Association with YY1 and the PRC2 complex mediates the transcriptional repressive functions of YAP/TEAD. Association with YY1 and the PRC2 complex mediates the transcriptional repressive functions of YAP/TEAD

Inhibition of cell proliferation through cell-cell contact (contact-inhibition or CI) is a major mechanism regulating development and homeostasis in multicellular organisms. However, the molecular mechanisms mediating CI remain largely unknown. The Hippo pathway has emerged as a central regulator of organ size and tissue homeostasis, by controlling the localization and activity of the transcriptional regulator YAP. As previous studies indicated YAP is regulated by cell-cell contact, we assessed the function of YAP in this context. Here we show that in addition to its function as a transcriptional activator, YAP functions as a repressor of a significant number of genes including the cyclin-dependent kinase (Cdk) inhibitor p27. We find that inhibition of p27 depends on the Ying-Yang 1 (YY1) transcription factor and recruitment of the Polycomb repressive complex (PRC2). Moreover, YAP marks co-localizes with YY1 and EZH2 marks on the genome to transcriptionally repress a network of genes mediating a host of cellular functions, including key regulators of the cell cycle. This work highlights a broad and underappreciated aspect of YAP function as a transcriptional repressor and details a mechanism through which these functions are mediated. Overall design: YAP, YY1, and EZH2 ChIP-Seq

细胞间接触介导的细胞增殖抑制（接触抑制，Contact Inhibition，CI）是调控多细胞生物发育与体内稳态的核心机制之一。然而，介导接触抑制的分子机制目前仍未被完全阐明。Hippo信号通路（Hippo pathway）已被证实为调控器官大小与组织稳态的核心通路，其通过控制转录调控因子YAP的定位与活性发挥功能。已有研究表明YAP的活性受细胞间接触调控，因此本研究针对YAP在该过程中的功能展开了评估。本研究发现，YAP除了作为转录激活因子发挥功能外，还可作为转录抑制因子调控大量基因的表达，其中包括细胞周期蛋白依赖性激酶（cyclin-dependent kinase，Cdk）抑制因子p27。研究发现，YAP对p27的抑制作用依赖于阴阳因子1（Ying-Yang 1，YY1）转录因子以及多梳抑制复合体2（Polycomb repressive complex 2，PRC2）的招募。此外，全基因组范围内，YAP结合峰与YY1及EZH2结合峰存在共定位，借此转录抑制一系列参与多种细胞功能的基因，其中包括细胞周期的关键调控因子。本研究揭示了YAP作为转录抑制因子的广泛且尚未被充分认知的功能层面，并阐明了其发挥这些功能的分子机制。实验设计：YAP、YY1及EZH2的染色质免疫共沉淀测序（ChIP-Seq）