SOX9 binds TCFs to mediate Wnt/β catenin target gene activation

Activation of the Wnt/{beta}-catenin pathway regulates gene expression by promoting the formation of a {beta}-catenin-TCF complex on target gene chromatin. The transcription factor SOX9 antagonises Wnt signalling in many contexts through its ability to down-regulate {beta}-catenin protein levels. Here, we find that SOX9 promotes the proliferation of Wnt-driven colorectal cancer (CRC) cells. We identify multiple enhancers activated by SOX9 working in concert with the Wnt pathway. These enhancers are co-occupied by TCFs and SOX9 and contain TCF and SOX9 binding sites that are necessary for transcriptional activation. In addition, we identify a physical interaction between the DNA-binding domains of TCFs and SOX9 and show that TCF-SOX9 interactions are important for target gene regulation and CRC cell growth. Our work demonstrates a highly context-dependent effect of SOX9 on Wnt targets, with activation or repression being dependent on the presence or absence of SOX9 binding sites on Wnt-regulated enhancers respectively.