STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma
The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2)-marked regulatory regions. Genetic suppression of STAG2 leads to a compens...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/131197 |
| _version_ | 1826204056308154368 |
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| author | Adane, Biniam Alexe, Gabriela Seong, Bo Kyung A. Lu, Diana Hwang, Elizabeth E. Hnisz, Denes Lareau, Caleb A. Ross, Linda Lin, Shan Dela Cruz, Filemon S. Richardson, Melissa Weintraub, Abraham Selby Wang, Sarah Iniguez, Amanda Balboni Dharia, Neekesh V. Conway, Amy Saur Robichaud, Amanda L. Tanenbaum, Benjamin Krill-Burger, John M. Vazquez, Francisca Schenone, Monica Berman, Jason N. Kung, Andrew L. Carr, Steven A. Aryee, Martin J. Young, Richard A. Crompton, Brian D. Stegmaier, Kimberly |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Adane, Biniam Alexe, Gabriela Seong, Bo Kyung A. Lu, Diana Hwang, Elizabeth E. Hnisz, Denes Lareau, Caleb A. Ross, Linda Lin, Shan Dela Cruz, Filemon S. Richardson, Melissa Weintraub, Abraham Selby Wang, Sarah Iniguez, Amanda Balboni Dharia, Neekesh V. Conway, Amy Saur Robichaud, Amanda L. Tanenbaum, Benjamin Krill-Burger, John M. Vazquez, Francisca Schenone, Monica Berman, Jason N. Kung, Andrew L. Carr, Steven A. Aryee, Martin J. Young, Richard A. Crompton, Brian D. Stegmaier, Kimberly |
| author_sort | Adane, Biniam |
| collection | MIT |
| description | The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, 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. |
| first_indexed | 2024-09-23T12:48:13Z |
| format | Article |
| id | mit-1721.1/131197 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:48:13Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1311972022-09-28T10:08:50Z STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma Adane, Biniam Alexe, Gabriela Seong, Bo Kyung A. Lu, Diana Hwang, Elizabeth E. Hnisz, Denes Lareau, Caleb A. Ross, Linda Lin, Shan Dela Cruz, Filemon S. Richardson, Melissa Weintraub, Abraham Selby Wang, Sarah Iniguez, Amanda Balboni Dharia, Neekesh V. Conway, Amy Saur Robichaud, Amanda L. Tanenbaum, Benjamin Krill-Burger, John M. Vazquez, Francisca Schenone, Monica Berman, Jason N. Kung, Andrew L. Carr, Steven A. Aryee, Martin J. Young, Richard A. Crompton, Brian D. Stegmaier, Kimberly Massachusetts Institute of Technology. Department of Biology The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, 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. 2021-08-24T20:53:03Z 2021-08-24T20:53:03Z 2021-06 2021-01 2021-08-09T14:52:09Z Article http://purl.org/eprint/type/JournalArticle 1535-6108 https://hdl.handle.net/1721.1/131197 Adane, Biniam et al. "STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma." 39, 6 (June 2016): P827-844.e10. © 2021 Elsevier Inc en http://dx.doi.org/10.1016/j.ccell.2021.05.007 Cancer Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Prof. Richard Young |
| spellingShingle | Adane, Biniam Alexe, Gabriela Seong, Bo Kyung A. Lu, Diana Hwang, Elizabeth E. Hnisz, Denes Lareau, Caleb A. Ross, Linda Lin, Shan Dela Cruz, Filemon S. Richardson, Melissa Weintraub, Abraham Selby Wang, Sarah Iniguez, Amanda Balboni Dharia, Neekesh V. Conway, Amy Saur Robichaud, Amanda L. Tanenbaum, Benjamin Krill-Burger, John M. Vazquez, Francisca Schenone, Monica Berman, Jason N. Kung, Andrew L. Carr, Steven A. Aryee, Martin J. Young, Richard A. Crompton, Brian D. Stegmaier, Kimberly STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma |
| title | STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma |
| title_full | STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma |
| title_fullStr | STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma |
| title_full_unstemmed | STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma |
| title_short | STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma |
| title_sort | stag2 loss reshapes oncogenic enhancer promoter looping in ewing sarcoma |
| url | https://hdl.handle.net/1721.1/131197 |
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