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Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [ChIP-seq]

ABSTRACT: Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [ChIP-seq]

PROVIDER: PRJNA798042 | ENA |

REPOSITORIES: ENA

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Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [HiChIP]

Project description:Tumor cell identity is the product of complex interactions between oncogenic drivers and mechanisms regulating normal differentiation pathways. Cell fate transitions observed in embryonic development involve structural changes in genomic organization that provide proper lineage specification, however, whether similar events also occur within tumor cells and contribute to cancer evolution remains largely unexplored. Here we modeled this process in the pediatric bone cancer Ewing sarcoma and investigated high resolution looping and large-scale 3D nuclear conformation changes associated with EWS-FLI1, the oncogenic fusion protein that drives this tumor. We find that chromatin interactions in Ewing sarcoma cells are dominated by highly connected looping hubs centered on EWS-FLI1 binding sites, which directly control the activity of linked enhancers and promoters to establish oncogenic expression programs. Depletion of EWS-FLI1 leads to the loss of looping networks associated with the fusion protein and, strikingly, also results in widespread nuclear reorganization through the establishment of new patterns of looping and large-scale inter-compartment connectivity that resemble the chromatin configuration of mesenchymal stem cells, a candidate cell of origin of this tumor. Our data thus demonstrate that major architectural features of nuclear organization in cancer cells can be linked to a single oncogenic event and readily reversed to re-establish latent differentiation programs.

2023-03-16 | GSE193828 | GEO

Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [HiChIP]

Project description:Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [HiChIP]

| PRJNA798049 | ENA

Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [HiC]

2023-03-16 | GSE193824 | GEO

Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [microC]

Project description:Tumor cell identity is the product of complex interactions between oncogenic drivers and mechanisms regulating normal differentiation pathways. Cell fate transitions observed in embryonic development involve structural changes in genomic organization that provide proper lineage specification, however, whether similar events also occur within tumor cells and contribute to cancer evolution remains largely unexplored. Here we modeled this process in the pediatric bone cancer Ewing sarcoma and investigated high resolution looping and large-scale 3D nuclear conformation changes associated with EWS-FLI1, the oncogenic fusion protein that drives this tumor. We find that chromatin interactions in Ewing sarcoma cells are dominated by highly connected looping hubs centered on EWS-FLI1 binding sites, wmicroCh directly control the activity of linked enhancers and promoters to establish oncogenic expression programs. Depletion of EWS-FLI1 leads to the loss of looping networks associated with the fusion protein and, strikingly, also results in widespread nuclear reorganization through the establishment of new patterns of looping and large-scale inter-compartment connectivity that resemble the chromatin configuration of mesenchymal stem cells, a candidate cell of origin of this tumor. Our data thus demonstrate that major architectural features of nuclear organization in cancer cells can be linked to a single oncogenic event and readily reversed to re-establish latent differentiation programs.

2023-03-16 | GSE211776 | GEO

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

Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [ChIP-seq]

2023-03-16 | GSE193823 | GEO

Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma.

Project description:Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma.

| PRJNA798045 | ENA

Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [HiC]

Project description:Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [HiC]

| PRJNA798040 | ENA

Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [microC]

Project description:Genome wide enhancer loops (HiChIP) and 3-D high order chromatin features associated with EWS-FLI1 in Ewing Sarcoma. [microC]

| PRJNA872101 | ENA

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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