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EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE248753 | GEO | 2023/12/01

REPOSITORIES: GEO

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EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and a Mouse Genetic Model.

Project description:Clear cell sarcoma (CCS) is a rare, aggressive malignancy that most frequently arises in the soft tissues of the extremities. It is defined and driven by expression of one member of a family of related translocation-generated fusion oncogenes, the most common of which is EWSR1::ATF1. The EWSR1::ATF1 fusion oncoprotein reprograms transcription. However, the binding distribution of EWSR1::ATF1 across the genome and its target genes remain unclear. Here, we interrogated the genomic distribution of V5-tagged EWSR1::ATF1 in tumors it had induced upon expression in mice that also recapitulated the transcriptome of human CCS. ChIP-sequencing of V5-EWSR1::ATF1 identified previously unreported motifs including the AP1 motif and motif comprised of TGA repeats that resemble GGAA-repeating microsatellites bound by EWSR1::FLI1 in Ewing sarcoma. ChIP-sequencing of H3K27ac identified super enhancers in the mouse model and human contexts of CCS, which showed a shared super enhancer structure that associates with activated genes.

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EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [RNA-Seq 1]

Project description:A particular fusion protein that drives the rare, but deadly pediatric cancer, clear cell sarcoma. The fusion protein was expressed in mice, leading to the formation of similar tumors as those it causes in humans. This permitted the study of fusion protein function in these tumors.

2023-12-01 | GSE248751 | GEO

EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [RNA-Seq 2]

Project description:a particular fusion protein that drives the rare, but deadly pediatric cancer, clear cell sarcoma. The fusion protein was expressed in mice, leading to the formation of similar tumors as those it causes in humans. This permitted the study of fusion protein function in these tumors.

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EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [ChIP-Seq 1]

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EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [ChIP-Seq 2]

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EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model

Project description:EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model

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EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma.

Project description:Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

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EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [ChIP-Seq 2]

Project description:EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [ChIP-Seq 2]

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EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [RNA-Seq 2]

Project description:EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [RNA-Seq 2]

| PRJNA1045702 | ENA

EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [ChIP-Seq 1]

Project description:EWSR1::ATF1 Orchestrates the Clear Cell Sarcoma Transcriptome in Human Tumors and A Mouse Genetic Model [ChIP-Seq 1]

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