Journal article Open Access

STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma

Surdez, D.; Zaidi, S.; Grossetete, S.; Laud-Duval; Sole Ferre, A.; Mous, L.; Vourc'h, T.; Tirode, F.; Pierron, G.; Raynal, V.; Baulande, S.; Brunet, E.; Hill, V.; Delattre, O.


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  <dc:creator>Surdez, D.</dc:creator>
  <dc:creator>Zaidi, S.</dc:creator>
  <dc:creator>Grossetete, S.</dc:creator>
  <dc:creator>Laud-Duval</dc:creator>
  <dc:creator>Sole Ferre, A.</dc:creator>
  <dc:creator>Mous, L.</dc:creator>
  <dc:creator>Vourc'h, T.</dc:creator>
  <dc:creator>Tirode, F.</dc:creator>
  <dc:creator>Pierron, G.</dc:creator>
  <dc:creator>Raynal, V.</dc:creator>
  <dc:creator>Baulande, S.</dc:creator>
  <dc:creator>Brunet, E.</dc:creator>
  <dc:creator>Hill, V.</dc:creator>
  <dc:creator>Delattre, O.</dc:creator>
  <dc:date>2021-04-29</dc:date>
  <dc:description>STAG2, a cohesin family gene, is among the most recurrently mutated genes in cancer. STAG2 loss of function (LOF) is associated with aggressive behavior in Ewing sarcoma, a childhood cancer driven by aberrant transcription induced by the EWSR1-FLI1 fusion oncogene. Here, using isogenic Ewing cells, we show that, while STAG2 LOF profoundly changes the transcriptome, it does not significantly impact EWSR1-FLI1, CTCF/cohesin, or acetylated H3K27 DNA binding patterns. In contrast, it strongly alters the anchored dynamic loop extrusion process at boundary CTCF sites and dramatically decreases promoter-enhancer interactions, particularly affecting the expression of genes regulated by EWSR1-FLI1 at GGAA microsatellite neo-enhancers. Down-modulation of cis-mediated EWSR1-FLI1 activity, observed in STAG2-LOF conditions, is associated with enhanced migration and invasion properties of Ewing cells previously observed in EWSR1-FLI1low cells. Our study illuminates a process whereby STAG2-LOF fine-tunes the activity of an oncogenic transcription factor through altered CTCF-anchored loop extrusion and cis-mediated enhancer mechanisms.</dc:description>
  <dc:identifier>https://zenodo.org/record/4748666</dc:identifier>
  <dc:identifier>10.1016/j.ccell.2021.04.001</dc:identifier>
  <dc:identifier>oai:zenodo.org:4748666</dc:identifier>
  <dc:language>eng</dc:language>
  <dc:relation>info:eu-repo/grantAgreement/EC/H2020/826121/</dc:relation>
  <dc:relation>url:https://zenodo.org/communities/ipc</dc:relation>
  <dc:rights>info:eu-repo/semantics/openAccess</dc:rights>
  <dc:rights>https://creativecommons.org/licenses/by/4.0/legalcode</dc:rights>
  <dc:source>Cancer Cell</dc:source>
  <dc:title>STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma</dc:title>
  <dc:type>info:eu-repo/semantics/article</dc:type>
  <dc:type>publication-article</dc:type>
</oai_dc:dc>
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