Similar Datasets
Project description:Chimeric proteins resulting from chromosomal translocations play a major role as driver oncogenes in cancer. Among them, fusions between EWSR1 and a set of transcription factors (TFs) generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs. However, specific EWSR1 fusion proteins have been implicated in distinct tumor types, suggesting an enhancement of their functional properties by permissive precursor cells. Here we combined functional epigenomics with nuclear topology mapping to define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma (CCS), one of the most aggressive forms of human cancer, driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 display a distinctive binding pattern that depends on the EWSR1 prion-like domain, and is divergent from wild type ATF1, despite the physical interaction between wt and EWSR1-ATF1 proteins. This cooperativity promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures shared with primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of a new set of connections controlling neural crest-related developmental programs. Accordingly, interrogation of more than 160,000 single cell expression profiles from the human skin atlas reveals loss of EWSR1-ATF1 expression to induce a more differentiated tumor cell state. Taken together, our study uncovers the cooperativity network of EWSR1-ATF1, delineates the molecular underpinnings of its epigenetic function in CCS, and points to precursor cells along the Schwann cell-melanocytic axis as a candidate origin for these tumors.
2022-03-04 | GSE180196 | GEO
Project description:Chimeric proteins resulting from chromosomal translocations play a major role as driver oncogenes in cancer. Among them, fusions between EWSR1 and a set of transcription factors (TFs) generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs. However, specific EWSR1 fusion proteins have been implicated in distinct tumor types, suggesting an enhancement of their functional properties by permissive precursor cells. Here we combined functional epigenomics with nuclear topology mapping to define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma (CCS), one of the most aggressive forms of human cancer, driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 display a distinctive binding pattern that depends on the EWSR1 prion-like domain, and is divergent from wild type ATF1, despite the physical interaction between wt and EWSR1-ATF1 proteins. This cooperativity promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures shared with primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of a new set of connections controlling neural crest-related developmental programs. Accordingly, interrogation of more than 160,000 single cell expression profiles from the human skin atlas reveals loss of EWSR1-ATF1 expression to induce a more differentiated tumor cell state. Taken together, our study uncovers the cooperativity network of EWSR1-ATF1, delineates the molecular underpinnings of its epigenetic function in CCS, and points to precursor cells along the Schwann cell-melanocytic axis as a candidate origin for these tumors.
2022-03-04 | GSE180187 | GEO
Project description:Chimeric proteins resulting from chromosomal translocations play a major role as driver oncogenes in cancer. Among them, fusions between EWSR1 and a set of transcription factors (TFs) generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs. However, specific EWSR1 fusion proteins have been implicated in distinct tumor types, suggesting an enhancement of their functional properties by permissive precursor cells. Here we combined functional epigenomics with nuclear topology mapping to define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma (CCS), one of the most aggressive forms of human cancer, driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 display a distinctive binding pattern that depends on the EWSR1 prion-like domain, and is divergent from wild type ATF1, despite the physical interaction between wt and EWSR1-ATF1 proteins. This cooperativity promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures shared with primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of a new set of connections controlling neural crest-related developmental programs. Accordingly, interrogation of more than 160,000 single cell expression profiles from the human skin atlas reveals loss of EWSR1-ATF1 expression to induce a more differentiated tumor cell state. Taken together, our study uncovers the cooperativity network of EWSR1-ATF1, delineates the molecular underpinnings of its epigenetic function in CCS, and points to precursor cells along the Schwann cell-melanocytic axis as a candidate origin for these tumors.
2022-03-04 | GSE180183 | GEO
Project description:Chimeric proteins resulting from chromosomal translocations play a major role as driver oncogenes in cancer. Among them, fusions between EWSR1 and a set of transcription factors (TFs) generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs. However, specific EWSR1 fusion proteins have been implicated in distinct tumor types, suggesting an enhancement of their functional properties by permissive precursor cells. Here we combined functional epigenomics with nuclear topology mapping to define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma (CCS), one of the most aggressive forms of human cancer, driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 display a distinctive binding pattern that depends on the EWSR1 prion-like domain, and is divergent from wild type ATF1, despite the physical interaction between wt and EWSR1-ATF1 proteins. This cooperativity promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures shared with primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of a new set of connections controlling neural crest-related developmental programs. Accordingly, interrogation of more than 160’000 single cell expression profiles from the human skin atlas reveals loss of EWSR1-ATF1 expression to induce a more differentiated tumor cell state. Taken together, our study uncovers the cooperativity network of EWSR1-ATF1, delineates the molecular underpinnings of its epigenetic function in CCS, and points to precursor cells along the Schwann cell-melanocytic axis as a candidate origin for these tumors.
2022-03-04 | GSE180194 | GEO
Project description:EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma
| PRJNA747002 | ENA
Project description:EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma [ChIP-Seq]
| PRJNA746997 | ENA
Project description:EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma [HiChIP-seq]
| PRJNA747005 | ENA
Project description:EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma [RNA-seq]
| PRJNA747008 | ENA
Project description:EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma [ATAC-Seq]
| PRJNA746990 | ENA
Project description:Clear cell odontogenic carcinoma (CCOC) is a rare, low-grade malignant epithelial neoplasm, occurring in the jawbones, mainly affecting the mandible of elderly patients. In addition to hyalinizing clear cell carcinoma of the salivary gland, it is one of the epithelial neoplasms known to harbor an EWSR1-ATF1 fusion. Therefore, a link between these tumors seems plausible. We describe six cases of CCOC showing EWSR1 rearrangements, with two cases being positive for the ATF1 partner gene using FISH analysis. In one case, an EWSR1-CREB1 fusion was identified using RT-PCR, which we report for the first time in this tumor type. The other three cases investigated by FISH were negative for ATF1, CREB1 and CREB3L2. In conclusion, our data show that EWSR1-CREB1 is an alternative fusion gene to EWSR1-ATF1 in CCOC.
| S-EPMC6514205 | biostudies-literature