EWS-FLI1 target genes recovered from Ewing's sarcoma chromatin

Oncogene. 2005 Apr 7;24(15):2512-24. doi: 10.1038/sj.onc.1208455.


In all, 85% of Ewing's sarcoma family tumors (ESFT), a neoplasm of unknown histogenesis, express EWS-FLI1 transcription factor gene fusions. To characterize direct target genes avoiding artificial model systems, we cloned genomic DNA from ESFT chromatin precipitating with EWS-FLI1. We now present a comprehensive list of 99 putative transcription factor targets identified, for the first time, by a hypothesis-free approach based on physical interaction. Gene-derived chromatin fragments co-precipitating with EWS-FLI1 were nonrandomly distributed over the human genome and localized predominantly to the upstream region and the first two introns of the genes. At least 20% of putative direct EWS-FLI1 targets were neural genes. One-third of genes recovered showed a significant ESFT-specific expression pattern and were found to be altered upon RNAi-mediated knockdown of EWS-FLI1. Among them, MK-STYX, encoding a MAP kinase phosphatase-like protein, was consistently expressed in ESFT. EWS-FLI1 was found to drive MK-STYX expression by binding to a single ETS binding motif within the first gene intron. MK-STYX serves as precedence for successful recovery of direct EWS-FLI1 targets from the authentic ESFT cellular context, the most relevant system to study oncogenic mechanisms for the discovery of new therapeutic targets in this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Neoplasms / genetics*
  • Chromatin / genetics*
  • DNA, Neoplasm / analysis
  • DNA-Binding Proteins / genetics*
  • Gene Expression Profiling
  • Humans
  • Immunoprecipitation
  • Oligonucleotide Array Sequence Analysis
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / pharmacology*
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS / genetics*
  • Sarcoma, Ewing / genetics*
  • Trans-Activators / genetics*


  • Chromatin
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • FLI1 protein, human
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
  • Trans-Activators
  • Protein Tyrosine Phosphatases