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.

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.

Files (5.2 MB)
Name Size
1-s2.0-S1535610821002087-main.pdf
md5:ef107b73bd2b0fb14c942565ba36dc92
5.2 MB Download
34
99
views
downloads
Views 34
Downloads 99
Data volume 515.2 MB
Unique views 31
Unique downloads 95

Share

Cite as