Coactivator condensation at super-enhancers links phase separation and gene control
Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear punc...
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| Format: | Article |
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American Association for the Advancement of Science (AAAS)
2019
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| Online Access: | http://hdl.handle.net/1721.1/120962 https://orcid.org/0000-0002-4167-9385 https://orcid.org/0000-0001-6263-2423 https://orcid.org/0000-0002-0385-6176 https://orcid.org/0000-0001-8091-6112 https://orcid.org/0000-0002-8272-658X https://orcid.org/0000-0002-8764-1809 https://orcid.org/0000-0003-1465-1691 https://orcid.org/0000-0003-1268-9602 https://orcid.org/0000-0001-8855-8647 |
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| author | Sabari, Benjamin R. Dall’Agnese, Alessandra Boija, Ann Klein, Isaac A. Abraham, Brian J. Hannett, Nancy M. Guo, Yang E. Day, Daniel S. Schuijers, Jurian Hnisz, Denes Lee, Tong Ihn Coffey, Eliot Leo Shrinivas, Krishna Zamudio Montes de Oca, Alicia Manteiga, John Colonnese Li, Charles Han Vasile, Eliza Cisse, Ibrahim I Chakraborty, Arup K Sharp, Phillip A. Young, Richard A. |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Sabari, Benjamin R. Dall’Agnese, Alessandra Boija, Ann Klein, Isaac A. Abraham, Brian J. Hannett, Nancy M. Guo, Yang E. Day, Daniel S. Schuijers, Jurian Hnisz, Denes Lee, Tong Ihn Coffey, Eliot Leo Shrinivas, Krishna Zamudio Montes de Oca, Alicia Manteiga, John Colonnese Li, Charles Han Vasile, Eliza Cisse, Ibrahim I Chakraborty, Arup K Sharp, Phillip A. Young, Richard A. |
| author_sort | Sabari, Benjamin R. |
| collection | MIT |
| description | Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets, and MED1-IDR droplets can compartmentalize and concentrate the transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in the control of key cell-identity genes. |
| first_indexed | 2024-09-23T10:17:36Z |
| format | Article |
| id | mit-1721.1/120962 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:17:36Z |
| publishDate | 2019 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1209622022-09-26T17:02:52Z Coactivator condensation at super-enhancers links phase separation and gene control Sabari, Benjamin R. Dall’Agnese, Alessandra Boija, Ann Klein, Isaac A. Abraham, Brian J. Hannett, Nancy M. Guo, Yang E. Day, Daniel S. Schuijers, Jurian Hnisz, Denes Lee, Tong Ihn Coffey, Eliot Leo Shrinivas, Krishna Zamudio Montes de Oca, Alicia Manteiga, John Colonnese Li, Charles Han Vasile, Eliza Cisse, Ibrahim I Chakraborty, Arup K Sharp, Phillip A. Young, Richard A. Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Physics Koch Institute for Integrative Cancer Research at MIT Coffey, Eliot Leo Shrinivas, Krishna Zamudio Montes de Oca, Alicia Manteiga, John Colonnese Li, Charles Han Vasile, Eliza Cisse, Ibrahim I Sharp, Phillip A Chakraborty, Arup K Young, Richard A Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets, and MED1-IDR droplets can compartmentalize and concentrate the transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in the control of key cell-identity genes. National Institutes of Health (U.S.) (Grant GM123511) National Institutes of Health (U.S.) (Grant P01-CA042063) National Science Foundation (U.S.) (Grant PHY-1743900) National Cancer Institute (U.S.) (Grant P30-CA14051) 2019-03-14T17:59:34Z 2019-03-14T17:59:34Z 2018-07 2018-04 2019-03-13T12:44:47Z Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/120962 Sabari, Benjamin R. et al. “Coactivator Condensation at Super-Enhancers Links Phase Separation and Gene Control.” Science 361, 6400 (June 2018): eaar3958 © 2018 The Authors https://orcid.org/0000-0002-4167-9385 https://orcid.org/0000-0001-6263-2423 https://orcid.org/0000-0002-0385-6176 https://orcid.org/0000-0001-8091-6112 https://orcid.org/0000-0002-8272-658X https://orcid.org/0000-0002-8764-1809 https://orcid.org/0000-0003-1465-1691 https://orcid.org/0000-0003-1268-9602 https://orcid.org/0000-0001-8855-8647 http://dx.doi.org/10.1126/science.aar3958 Science Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Sabari, Benjamin R. Dall’Agnese, Alessandra Boija, Ann Klein, Isaac A. Abraham, Brian J. Hannett, Nancy M. Guo, Yang E. Day, Daniel S. Schuijers, Jurian Hnisz, Denes Lee, Tong Ihn Coffey, Eliot Leo Shrinivas, Krishna Zamudio Montes de Oca, Alicia Manteiga, John Colonnese Li, Charles Han Vasile, Eliza Cisse, Ibrahim I Chakraborty, Arup K Sharp, Phillip A. Young, Richard A. Coactivator condensation at super-enhancers links phase separation and gene control |
| title | Coactivator condensation at super-enhancers links phase separation and gene control |
| title_full | Coactivator condensation at super-enhancers links phase separation and gene control |
| title_fullStr | Coactivator condensation at super-enhancers links phase separation and gene control |
| title_full_unstemmed | Coactivator condensation at super-enhancers links phase separation and gene control |
| title_short | Coactivator condensation at super-enhancers links phase separation and gene control |
| title_sort | coactivator condensation at super enhancers links phase separation and gene control |
| url | http://hdl.handle.net/1721.1/120962 https://orcid.org/0000-0002-4167-9385 https://orcid.org/0000-0001-6263-2423 https://orcid.org/0000-0002-0385-6176 https://orcid.org/0000-0001-8091-6112 https://orcid.org/0000-0002-8272-658X https://orcid.org/0000-0002-8764-1809 https://orcid.org/0000-0003-1465-1691 https://orcid.org/0000-0003-1268-9602 https://orcid.org/0000-0001-8855-8647 |
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