{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE314nnn/GSE314154/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314154"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"STAG2 loss amplifies EWS-FLI1-driven microsatellite enhancer activity promoting Ewing's sarcoma aggressiveness [RNA-Seq]","description":"Ewing sarcomas are driven by chromosomal translocations that fuse a FET RNA‑binding protein to an ETS transcription factor, most commonly generating the EWS-FLI1 fusion oncoprotein. EWS-FLI1 engages GGAA microsatellite repeats to create de novo enhancers and activate oncogenic transcriptional programs—a neomorphic gain-of-function essential for Ewing sarcoma pathogenesis. In addition to the truncal fusion, recurrent loss‑of‑function alterations in the cohesin subunit STAG2 occur in approximately 10–15% of Ewing sarcomas and are associated with adverse clinical outcomes. Yet, how STAG2-cohesin deficiency remodels EWS-FLI1 chromatin occupancy and gene regulatory network remains incompletely understood. Here, using genetic STAG2 loss‑of‑function models combined with functional multi-omic profiling, we show that STAG2-cohesin loss in Ewing sarcoma cells reprograms the EWS-FLI1 cistrome by shifting its binding preference at GGAA microsatellite repeats. Despite increased EWS–FLI1 protein abundance, disruption of STAG2 eliminates more than 40% of EWS-FLI1 binding sites. The lost sites are enriched for elements harboring 1–4 GGAA repeat motifs, with a simultaneous gain in EWS-FLI1 binding at multimeric enhancers containing ≥5 GGAA repeat sequences. Notably, reprogrammed EWS-FLI1 sites show concomitant changes in chromatin accessibility and H3K27ac abundance, which preferentially amplify EWS-FLI1 activity at multimeric enhancers and drive marked up‑regulation of canonical microsatellite‑regulated target genes in STAG2‑null cells. By integrating Hi‑C–derived chromatin interaction maps with altered EWS-FLI1 occupancy, we derive distinct monomeric (1xGGAA) and multimeric (≥10xGGAA) EWS-FLI1 transcriptional signatures and show that STAG2 inactivation selectively augments the multimeric signature while attenuating monomeric activity. We further define a prognostic signature of GGAA-repeat enhancers that is significantly upregulated in patient tumors with aggressive clinical features and deleterious STAG2 alterations. Together, these findings reveal that loss of STAG2–cohesin does not simply attenuate EWS-FLI1 function but reprograms its cistrome toward microsatellite multimeric GGAA neo‑enhancers, thereby amplifying a high‑risk EWS–FLI1 transcriptional state in Ewing sarcoma.","dates":{"publication":"2026/04/15"},"accession":"GSE314154","cross_references":{"GSM":["GSM9382796","GSM9382795","GSM9382794","GSM9382793","GSM9382792","GSM9382791","GSM9382790","GSM9382805","GSM9382804","GSM9382803","GSM9382802","GSM9382801","GSM9382789","GSM9382800","GSM9382799","GSM9382788","GSM9382787","GSM9382798","GSM9382786","GSM9382797"],"GPL":["16791"],"GSE":["314154"],"taxon":["Homo sapiens"],"PMID":["[41950086]"]}}