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

Verzi, M. P. and Hatzis, P. and Sulahian, R. and Philips, J. and Schuijers, J. and Shin, H.D. and Freed, E. and Lynch, J. P. and Dang, D. T. and Brown, M. and Clevers, H. and Liu, X. S. and Shivdasani, R. A. (2010) TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions. Proceedings of the National Academy of Sciences of the United States of America, 107, 15157-62. ISSN 0027-8424.

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Official URL: http://dx.doi.org/10.1073/pnas.1003822107

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.

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:9455
Deposited On:04 Jan 2011 01:00
Last Modified:07 Sep 2011 17:01

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