Abstract

The Wnt/β-catenin signaling pathway plays many important roles in animal development, tissue homeostasis and human disease. Transcription factors of the TCF family mediate many Wnt transcriptional responses, promoting signal-dependent activation or repression of target gene expression. The mechanism of this specificity is poorly understood. Previously, we demonstrated that for activated targets in Drosophila, TCF/Pangolin (the fly TCF) recognizes regulatory DNA through two DNA binding domains, with the High Mobility Group (HMG) domain binding HMG sites and the adjacent C-clamp domain binding Helper sites. Here, we report that TCF/Pangolin utilizes a similar bipartite mechanism to recognize and regulate several Wnt-repressed targets, but through HMG and Helper sites whose sequences are distinct from those found in activated targets. The type of HMG and Helper sites is sufficient to direct activation or repression of Wnt regulated cis-regulatory modules, and protease digestion studies suggest that TCF/Pangolin adopts distinct conformations when bound to either HMG-Helper site pair. This repressive mechanism occurs in the fly lymph gland, the larval hematopoietic organ, where Wnt/β-catenin signaling controls prohemocytic differentiation. Our study provides a paradigm for direct repression of target gene expression by Wnt/β-catenin signaling and allosteric regulation of a transcription factor by DNA.

Highlights

  • It is a common theme in gene regulation that the same transcription factor (TF) can directly activate or repress target gene expression, increasing the transcriptional complexity these TFs can achieve [1,2]

  • What determines whether T-cell factor (TCF) will positively or negatively regulate Wnt targets? We demonstrate that activated and repressed targets have distinct DNA sequences that dock TCF on their regulatory DNA

  • We find that TCF adopts different conformations when bound to either DNA sequence, which most likely influences its regulatory activity

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Summary

Introduction

It is a common theme in gene regulation that the same transcription factor (TF) can directly activate or repress target gene expression, increasing the transcriptional complexity these TFs can achieve [1,2]. For other CRMs regulated by nuclear receptors [14,15], P53 [16], the POU TF Pit1 [17] and some Smads [18,19], it is the type of the TF binding site itself that determines output. For the latter cases, it has been proposed that the DNA binding site allosterically regulates the TF, leading to differential recruitment of co-regulators [17,20]

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