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The oncogenic EWS-FLI1 protein binds in vivo GGAA microsatellite sequences with potential transcriptional activation

Noëlle Guillon1, Franck Tirode, Valentina Boeva

  • 1Institut Curie, Paris, France.

Plos One
|March 24, 2009
PubMed

Insights

Ewing sarcoma research reveals the EWS-FLI1 fusion protein binds microsatellite DNA. This binding is crucial for activating genes involved in oncogenesis, highlighting a new regulatory mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The EWS-FLI1 fusion protein is a primary driver of Ewing tumors.
  • Previous studies identified EWS-FLI1 targets but lacked genome-wide analysis of binding sites.

Purpose of the Study:

  • To conduct a comprehensive, genome-wide analysis of in vivo EWS-FLI1 binding sites.
  • To identify novel DNA sequences targeted by EWS-FLI1.

Main Methods:

  • Chromatin immunoprecipitation sequencing (ChIP-Seq) was used to identify EWS-FLI1-bound DNA in Ewing cell lines.
  • Reporter gene assays were performed to assess transcriptional activation dependent on microsatellite repeats.

Main Results:

  • EWS-FLI1 preferentially binds to consensus ETS motifs and microsatellite sequences.
  • Binding sites are predominantly located outside of gene promoter regions.
  • Microsatellites with >9 GGAA repeats are significantly enriched and drive EWS-FLI1-mediated gene activation.

Conclusions:

  • EWS-FLI1 binding to microsatellites contributes significantly to gene activation and oncogenesis in Ewing tumors.
  • Microsatellite elements play a role in long-distance transcriptional regulation.

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