Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation
Martin F. Orth, Didier Surdez, Tobias Faehling, Anna C. Ehlers, Aruna Marchetto, Sandrine Grossetête, Richard Volckmann, Danny A. Zwijnenburg, Julia S. Gerke, Sakina Zaïdi, Javier Alonso, Ana Sastre, Sylvain Baulande, Martin Sill, Florencia Cidre‐Aranaz, Shunya Ohmura, Thomas Kirchner, Stefanie M. Hauck, Eva Reischl, Melissa Gymrek, Stefan M. Pfister, Konstantin Strauch, Jan Köster, Olivier Delattre, Thomas G. P. Grünewald
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 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.