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. YAP, YY1, and EZH2 ChIP-Seq