EWS-FLI1 Utilizes Divergent Chromatin Remodeling Mechanisms to Directly Activate or Repress Enhancer Elements in Ewing Sarcoma

• DOI: 10.1016/j.ccell.2014.10.004
• Publication Date: 2014-10-30T16:05:49Z
• Authors: Nicolò Riggi; Birgit Knoechel; Shawn M. Gillespie; Esther Rheinbay; Gaylor Boulay; Mario L. Suvà; Nikki E. Rossetti; Wannaporn E. Boon...; Ozgur Oksuz; Edward B. Cook; Aurélie Formey; Anoop Patel; Melissa Gymrek; Vishal Thapar; Vikram Deshpande; David T. Ting; Francis J. Hornicek; G. Petur Nielsen; Ivan Stamenkovic; Martin J. Aryee; Bradley E. Bernstein; Miguel N. Rivera
• Keywords: FLI1

The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation.