STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma
作者： Olivier Delattre , Olivier Delattre , Franck Tirode , Karine Laud-Duval , Gaelle Pierron
DOI: 10.1016/J.CCELL.2021.04.001
关键词:
摘要: STAG2, a cohesin family gene, is among the most recurrently mutated genes in cancer. STAG2 loss of function (LOF) associated with aggressive behavior Ewing sarcoma, childhood cancer driven by aberrant transcription induced EWSR1-FLI1 fusion oncogene. Here, using isogenic cells, we show that, while LOF profoundly changes transcriptome, it does not significantly impact EWSR1-FLI1, CTCF/cohesin, or acetylated H3K27 DNA binding patterns. In contrast, strongly alters anchored dynamic loop extrusion process at boundary CTCF sites and dramatically decreases promoter-enhancer interactions, particularly affecting expression regulated GGAA microsatellite neo-enhancers. Down-modulation cis-mediated activity, observed STAG2-LOF conditions, enhanced migration invasion properties cells previously EWSR1-FLI1low cells. Our study illuminates whereby fine-tunes activity an oncogenic factor through altered CTCF-anchored enhancer mechanisms.
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