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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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{
  "inLanguage": {
    "alternateName": "eng", 
    "@type": "Language", 
    "name": "English"
  }, 
  "description": "<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>", 
  "license": "https://creativecommons.org/licenses/by/4.0/legalcode", 
  "creator": [
    {
      "affiliation": "INSERM U830, \u00c9quipe Labellis\u00e9e LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Surdez, D."
    }, 
    {
      "affiliation": "INSERM U830, \u00c9quipe Labellis\u00e9e LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Zaidi, S."
    }, 
    {
      "affiliation": "INSERM U830, \u00c9quipe Labellis\u00e9e LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Grossetete, S."
    }, 
    {
      "affiliation": "INSERM U830, \u00c9quipe Labellis\u00e9e LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Laud-Duval"
    }, 
    {
      "affiliation": "INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellis\u00e9e Ligue contre le Cancer and Universit\u00e9 de Paris, Imagine Institute, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Sole Ferre, A."
    }, 
    {
      "affiliation": "INSERM U830, \u00c9quipe Labellis\u00e9e LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Mous, L."
    }, 
    {
      "affiliation": "UMR 168, Biology Inspired Physics at Mesoscales, PSL Research University, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Vourc'h, T."
    }, 
    {
      "affiliation": "Univ Lyon, Universit\u00e9 Claude Bernard Lyon 1, CNRS 5286, INSERM U1052, Cancer Research Center of Lyon, 69008 Lyon, France", 
      "@type": "Person", 
      "name": "Tirode, F."
    }, 
    {
      "affiliation": "Unit\u00e9 de G\u00e9n\u00e9tique Somatique, Service d'oncog\u00e9n\u00e9tique, Institut Curie, Centre Hospitalier, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Pierron, G."
    }, 
    {
      "affiliation": "INSERM U830, \u00c9quipe Labellis\u00e9e LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Raynal, V."
    }, 
    {
      "affiliation": "Institut Curie Genomics of Excellence (ICGex) Platform, PSL Universit\u00e9, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Baulande, S."
    }, 
    {
      "affiliation": "INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellis\u00e9e Ligue contre le Cancer and Universit\u00e9 de Paris, Imagine Institute, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Brunet, E."
    }, 
    {
      "affiliation": "INSERM U830, \u00c9quipe Labellis\u00e9e LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Hill, V."
    }, 
    {
      "affiliation": "INSERM U830, \u00c9quipe Labellis\u00e9e LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France", 
      "@type": "Person", 
      "name": "Delattre, O."
    }
  ], 
  "headline": "STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma", 
  "image": "https://zenodo.org/static/img/logos/zenodo-gradient-round.svg", 
  "datePublished": "2021-04-29", 
  "url": "https://zenodo.org/record/4748666", 
  "@context": "https://schema.org/", 
  "identifier": "https://doi.org/10.1016/j.ccell.2021.04.001", 
  "@id": "https://doi.org/10.1016/j.ccell.2021.04.001", 
  "@type": "ScholarlyArticle", 
  "name": "STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma"
}
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