Abstract B37: Genomic view of YAP1 dependent transcription

YAP1 is a transcriptional coactivator regulated by the Hippo pathway, mechano-transduction, G-protein coupled receptors, and WNT signaling. YAP1 activity depends on its stabilization and its nuclear localization. Once in the nucleus, YAP1 can regulate gene expression by interacting with transcription factors with DNA binding capability. While YAP1 main transcriptional partners belong to the TEAD family, several reports indicate that YAP1 can also associate with SMADs, RUNX, and other transcription factors. YAP1 acts as a broad regulator of cell growth and differentiation, thus playing a pivotal role in regeneration, reprogramming, and cancer. How YAP1 may control such a large number of cellular processes is still to be fully understood. In the adult mouse liver, activation of YAP1 supports proficient cell proliferation and triggers dedifferentiation of hepatocytes towards a bipotent progenitor-like state. Overall, this results in abnormal liver growth, which, upon prolonged YAP1 activation, may lead to the emergence of focal hepatocellular carcinomas. In order to gain further insight into the role of YAP1 in these processes, we conducted a genome-wide investigation in the mouse liver, to identify how YAP1 controls transcription and to define gene expression programs directly regulated by YAP1. YAP1 binding to the genome was exclusively mediated by TEAD, yet given the preponderance of TEAD bound loci, only a subset of these sites was bound by YAP1. Such loci showed a defined pattern of epigenetic bookmarking and selective binding of transcription factors, thus indicating that pre-existing chromatin modifications and transcription factors are pivotal in biasing YAP1 binding to a defined set of TEAD bound genomic regions. Integrated analyses of ChIP-seq and RNA-seq data indicated that YAP1 can act both as an activator and as a repressor in a context-dependent way and allowed the dissection of transcriptional mechanisms. Longitudinal analysis by ChIP-seq and RNA-seq highlighted differences in genome binding and transcriptional control, which allowed the identification of acute and tonic YAP1 dependent responses. While during acute activation YAP1 triggered cell cycle and signal transduction programs, its prolonged activation sustained a feed-forward loop that potentiated and expanded YAP1-dependent transcription, thus leading to the direct engagement of cell identity programs. Overall this study provides a genome-scale understanding of how YAP1 controls gene expression and reveals principles in gene regulation that account for YAP1 ability to orchestrate development, regeneration, and cell reprogramming. Citation Format: Francesca Biagioni, Ottavio Croci, Elisa Donato, Silvia Sberna, Serena De Fazio, Arianna Sabo, Bruno Amati, Stefano Campaner. Genomic view of YAP1 dependent transcription [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B37.