YAP1 Exerts Its Transcriptional Control via TEAD-Mediated Activation of Enhancers

Claudia Stein; Anaïs Flore Bardet; Guglielmo Roma; Sebastian Bergling; Ieuan Clay; Alexandra Ruchti; Claudia Agarinis; Tobias Schmelzle; Tewis Bouwmeester; Dirk Schübeler; Andreas Bauer

doi:10.1371/journal.pgen.1005465

YAP1 Exerts Its Transcriptional Control via TEAD-Mediated Activation of Enhancers

PLoS Genet. 2015 Aug 21;11(8):e1005465. doi: 10.1371/journal.pgen.1005465. eCollection 2015 Aug.

Affiliations

¹ Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
² Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
³ Oncology, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
⁴ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; University of Basel, Faculty of Sciences, Basel, Switzerland.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Adaptor Proteins, Signal Transducing / physiology*
Base Sequence
Binding Sites
Cell Line, Tumor
Consensus Sequence
DNA-Binding Proteins / metabolism*
Enhancer Elements, Genetic
Histones / metabolism
Humans
Nuclear Proteins / metabolism*
Phosphoproteins / physiology*
Protein Binding
Protein Processing, Post-Translational
TEA Domain Transcription Factors
Transcription Factors / metabolism*
Transcriptional Activation
Transcriptome
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
DNA-Binding Proteins
Histones
Nuclear Proteins
Phosphoproteins
TEA Domain Transcription Factors
TEAD1 protein, human
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human

Grants and funding

CS is a NIBR presidential postdoctoral fellow. AFB is an EMBO long-term postdoctoral fellow. Research in the DS laboratory is supported by the Novartis Research Foundation, the European Union (NoE ‘‘EpiGeneSys’’ FP7- HEALTH-2010-257082, and the ‘‘Blueprint’’ consortium FP7-282510), the European Research Council (EpiGePlas) and Swiss Initiative in Systems Biology (RTD Cell Plasticity). CS, GR, SB, IC, AR, CA, TS, TB and AB are employees of Novartis Pharmaceuticals. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.