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STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

ABSTRACT: STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

PROVIDER: PRJNA1110264 | ENA |

REPOSITORIES: ENA

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STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

Project description:Cohesin complexes carrying STAG1 or STAG2 organize the genome into chromatin loops. STAG2 loss-of-function mutations promote metastasis in Ewing sarcoma, a pediatric cancer that is driven by the fusion transcription factor EWS-FLI1. We have integrated transcriptomic data from patients and cellular models to identify a STAG2-dependent gene signature associated with worse prognosis. Subsequent genomic profiling and high-resolution chromatin interaction data from Capture Hi-C indicate that cohesin-STAG2 facilitates the communication between EWS-FLI1-bound long GGAA repeats acting as neoenhancers and their target promoters. Changes in CTCF-dependent chromatin contacts, unrelated to EWS-FLI1 binding, also contribute to the aggressive phenotype. STAG1 is unable to compensate for STAG2 loss and chromatin-bound cohesin is severely decreased, while levels of the processivity factor NIPBL remain unchanged, resulting in altered DNA looping dynamics. These results illuminate how STAG2 loss rewires the Ewing sarcoma chromatin interactome to promote metastasis and provide a list of potential biomarkers and therapeutic targets.

2024-09-18 | GSE267222 | GEO

STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

2024-09-18 | GSE267221 | GEO

STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

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USP1 expression driven by EWS-FLI1 transcription factor stabilizes Survivin and promotes Ewing sarcoma cell survival

Project description:Ewing sarcoma (EWS) is a malignant pediatric bone cancer. Most Ewing sarcomas are driven by EWS-FLI1 oncogenic transcription factor that plays roles in transcriptional regulation, DNA damage response, cell cycle checkpoint control, and alternative splicing. USP1, a deubiquitylase which regulates DNA damage and replication stress responses, is overexpressed at both the mRNA and protein levels in EWS cell lines compared to human mesenchymal stem cells, the EWS cell of origin. The functional significance of high USP1 expression in Ewing sarcoma is not known. Here, we identify USP1 as a transcriptional target of EWS-FLI1 and a key regulator of EWS cell survival. We show that EWS-FLI1 knockdown decreases USP1 mRNA and protein levels. ChIP and ChIP-seq analyses show EWS-FLI1 occupancy on the USP1 promoter. Importantly, USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. We observe destabilization of Survivin (also known as BIRC5 or IAP4) and activation of caspases-3 and -7 following USP1 knockdown or inhibition in the absence of external DNA damage stimuli. Notably, EWS cells display hypersensitivity to combinatorial treatment of doxorubicin or etoposide, EWS standard of care drugs, and USP1 inhibitor compared to single agents alone. Together, our study demonstrates that USP1 is regulated by EWS-FLI1, the USP1-Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes EWS cells to standard of care chemotherapy.

2024-01-26 | PXD041033 | Pride

STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

Project description:STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

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STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

Project description:STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

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STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

Project description:STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1

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RNA-seq data in A673 & TC71 Ewing cell lines (STAG1 and STAG2 knock-out and proficient models and silenced for EWS-FLI1)

Project description:STAG2, a member of cohesin, is one of the most recurrently mutated genes in human cancer. Here, we investigated STAG2 function in the context of Ewing sarcoma, an aggressive bone tumor driven by EWS-FLI1 oncogene chimeric transcription factor. Using a CRISPR/Cas9 approach, we generated three STAG2 knock-out isogenic clones (A673SA2m#1, TC71SA2m#1 and TC71SA2m#2) derived from A673 and TC71 STAG2 wild type (WT) Ewing sarcoma cell line. A STAG2 rescue model (A673_SA2r) generated by correcting the CRISPR mutation in the A673SA2m#1 model was also profiled using RNA-seq. Comparison of RNA-seq data allowed highlighting a broad transcriptional modulation upon STAG2 knock-out. In addition, we compared these analyses with STAG1 knock-out A673 derived model (A673SA1m#1) and with A673 (WT) and TC71 (WT) parental cells lines transfected with siCT or siEWS-FLI1.

2021-04-29 | GSE132966 | GEO

RNA-seq data of knowk-down of STAG2 or EWSR1-FLI1 in Ewing sarcoma cell lines (siCT, siEF1 & siSA2)

Project description:STAG2, a member of cohesin, is one of the most recurrently mutated genes in human cancer. Here, we investigated STAG2 function in the context of Ewing sarcoma, an aggressive bone tumor driven by EWS-FLI1 oncogene chimeric transcription factor. Five different Ewing sarcoma cell lines were transfected with siCT or 2 different siRNAs targeting STAG2 (siSA2#6 or siSA2#8). RNA in A673 & TC71 (siSTAG2) was extracted 24, 48 and 72 hours post-transfection. RNA in EW1, CHLA-10 and CHLA-258 (siSTAG2 and siEWSR1-FLI1) was extracted 72 hours post-transfection. RNA-seq based anlayses of these experiments highligted that STAG2 knock-down alters EWSR1-FLI1 activation signature.

2021-04-29 | GSE156653 | GEO

Identification of genes regulated by knockdown of EWS-FLI1 in Ewing sarcoma cells.

Project description:EWS-FLI1 is the driver oncogene in >85% of Ewing sarcoma tumors. We used siRNA to knock down EWS-FLI1 for 48h hours in two Ewing sarcoma cell lines (EW8, TC71) to identify downstream genes and pathways affected by loss of EWS-FLI1 activity. RNAseq analysis was performed after 48 hours of treatment with a nontargeting siControl or siEWS-FLI1.

2024-09-30 | GSE263504 | GEO

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