10779/crick.12639992.v1 Dana Elster Dana Elster Marie Tollot Marie Tollot Karin Schlegelmilch Karin Schlegelmilch Alessandro Ori Alessandro Ori Andreas Rosenwald Andreas Rosenwald Erik Sahai Erik Sahai Björn von Eyss Björn von Eyss TRPS1 shapes YAP/TEAD-dependent transcription in breast cancer cells The Francis Crick Institute 2020 Acetylation Animals Binding Sites Breast Neoplasms CRISPR-Cas Systems Cell Line, Tumor Chromatin DNA-Binding Proteins Enhancer Elements, Genetic Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Genomics HEK293 Cells Humans MCF-7 Cells Mice Mice, Inbred BALB C Neoplasm Transplantation Promoter Regions, Genetic RNA, Small Interfering Tissue Array Analysis Transcription Factors Transcriptional Activation Sahai FC001144 2020-07-15 11:11:47 Journal contribution https://crick.figshare.com/articles/journal_contribution/TRPS1_shapes_YAP_TEAD-dependent_transcription_in_breast_cancer_cells/12639992 Yes-associated protein (YAP), the downstream transducer of the Hippo pathway, is a key regulator of organ size, differentiation and tumorigenesis. To uncover Hippo-independent YAP regulators, we performed a genome-wide CRISPR screen that identifies the transcriptional repressor protein Trichorhinophalangeal Syndrome 1 (TRPS1) as a potent repressor of YAP-dependent transactivation. We show that TRPS1 globally regulates YAP-dependent transcription by binding to a large set of joint genomic sites, mainly enhancers. TRPS1 represses YAP-dependent function by recruiting a spectrum of corepressor complexes to joint sites. Loss of TRPS1 leads to activation of enhancers due to increased H3K27 acetylation and an altered promoter-enhancer interaction landscape. TRPS1 is commonly amplified in breast cancer, which suggests that restrained YAP activity favours tumour growth. High TRPS1 activity is associated with decreased YAP activity and leads to decreased frequency of tumour-infiltrating immune cells. Our study uncovers TRPS1 as an epigenetic regulator of YAP activity in breast cancer.