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Mol. Cell. Biol. doi:10.1128/MCB.00555-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Differential control of Wnt target genes involves epigenetic mechanisms and selective promoter occupancy by TCFs

Institute of Molecular Medicine and Cell Research, University of Freiburg, D-79104 Freiburg, Germany

^* To whom correspondence should be addressed. Email: andreas.hecht{at}mol-med.uni-freiburg.de.

	Abstract

Canonical Wnt signaling and its nuclear effectors, -catenin and the family of T-cell factor (TCF) DNA-binding proteins, belong to the small number of regulatory systems which are repeatedly used for context-dependent control of distinct genetic programs. The apparent ability to elicit a large variety of transcriptional responses necessitates that -catenin and TCFs distinguish precisely between genes to be activated and genes to remain silent in a specific context. How this is achieved is unclear. Here, we examined patterns of Wnt target gene activation and promoter occupancy by TCFs in different mouse cell culture models. Remarkably, within a given cell-type only Wnt-responsive promoters are bound by specific subsets of TCFs, whereas non-responsive Wnt target promoters remain unoccupied. Wnt-responsive, TCF-bound states correlate with DNA hypomethylation, histone H3 hyperacetylation, and H3K4 trimethylation. Inactive, non-responsive promoter chromatin shows DNA hypermethylation, is devoid of active histone marks, and can additionally show repressive H3K27 trimethylation. Furthermore, chromatin structural states appear to be independent of Wnt pathway activity. Apparently, cell-type specific regulation of Wnt target genes comprises multi-layered control systems. These involve epigenetic modifications of promoter chromatin and differential promoter occupancy by functionally distinct TCF proteins which together determine susceptibility to Wnt signaling.

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