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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{
  "DOI": "10.1016/j.ccell.2021.04.001", 
  "container_title": "Cancer Cell", 
  "language": "eng", 
  "title": "STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma", 
  "issued": {
    "date-parts": [
      [
        2021, 
        4, 
        29
      ]
    ]
  }, 
  "abstract": "<p>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.</p>", 
  "author": [
    {
      "family": "Surdez, D."
    }, 
    {
      "family": "Zaidi, S."
    }, 
    {
      "family": "Grossetete, S."
    }, 
    {
      "family": "Laud-Duval"
    }, 
    {
      "family": "Sole Ferre, A."
    }, 
    {
      "family": "Mous, L."
    }, 
    {
      "family": "Vourc'h, T."
    }, 
    {
      "family": "Tirode, F."
    }, 
    {
      "family": "Pierron, G."
    }, 
    {
      "family": "Raynal, V."
    }, 
    {
      "family": "Baulande, S."
    }, 
    {
      "family": "Brunet, E."
    }, 
    {
      "family": "Hill, V."
    }, 
    {
      "family": "Delattre, O."
    }
  ], 
  "type": "article-journal", 
  "id": "4748666"
}
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