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

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          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.

          Author Summary

          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.

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          Most cited references48

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          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

            The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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              A unique chromatin signature uncovers early developmental enhancers in humans.

              Cell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of genomic sequences that control human embryonic development represents a formidable challenge. Here we show that in human embryonic stem cells (hESCs), unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, monomethylation of histone H3 at lysine 4 (H3K4me1), and low nucleosomal density. In addition, elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized hESC enhancers, and are located proximally to genes expressed in hESCs and the epiblast. In contrast, elements of the second class, which we term 'poised enhancers', are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3), and are linked to genes inactive in hESCs and instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafish embryos, poised enhancers are able to direct cell-type and stage-specific expression characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that early developmental enhancers are epigenetically pre-marked in hESCs and indicate an unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the wealth of new regulatory sequences identified here provides an invaluable resource for studies and isolation of transient, rare cell populations representing early stages of human embryogenesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                21 August 2015
                August 2015
                : 11
                : 8
                : e1005465
                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 ]University of Basel, Faculty of Sciences, Basel, Switzerland
                The University of North Carolina at Chapel Hill, UNITED STATES
                Author notes

                The authors of this manuscript have read the journal's policy and have the following competing interests: CS, GR, SB, IC, AR, CA, TS, TB and AB are employees of Novartis Pharmaceuticals.

                Conceived and designed the experiments: CS AFB DS AB. Performed the experiments: CS AR CA. Analyzed the data: AFB GR SB IC. Wrote the paper: CS AFB TB DS AB. Commented on and revised the manuscript: CS AFB GR SB IC AR CA TS TB DS AB. Supervised the project and revised the manuscript: TS TB DS AB. Supported design, data acquisition and analysis for the RNA-seq and ChIP-seq experiments: GR SB.

                Article
                PGENETICS-D-15-00886
                10.1371/journal.pgen.1005465
                4546604
                26295846
                cbfaef16-8282-47e7-ae04-7e7b69a3734a
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 10 April 2015
                : 23 July 2015
                Page count
                Figures: 7, Tables: 7, Pages: 28
                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.
                Categories
                Research Article
                Custom metadata
                Raw and processed ChIP-seq data are deposited in the Gene Expression Omnibus (GEO) under the accession number GSE61852. The raw RNA-sequencing reads are available in the NCBI Short Read Archive under the accession number SRP056665.

                Genetics
                Genetics

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