pnas.1003822107.0027-8424http://nrs.harvard.edu/urn-3:HUL.InstRepos:35141070Surprisingly few pathways signal between cells, raising questions about mechanisms for tissue-specific responses. In particular, Wnt ligands signal in many mammalian tissues, including the intestinal epithelium, where constitutive signaling causes cancer. Genome-wide analysis of DNA cis-regulatory regions bound by the intestine-restricted transcription factor CDX2 in colonic cells uncovered highly significant overrepresentation of sequences that bind TCF4, a transcriptional effector of intestinal Wnt signaling. Chromatin immunoprecipitation confirmed TCF4 occupancy at most such sites and co-occupancy of CDX2 and TCF4 across short distances. A region spanning the single nucleotide polymorphism rs6983267, which lies within a MYC enhancer and confers colorectal cancer risk in humans, represented one of many co-occupied sites. Co-occupancy correlated with intestine-specific gene expression and CDX2 loss reduced TCF4 binding. These results implicate CDX2 in directing TCF4 binding in intestinal cells. Co-occupancy of regulatory regions by signal-effector and tissue-restricted transcription factors may represent a general mechanism for ubiquitous signaling pathways to achieve tissue-specific outcomes.en-UScontext specificity of signalinggenome-wide chromatin immunoprecipitationsignalingWnt signaling in intestinetissue-specific gene regulationJournal Article10.1073/pnas.1003822107