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Orth, M.F.* ; Surdez, D.* ; Faehling, T.* ; Ehlers, A.C.* ; Marchetto, A.* ; Grossetete, S.* ; Volckmann, R.* ; Zwijnenburg, D.A.* ; Gerke, J.S.* ; Zaidi, S.* ; Alonso, J.* ; Sastre, A.* ; Baulande, S.* ; Sill, M.* ; Cidre-Aranaz, F.* ; Ohmura, S.* ; Kirchner, T.* ; Hauck, S.M. ; Reischl, E. ; Gymrek, M.* ; Pfister, S.M.* ; Strauch, K. ; Koster, J.* ; Delattre, O.* ; Grunewald, T.G.P.*

Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation.

Cell Rep. 41:111761 (2022)

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	Open Access Gold

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Ewing sarcoma (EwS) is characterized by EWSR1-ETS fusion transcription factors converting polymorphic GGAA microsatellites (mSats) into potent neo-enhancers. Although the paucity of additional mutations makes EwS a genuine model to study principles of cooperation between dominant fusion oncogenes and neo-enhancers, this is impeded by the limited number of well-characterized models. Here we present the Ewing Sarcoma Cell Line Atlas (ESCLA), comprising whole-genome, DNA methylation, transcriptome, proteome, and chromatin immunoprecipitation sequencing (ChIP-seq) data of 18 cell lines with inducible EWSR1-ETS knockdown. The ESCLA shows hundreds of EWSR1-ETS-targets, the nature of EWSR1-ETS-preferred GGAA mSats, and putative indirect modes of EWSR1-ETS-mediated gene regulation, converging in the duality of a specific but plastic EwS signature. We identify heterogeneously regulated EWSR1-ETS-targets as potential prognostic EwS biomarkers. Our freely available ESCLA (http://r2platform.com/escla/) is a rich resource for EwS research and highlights the power of comprehensive datasets to unravel principles of heterogeneous gene regulation by chimeric transcription factors.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Chip-seq ; Cp: Cancer ; Enhancer ; Ewing Sarcoma ; Ewsr1-erg ; Ewsr1-ets ; Ewsr1-fli1 ; Microsatellites ; Multi-omics ; Pediatric Sarcoma ; Tumor Heterogeneity; Transcription Factor; Ewsr1-fli1 Activity; Genomic Landscape; Tumor; Expression; Target; Ews-fli1; Generation; Chromatin; Elements

ISSN (print) / ISBN 2211-1247

e-ISSN 2211-1247

Journal Cell Reports

Quellenangaben Volume: 41, Issue: 10, Article Number: 111761

Publisher Cell Press

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CF Metabolomics & Proteomics (CF-MPC)
Institute of Genetic Epidemiology (IGE)

Grants LMU Munich's Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative
Mehr LEBEN fur Krebskranke Kinder - Bettina-Brau-Stiftung
Wilhelm Sander Foundation
Friedrich-Baur Foundation
Matthias Lackas Foundation
Dr. Leopold und Carmen Ellinger Foundation
Deutsche Forschungsgemeinschaft
SMARCB1 Association
German Cancer Aid
Boehringer Ingelheim Foundation
Barbara and Wilfried Mohr Foundation
Helmholtz Zentrum Munchen - German Research Center for Environmental Health
Munich Center of Health Sciences (MC-Health) as part of LMUinnovativ
EU
Agence Nationale de la Recherche ("Investissements d'Avenir" program)
Canceropole Ile-de-France
SiRIC-Curie program - SiRIC
Heinrich F.C. Behr Foundation
Federal Ministry of Education and Research