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.