FOX transcription factors are common regulators of Wnt/beta- catenin-dependent gene transcription

The Wnt/fl-catenin pathway is a critical regulator of devel-opment and stem cell maintenance. Mounting evidence suggests that the outcome of Wnt signaling is determined by the collab-orative action of multiple transcription factors, including members of the highly conserved forkhead box (FOX) protein family. However, the contribution of FOX transcription factors to Wnt signaling has not been investigated in a systematic manner. Here, we performed complementary screens of all 44 human FOX proteins to identify new Wnt pathway regulators. By combining fl-catenin reporter assays with Wnt pathway-focused qPCR arrays and proximity proteomics of selected candidates, we determine that most FOX proteins are involved in the regu-lation of Wnt pathway activity. As proof-of-principle, we addi-tionally characterize class D and I FOX transcription factors as physiologically relevant regulators of Wnt/fl-catenin signaling. We conclude that FOX proteins are common regulators of Wnt/ fl-catenin-dependent gene transcription that may control Wnt pathway activity in a tissue-specific manner.