YAP1 is a major effector of the Hippo pathway and a well-established oncogene. Elevated YAP1 activity due to mutations in Hippo pathway components or YAP1 amplification is observed in several types of human cancers. Here we investigated its genomic binding landscape in YAP1-activated cancer cells, as well as in non-transformed cells. We demonstrate that TEAD transcription factors mediate YAP1 chromatin-binding genome-wide, further explaining their dominant role as primary mediators of YAP1-transcriptional activity. Moreover, we show that YAP1 largely exerts its transcriptional control via distal enhancers that are marked by H3K27 acetylation and that YAP1 is necessary for this chromatin mark at bound enhancers and the activity of the associated genes. This work establishes YAP1-mediated transcriptional regulation at distal enhancers and provides an expanded set of target genes resulting in a fundamental source to study YAP1 function in a normal and cancer setting.
The YAP1/Hippo signaling pathway is a key regulator of organ size and tissue homeostasis, and its dysregulation is linked to cancer development. Elevated activity of YAP1, a transcriptional coactivator and well-established oncogene has been reported to occur in human cancers. Comprehensive identification of YAP1 regulated genes and its mode of action will be of high importance to uncover YAP1 biology that could be exploited for a therapeutic intervention. To this end, we performed genome-wide analyses to identify YAP1 occupied sites in cancer cell lines representing different YAP1/Hippo pathway tumor etiologies and in non-transformed fibroblasts. Our data demonstrate that YAP1 activity is mediated predominantly via TEAD transcription factors supporting the importance of TEADs as main mediators of YAP1-coactivator activity. We further show that YAP1 and TEAD1 exert their transcriptional control via binding to enhancers, leading to characteristic chromatin changes and distal activation of genes. By linking enhancers to genes, we provide a list of novel YAP1 target genes in an oncogenic setting that we show can readily be exploited in tumor classification and provides a foundation for further investigations.