期刊
EMBO JOURNAL
卷 33, 期 2, 页码 146-156出版社
WILEY
DOI: 10.1002/embj.201385358
关键词
beta-catenin; ChIP-Seq; Wnt pathway; transcriptional regulation; TCF
资金
- Cancer Genomics Centre II, Molecular mechanisms
- Marie Curie-Career Integration Grant [293968]
- Fondation Sante Research Grant
Active canonical Wnt signaling results in recruitment of beta-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 beta-catenin and tether it to DNA. Here, we describe the genome-wide pattern of beta-catenin DNA binding in murine intestinal epithelium, Wnt-responsive colorectal cancer (CRC) cells and HEK293 embryonic kidney cells. We identify two classes of beta-catenin binding sites. The first class represents the majority of the DNA-bound beta-catenin and co-localizes with TCF4, the prominent TCF/LEF family member in these cells. The second class consists of beta-catenin binding sites that co-localize with a minimal amount of TCF4. The latter consists of lower affinity beta-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 beta-catenin/DNA interaction of both classes of binding sites, implying that the second class comprises low affinity TCF-DNA complexes. Our results indicate that beta-catenin is tethered to chromatin overwhelmingly through the TCF/LEF transcription factors in these three systems. Synopsis image Integrated genome-wide ChIP-seq data in multiple cell types reveals that Tcf4 globally determines Wnt/beta-catenin transcriptional programs. beta-catenin-bound elements can be divided in two classes according to TCF4 co-occupancy. However, all beta-catenin was displaced by a dominant negative form of TCF4. These data show that beta-catenin recruitment is overwhelmingly mediated by TCF/LEF.
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