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,...

Full description

Saved in:

Bibliographic Details
Published in:	Cancer cell Vol. 39; no. 6; pp. 810 - 826.e9
Main Authors:	Surdez, Didier, Zaidi, Sakina, Grossetête, Sandrine, Laud-Duval, Karine, Ferre, Anna Sole, Mous, Lieke, Vourc'h, Thomas, Tirode, Franck, Pierron, Gaelle, Raynal, Virginie, Baulande, Sylvain, Brunet, Erika, Hill, Véronique, Delattre, Olivier
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 14-06-2021 Elsevier
Subjects:	anchorage Bone Neoplasms - genetics Bone Neoplasms - mortality Bone Neoplasms - pathology Cancer CCCTC-Binding Factor - chemistry CCCTC-Binding Factor - genetics CCCTC-Binding Factor - metabolism Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Line, Tumor Cell Movement - genetics chromatin extrusion Chromatin Immunoprecipitation Chromosomal Proteins, Non-Histone - metabolism cohesin Cohesins CTCF enhancer Enhancer Elements, Genetic Ewing sarcoma Gene Expression Regulation, Neoplastic Histones - metabolism Humans Life Sciences loop Loss of Function Mutation Lysine - metabolism migration Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Promoter Regions, Genetic Sarcoma, Ewing - genetics Sarcoma, Ewing - mortality Sarcoma, Ewing - pathology STAG1 STAG2 STAG1 chromatin extrusion Ewing sarcoma enhancer STAG2 cohesin loop migration CTCF anchorage
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. [Display omitted] •STAG2 promotes anchored chromatin extrusion at CTCF loop boundaries•STAG2 LOF reduces cis-mediated EWSR1-FLI1 transcriptional activity•STAG2 LOF increases mesenchymal features and migratory potential of Ewing cells•STAG2 LOF signature is associated with adverse prognosis in Ewing sarcoma Surdez et al. find that STAG2, an integral member of the cohesin complex, promotes anchored chromatin loop extrusion and favors promoter-enhancer interactions. In Ewing sarcoma, STAG2 mutations do not affect EWSR1-FLI1 expression level but reduce its cis-mediated enhancer activity, increasing mesenchymal features of Ewing sarcoma cells.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Undefined-1 ObjectType-Feature-3 content type line 23
ISSN:	1535-6108 1878-3686
DOI:	10.1016/j.ccell.2021.04.001