Orth, Martin FSurdez, DidierFaehling, TobiasEhlers, Anna CMarchetto, ArunaGrossetête, SandrineVolckmann, RichardZwijnenburg, Danny AGerke, Julia SZaidi, SakinaAlonso, JavierSastre, AnaBaulande, SylvainSill, MartinCidre-Aranaz, FlorenciaOhmura, ShunyaKirchner, ThomasHauck, Stefanie MReischl, EvaGymrek, MelissaPfister, Stefan MStrauch, KonstantinKoster, JanDelattre, OlivierGrünewald, Thomas G P2023-04-252023-04-252022-12-06Cell Rep. 2022 Dec 6;41(10):111761.http://hdl.handle.net/20.500.12105/15882Ewing 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/CP: CancerChiP-seqEWSR1-ERGEWSR1-ETSEWSR1-FLI1Ewing sarcomaEnhancerMicrosatellitesMulti-omicsPediatric sarcomaTumor heterogeneitySarcoma, EwingHumansMultiomicsOncogenesCell LineTranscription FactorsAttribution-NonCommercial-NoDerivatives 4.0 Internacional36476851411011176110.1016/j.celrep.2022.1117612211-1247Cell reportsopen access