The Hippo TEAD-transcriptional regulators YAP1 and TAZ are central for cell renewal and cancer growth; however, the specific downstream gene networks involved in their activity are not completely understood. Here we introduce TEADi, a genetically encoded inhibitor of the interaction of YAP1 and TAZ with TEAD, as a tool to characterize the transcriptional networks and biological effects regulated by TEAD transcription factors. Blockage of TEAD activity by TEADi in human keratinocytes and mouse skin leads to reduced proliferation and rapid activation of differentiation programs. Analysis of gene networks affected by TEADi and YAP1/TAZ knockdown identifies KLF4 as a central transcriptional node regulated by YAP1/TAZ-TEAD in keratinocyte differentiation. Moreover, we show that TEAD and KLF4 can regulate the activity of each other, indicating that these factors are part of a transcriptional regulatory loop. Our study establishes TEADi as a resource for studying YAP1/TAZ-TEAD dependent effects.

Hippo TEAD 转录调节因子 YAP1 和 TAZ 对于细胞更新和癌症生长至关重要；然而，参与其活动的特定下游基因网络尚未完全了解。在这里，我们介绍 TEADi，一种 YAP1 和 TAZ 与 TEAD 相互作用的基因编码抑制剂，作为表征 TEAD 转录因子调节的转录网络和生物效应的工具。 TEADi 在人角质形成细胞和小鼠皮肤中阻断 TEAD 活性，导致增殖减少和分化程序快速激活。对 TEADi 和 YAP1/TAZ 敲低影响的基因网络的分析表明，KLF4 是角质形成细胞分化中受 YAP1/TAZ-TEAD 调节的中央转录节点。此外，我们发现 TEAD 和 KLF4 可以相互调节活性，表明这些因子是转录调节环的一部分。我们的研究将 TEADi 确立为研究 YAP1/TAZ-TEAD 依赖性效应的资源。