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ChIP-seq data in A673 & TC71 Ewing cell lines (STAG1 and STAG2 knock-out)

ABSTRACT: 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 (A673_SA2m#1, TC71_SA2m#1 and TC71_SA2m#2) derived from A673 and TC71 STAG2 wild type (WT) Ewing sarcoma cell line. Similarly, a STAG1 knock-out isogenic clone (A673_SA1m#1) was generated. Finally, a STAG2 rescue model (A673_SA2r) was generated by correcting the CRISPR mutation in the A673_SA2m#1 model. These STAG1/2 proficient and deficient models were profiled by ChIP-seq for EWS-FLI1, CTCF, cohesin members, and histone marks and allowed to highlight a global conservation of binding for these marks upon STAG2 mutation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133154 | GEO | 2021/04/29

REPOSITORIES: GEO

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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

ChIP-seq data in A673 Ewing cell line (siCT & siSA2)

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The effect of STAG2 loss in Ewing sarcoma [HiChIP]

Project description:Ewing sarcoma is an aggressive malignancy characterized by oncogenic rearrangements of the EWS gene with an ETS-family transcription factor, most commonly FLI. Recent comprehensive next-generation sequencing efforts have revealed few other highly recurrent mutations in this disease apart from loss-of-function mutations in STAG2 which occur in 15-20% of tumors. STAG2 is a member of the cohesin complex, which regulates sister chromatid alignment during mitosis and epigenetic regulation of gene expression. While some studies suggest that loss of STAG2 is associated with the development of aneuploidy, this is not the case in Ewing sarcoma. To investigate whether STAG2 loss affects epigenetic regulation of gene expression in Ewing sarcoma, we developed isogenic Ewing sarcoma cell lines with STAG2 knockout. We found that Ewing sarcoma cells engineered for loss of STAG2 maintain an intact cohesion complex that alternately incorporates STAG1.

2021-05-14 | GSE165977 | GEO

The effect of STAG2 loss in Ewing sarcoma [ATAC-Seq]

Project description:Ewing sarcoma is an aggressive malignancy characterized by oncogenic rearrangements of the EWS gene with an ETS-family transcription factor, most commonly FLI. Recent comprehensive next-generation sequencing efforts have revealed few other highly recurrent mutations in this disease apart from loss-of-function mutations in STAG2 which occur in 15-20% of tumors. STAG2 is a member of the cohesin complex, which regulates sister chromatid alignment during mitosis and epigenetic regulation of gene expression. While some studies suggest that loss of STAG2 is associated with the development of aneuploidy, this is not the case in Ewing sarcoma. To investigate whether STAG2 loss effects epigenetic regulation of gene expression in Ewing sarcoma, we developed isogenic Ewing sarcoma cell lines with STAG2 knockout. We found that Ewing sarcoma cells engineered for loss of STAG2 maintain an intact cohesion complex that alternately incorporates STAG1.

2021-05-14 | GSE116494 | GEO

The effect of STAG2 loss in Ewing sarcoma [RNA-Seq]

Project description:Ewing sarcoma is an aggressive malignancy characterized by oncogenic rearrangements of the EWS gene with an ETS-family transcription factor, most commonly FLI. Recent comprehensive next-generation sequencing efforts have revealed few other highly recurrent mutations in this disease apart from loss-of-function mutations in STAG2 which occur in 15-20% of tumors. STAG2 is a member of the cohesin complex, which regulates sister chromatid alignment during mitosis and epigenetic regulation of gene expression. While some studies suggest that loss of STAG2 is associated with the development of aneuploidy, this is not the case in Ewing sarcoma. To investigate whether STAG2 loss effects epigenetic regulation of gene expression in Ewing sarcoma, we developed isogenic Ewing sarcoma cell lines with STAG2 knockout. We found that Ewing sarcoma cells engineered for loss of STAG2 maintain an intact cohesion complex that alternately incorporates STAG1.

2021-05-14 | GSE116492 | GEO

The effect of STAG2 loss in Ewing sarcoma [ChIP-seq]

Project description:Ewing sarcoma is an aggressive malignancy characterized by oncogenic rearrangements of the EWS gene with an ETS-family transcription factor, most commonly FLI. Recent comprehensive next-generation sequencing efforts have revealed few other highly recurrent mutations in this disease apart from loss-of-function mutations in STAG2 which occur in 15-20% of tumors. STAG2 is a member of the cohesin complex, which regulates sister chromatid alignment during mitosis and epigenetic regulation of gene expression. While some studies suggest that loss of STAG2 is associated with the development of aneuploidy, this is not the case in Ewing sarcoma. To investigate whether STAG2 loss effects epigenetic regulation of gene expression in Ewing sarcoma, we developed isogenic Ewing sarcoma cell lines with STAG2 knockout. We found that Ewing sarcoma cells engineered for loss of STAG2 maintain an intact cohesion complex that alternately incorporates STAG1.

2021-05-14 | GSE165783 | GEO

STAG2 Loss Rewires Oncogenic and Developmental Programs to Promote Metastasis in Ewing Sarcoma

Project description:Adane B, Alexe G, Seong BKA, Lu D, Hwang E, Hnisz D, Lareau CA, Ross L, Lin S, Dela Cruz FS, Richardson M, Weintraub AS, Wang S, Balboni-Iniguez A, Dharia NV, Conway AS, Robichaud AL, Tanenbaum B, Krill-Burger JM, Vazquez F, Schenone M, Berman JN, Kung A, Carr SA, Aryee MJ, Young RA, Crompton BD, Stegmaier K. 2021 Cancer Cell. The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Herein, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2) marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer rich regions, and results in reprogramming of cis-chromatin interactions. Strikingly, in STAG2 knockout cells, the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype.

| MSV000082954 | MassIVE

HiChIP data in A673 & TC71 Ewing cell lines (STAG1 and STAG2 knock-out)

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. Using a CRISPR/Cas9 approach, we generated two STAG2 knock-out isogenic clones (A673_SA2m#1 and TC71_SA2m#2) derived from A673 and TC71 STAG2 wild type (WT) Ewing sarcoma cell line. A STAG2 rescue model (A673_SA2r) was generated by correcting the CRISPR mutation in the A673_SA2m#1 model. These STAG1/2 proficient and deficient models were profiled by CTCF HiChIP experiments. STAG2 isogenic models were also profiled by H3K27ac HiChIP experiments. Analyses of HiChIP data allowed to show that STAG2 promotes CTCF-anchored loop extrusion and cis-promoter and -enhancer interactions.

2021-04-29 | GSE133227 | GEO

CTCF HiChIP data in A673 Ewing sarcoma cell lines (siCT & siSA2)

2021-04-29 | GSE156650 | 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.

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