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

Cell Rep. 2022 Dec 6;41(10):111761. 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 ( 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.

Keywords: CP: Cancer; ChiP-seq; EWSR1-ERG; EWSR1-ETS; EWSR1-FLI1; Ewing sarcoma; enhancer; microsatellites; multi-omics; pediatric sarcoma; tumor heterogeneity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Humans
  • Multiomics
  • Oncogenes
  • Sarcoma, Ewing* / genetics
  • Transcription Factors


  • Transcription Factors