Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland.
Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
Elife. 2020 Aug 18;9:e58123. doi: 10.7554/eLife.58123.
BCL9 and PYGO are β-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of β-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the β-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a β-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/β-catenin-dependent transcriptional complex.
BCL9 和 PYGO 是 β-连环蛋白的共激活因子，可增强 Wnt 靶基因的转录。它们被提议作为治疗靶点，以减少肠道恶性肿瘤中的 Wnt 信号输出。在这里，我们发现，在结直肠癌细胞和发育中的小鼠前肢中，BCL9 蛋白以很大程度上不依赖于 PYGO 的方式维持 β-连环蛋白的作用。我们的遗传分析表明，BCL9 在介导其转录输出中需要其他相互作用伙伴。我们将转录因子 TBX3 鉴定为 β-连环蛋白转录复合物中的候选组织特异性成员。在发育中的前肢中，TBX3 和 BCL9 都占据了大量的 Wnt 反应性调节元件，在全基因组范围内。此外，中的突变会影响体内 TBX3 靶基因的表达，而 TBX3 丰度的调节以 β-连环蛋白和 TCF/LEF 依赖的方式影响 Wnt 靶基因的转录。最后，TBX3 的过表达加剧了依赖 Wnt 的人结直肠癌细胞的转移潜力。我们的工作表明 TBX3 是 Wnt/β-连环蛋白依赖性转录复合物的上下文相关组成部分。
