BET bromodomain proteins regulate enhancer function during adipogenesis
Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/E...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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National Academy of Sciences (U.S.)
2018
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| Online Access: | http://hdl.handle.net/1721.1/118467 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1826201591923867648 |
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| author | Brown, Jonathan D. Feldman, Zachary B. Doherty, Sean P. Reyes, Jaime M. Rahl, Peter B. Lin, Charles Y. Sheng, Quanhu Duan, Qiong Federation, Alexander J. Kung, Andrew L. Haldar, Saptarsi M. Plutzky, Jorge Bradner, James E. Young, Richard A. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Brown, Jonathan D. Feldman, Zachary B. Doherty, Sean P. Reyes, Jaime M. Rahl, Peter B. Lin, Charles Y. Sheng, Quanhu Duan, Qiong Federation, Alexander J. Kung, Andrew L. Haldar, Saptarsi M. Plutzky, Jorge Bradner, James E. Young, Richard A. |
| author_sort | Brown, Jonathan D. |
| collection | MIT |
| description | Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomaincontaining protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition. Keywords: chromatin; coactivator; BET bromodomain; adipogenesis; transcription |
| first_indexed | 2024-09-23T11:54:09Z |
| format | Article |
| id | mit-1721.1/118467 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T11:54:09Z |
| publishDate | 2018 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1184672022-09-27T22:42:21Z BET bromodomain proteins regulate enhancer function during adipogenesis Brown, Jonathan D. Feldman, Zachary B. Doherty, Sean P. Reyes, Jaime M. Rahl, Peter B. Lin, Charles Y. Sheng, Quanhu Duan, Qiong Federation, Alexander J. Kung, Andrew L. Haldar, Saptarsi M. Plutzky, Jorge Bradner, James E. Young, Richard A. Massachusetts Institute of Technology. Department of Biology Young, Richard A Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomaincontaining protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation. Inhibition of the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition. Keywords: chromatin; coactivator; BET bromodomain; adipogenesis; transcription 2018-10-12T18:19:54Z 2018-10-12T18:19:54Z 2017-02 2017-06 2018-09-26T12:15:47Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/118467 Brown, Jonathan D. et al. “BET Bromodomain Proteins Regulate Enhancer Function During Adipogenesis.” Proceedings of the National Academy of Sciences 115, 9 (February 2018): 2144–2149 © 2018 National Academy of Sciences https://orcid.org/0000-0001-8855-8647 http://dx.doi.org/10.1073/PNAS.1711155115 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Brown, Jonathan D. Feldman, Zachary B. Doherty, Sean P. Reyes, Jaime M. Rahl, Peter B. Lin, Charles Y. Sheng, Quanhu Duan, Qiong Federation, Alexander J. Kung, Andrew L. Haldar, Saptarsi M. Plutzky, Jorge Bradner, James E. Young, Richard A. BET bromodomain proteins regulate enhancer function during adipogenesis |
| title | BET bromodomain proteins regulate enhancer function during adipogenesis |
| title_full | BET bromodomain proteins regulate enhancer function during adipogenesis |
| title_fullStr | BET bromodomain proteins regulate enhancer function during adipogenesis |
| title_full_unstemmed | BET bromodomain proteins regulate enhancer function during adipogenesis |
| title_short | BET bromodomain proteins regulate enhancer function during adipogenesis |
| title_sort | bet bromodomain proteins regulate enhancer function during adipogenesis |
| url | http://hdl.handle.net/1721.1/118467 https://orcid.org/0000-0001-8855-8647 |
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