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Seminar

Friday, May 21st, 2021
11h30
Centre de recherche - Paris - Webinar

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

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 through binding GGAA microsatellite elements. 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.

Speaker(s)

Dr. Olivier Delattre
INSERM Research Director. Director INSERM/ Institut Curie U 830, Cancer, Heterogeneity, Instability and Plasticity, 2020- Director of the Center Oncology SIREDO
Domain 3 - U830 - Cancer, Heterogeneity, Instability and Plasticity (CHIP)

Institut Curie

Hosted by

Dr. Chunlong Chen
Domain 2 - UMR 3244 - Dynamics of genetic Information

Institut Curie

Invited by

Dr. Chunlong Chen
Group leader Replication program and genome instability
Domain 2 - UMR 3244 - Dynamics of genetic Information

Institut Curie