Wnt-induced transcriptional activation is exclusively mediated by TCF/LEF

Authors


Abstract

Active canonical Wnt signaling results in recruitment of β-catenin to DNA by TCF/LEF family members, leading to transcriptional activation of TCF target genes. However, additional transcription factors have been suggested to recruit β-catenin and tether it to DNA. Here, we describe the genome-wide pattern of β-catenin DNA binding in murine intestinal epithelium, Wnt-responsive colorectal cancer (CRC) cells and HEK293 embryonic kidney cells. We identify two classes of β-catenin binding sites. The first class represents the majority of the DNA-bound β-catenin and co-localizes with TCF4, the prominent TCF/LEF family member in these cells. The second class consists of β-catenin binding sites that co-localize with a minimal amount of TCF4. The latter consists of lower affinity β-catenin binding events, does not drive transcription and often does not contain a consensus TCF binding motif. Surprisingly, a dominant-negative form of TCF4 abrogates the β-catenin/DNA interaction of both classes of binding sites, implying that the second class comprises low affinity TCF-DNA complexes. Our results indicate that β-catenin is tethered to chromatin overwhelmingly through the TCF/LEF transcription factors in these three systems.

Synopsis

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Integrated genome-wide ChIP-seq data in multiple cell types reveals that Tcf4 globally determines Wnt/beta-catenin transcriptional programs.

  • β-catenin-bound elements can be divided in two classes according to TCF4 co-occupancy.
  • However, all β-catenin was displaced by a dominant negative form of TCF4.
  • These data show that β-catenin recruitment is overwhelmingly mediated by TCF/LEF.

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