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EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046276/ https://www.ncbi.nlm.nih.gov/pubmed/35477713 http://dx.doi.org/10.1038/s41467-022-29910-4 |
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author | Möller, Emely Praz, Viviane Rajendran, Sanalkumar Dong, Rui Cauderay, Alexandra Xing, Yu-Hang Lee, Lukuo Fusco, Carlo Broye, Liliane C. Cironi, Luisa Iyer, Sowmya Rengarajan, Shruthi Awad, Mary E. Naigles, Beverly Letovanec, Igor Ormas, Nicola Finzi, Giovanna La Rosa, Stefano Sessa, Fausto Chebib, Ivan Petur Nielsen, G. Digklia, Antonia Spentzos, Dimitrios Cote, Gregory M. Choy, Edwin Aryee, Martin Stamenkovic, Ivan Boulay, Gaylor Rivera, Miguel N. Riggi, Nicolò |
author_facet | Möller, Emely Praz, Viviane Rajendran, Sanalkumar Dong, Rui Cauderay, Alexandra Xing, Yu-Hang Lee, Lukuo Fusco, Carlo Broye, Liliane C. Cironi, Luisa Iyer, Sowmya Rengarajan, Shruthi Awad, Mary E. Naigles, Beverly Letovanec, Igor Ormas, Nicola Finzi, Giovanna La Rosa, Stefano Sessa, Fausto Chebib, Ivan Petur Nielsen, G. Digklia, Antonia Spentzos, Dimitrios Cote, Gregory M. Choy, Edwin Aryee, Martin Stamenkovic, Ivan Boulay, Gaylor Rivera, Miguel N. Riggi, Nicolò |
author_sort | Möller, Emely |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-9046276 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90462762022-04-29 EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma Möller, Emely Praz, Viviane Rajendran, Sanalkumar Dong, Rui Cauderay, Alexandra Xing, Yu-Hang Lee, Lukuo Fusco, Carlo Broye, Liliane C. Cironi, Luisa Iyer, Sowmya Rengarajan, Shruthi Awad, Mary E. Naigles, Beverly Letovanec, Igor Ormas, Nicola Finzi, Giovanna La Rosa, Stefano Sessa, Fausto Chebib, Ivan Petur Nielsen, G. Digklia, Antonia Spentzos, Dimitrios Cote, Gregory M. Choy, Edwin Aryee, Martin Stamenkovic, Ivan Boulay, Gaylor Rivera, Miguel N. Riggi, Nicolò Nat Commun Article 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. Nature Publishing Group UK 2022-04-27 /pmc/articles/PMC9046276/ /pubmed/35477713 http://dx.doi.org/10.1038/s41467-022-29910-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Möller, Emely Praz, Viviane Rajendran, Sanalkumar Dong, Rui Cauderay, Alexandra Xing, Yu-Hang Lee, Lukuo Fusco, Carlo Broye, Liliane C. Cironi, Luisa Iyer, Sowmya Rengarajan, Shruthi Awad, Mary E. Naigles, Beverly Letovanec, Igor Ormas, Nicola Finzi, Giovanna La Rosa, Stefano Sessa, Fausto Chebib, Ivan Petur Nielsen, G. Digklia, Antonia Spentzos, Dimitrios Cote, Gregory M. Choy, Edwin Aryee, Martin Stamenkovic, Ivan Boulay, Gaylor Rivera, Miguel N. Riggi, Nicolò EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma |
title | EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma |
title_full | EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma |
title_fullStr | EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma |
title_full_unstemmed | EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma |
title_short | EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma |
title_sort | ewsr1-atf1 dependent 3d connectivity regulates oncogenic and differentiation programs in clear cell sarcoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046276/ https://www.ncbi.nlm.nih.gov/pubmed/35477713 http://dx.doi.org/10.1038/s41467-022-29910-4 |
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