TCF/LEF dependent and independent transcriptional regulation of Wnt/β-catenin target genes.

Abstract During canonical Wnt signalling, the activity of nuclear β‐catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view, we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones lacking all four TCF/LEF genes. By performing unbiased whole transcriptome sequencing analysis, we found that a subset of β‐catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome‐wide analysis that β‐catenin occupied specific genomic regions in the absence of TCF/LEF. Finally, we revealed the existence of a transcriptional activity of β‐catenin that specifically appears when TCF/LEF factors are absent, and refer to this as β‐catenin‐GHOST response. Collectively, this study uncovers a previously neglected modus operandi of β‐catenin that bypasses the TCF/LEF transcription factors.