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

• Published in: Cell reports (Cambridge) 2022-12, Vol.41 (10), p.111761-111761, Article 111761
• Main Authors: Orth, Martin F., Surdez, Didier, Faehling, Tobias, Ehlers, Anna C., Marchetto, Aruna, Grossetête, 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, Grünewald, Thomas G.P.
• Format: Article
• Language: English
• Subjects: Cell Line; ChiP-seq; enhancer; Ewing sarcoma; EWSR1-ERG; EWSR1-ETS; EWSR1-FLI1; Humans; microsatellites; multi-omics; Multiomics; Oncogenes; pediatric sarcoma; Sarcoma, Ewing - genetics; Transcription Factors; tumor heterogeneity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111761

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. [Display omitted] •A comprehensive multi-omics dataset of 18 Ewing sarcoma (EwS) cell lines is presented•DNA binding of EWSR1-ETS depends on GGAA mSat enrichment and their architecture•EwS exhibits a specific gene signature despite strong inter-patient plasticity•Certain heterogeneously EWSR1-ETS-regulated genes may serve as prognostic biomarkers Orth et al. leverage multi-omics analyses to study heterogeneity in the pediatric cancer Ewing sarcoma. They present a comprehensive dataset of 18 cell lines to illustrate heterogeneous binding of pathognomonic fusion oncoproteins to polymorphic regulatory DNA elements, which may contribute to the variable expression of prognostically relevant genes.