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Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15157-62. doi: 10.1073/pnas.1003822107. Epub 2010 Aug 9.

TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions.

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  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Abstract

Surprisingly 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.

PMID:
20696899
[PubMed - indexed for MEDLINE]
PMCID:
PMC2930576
Free PMC Article

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