iPC
Published April 29, 2021 | Version v1
Journal article Open

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

Creators

  • 1. INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Centre, Institut Curie Research Centre, 75005 Paris, France
  • 2. INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer and Université de Paris, Imagine Institute, 75005 Paris, France
  • 3. UMR 168, Biology Inspired Physics at Mesoscales, PSL Research University, Institut Curie Research Centre, 75005 Paris, France
  • 4. Univ Lyon, Université Claude Bernard Lyon 1, CNRS 5286, INSERM U1052, Cancer Research Center of Lyon, 69008 Lyon, France
  • 5. Unité de Génétique Somatique, Service d'oncogénétique, Institut Curie, Centre Hospitalier, 75005 Paris, France
  • 6. Institut Curie Genomics of Excellence (ICGex) Platform, PSL Université, Institut Curie Research Centre, 75005 Paris, France

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.

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Additional details

Funding

European Commission
iPC – individualizedPaediatricCure: Cloud-based virtual-patient models for precision paediatric oncology 826121