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

Orth, Martin F.; Surdez, Didier; Faehling, Tobias; Ehlers, Anna C.; Marchetto, Aruna; Grossetete, Sandrine; Volckmann, Richard; Zwijnenburg, Danny A.; Gerke, Julia S.; Zaidi, Sakina; Alonso, Javier; Sastre, Ana; Baulande, Sylvain; Sill, Martin; Cidre-Aranaz, Florencia; Ohmura, Shunya; Kirchner, Thomas; Hauck, Stefanie M.; Reischl, Eva; Gymrek, Melissa; Pfister, Stefan M.; Strauch, Konstantin; Koster, Jan; Delattre, Olivier und Grunewald, Thomas G. . P. (2022): Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation. In: Cell Reports, Bd. 41, Nr. 10, 111761

Abstract

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 Ew-ing Sarcoma Cell Line Atlas (ESCLA), comprising whole-genome, DNA methylation, transcriptome, prote-ome, 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-tar-gets 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2211-1247
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 458891500