Nucleosome-mediated cooperativity between transcription factors
Cooperative binding of transcription factors (TFs) to promoters and other regulatory regions is essential for precise gene expression. The classical model of cooperativity requires direct interactions between TFs, thus constraining the arrangement of TF sites in regulatory regions. Recent genomic an...
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National Academy of Sciences (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/112801 https://orcid.org/0000-0002-0785-5410 |
| _version_ | 1811093495788601344 |
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| author | Mirny, Leonid A |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Mirny, Leonid A |
| author_sort | Mirny, Leonid A |
| collection | MIT |
| description | Cooperative binding of transcription factors (TFs) to promoters and other regulatory regions is essential for precise gene expression. The classical model of cooperativity requires direct interactions between TFs, thus constraining the arrangement of TF sites in regulatory regions. Recent genomic and functional studies, however, demonstrate a great deal of flexibility in such arrangements with variable distances, numbers of sites, and identities of TF sites located in cis-regulatory regions. Such flexibility is inconsistent with cooperativity by direct interactions between TFs. Here, we demonstrate that strong cooperativity among noninteracting TFs can be achieved by their competition with nucleosomes. We find that the mechanism of nucleosome-mediated cooperativity is analogous to cooperativity in another multimolecular complex: hemoglobin. This surprising analogy provides deep insights, with parallels between the heterotropic regulation of hemoglobin (e.g., the Bohr effect) and the roles of nucleosome-positioning sequences and chromatin modifications in gene expression. Nucleosome-mediated cooperativity is consistent with several experimental studies, is equally applicable to repressors and activators, allows substantial flexibility in and modularity of regulatory regions, and provides a rationale for a broad range of genomic and evolutionary observations. Striking parallels between cooperativity in hemoglobin and in transcriptional regulation point to a general mechanism that can be used in various biological systems. |
| first_indexed | 2024-09-23T15:45:46Z |
| format | Article |
| id | mit-1721.1/112801 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:45:46Z |
| publishDate | 2017 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1128012022-09-29T16:00:09Z Nucleosome-mediated cooperativity between transcription factors Mirny, Leonid A Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Physics Mirny, Leonid A Cooperative binding of transcription factors (TFs) to promoters and other regulatory regions is essential for precise gene expression. The classical model of cooperativity requires direct interactions between TFs, thus constraining the arrangement of TF sites in regulatory regions. Recent genomic and functional studies, however, demonstrate a great deal of flexibility in such arrangements with variable distances, numbers of sites, and identities of TF sites located in cis-regulatory regions. Such flexibility is inconsistent with cooperativity by direct interactions between TFs. Here, we demonstrate that strong cooperativity among noninteracting TFs can be achieved by their competition with nucleosomes. We find that the mechanism of nucleosome-mediated cooperativity is analogous to cooperativity in another multimolecular complex: hemoglobin. This surprising analogy provides deep insights, with parallels between the heterotropic regulation of hemoglobin (e.g., the Bohr effect) and the roles of nucleosome-positioning sequences and chromatin modifications in gene expression. Nucleosome-mediated cooperativity is consistent with several experimental studies, is equally applicable to repressors and activators, allows substantial flexibility in and modularity of regulatory regions, and provides a rationale for a broad range of genomic and evolutionary observations. Striking parallels between cooperativity in hemoglobin and in transcriptional regulation point to a general mechanism that can be used in various biological systems. 2017-12-19T15:35:23Z 2017-12-19T15:35:23Z 2010-12 2009-12 2017-12-18T21:25:18Z Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/112801 Mirny, L. A. “Nucleosome-Mediated Cooperativity Between Transcription Factors.” Proceedings of the National Academy of Sciences 107, 52 (December 2010): 22534–22539 © 2010 National Academy of Sciences https://orcid.org/0000-0002-0785-5410 http://dx.doi.org/10.1073/pnas.0913805107 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 | Mirny, Leonid A Nucleosome-mediated cooperativity between transcription factors |
| title | Nucleosome-mediated cooperativity between transcription factors |
| title_full | Nucleosome-mediated cooperativity between transcription factors |
| title_fullStr | Nucleosome-mediated cooperativity between transcription factors |
| title_full_unstemmed | Nucleosome-mediated cooperativity between transcription factors |
| title_short | Nucleosome-mediated cooperativity between transcription factors |
| title_sort | nucleosome mediated cooperativity between transcription factors |
| url | http://hdl.handle.net/1721.1/112801 https://orcid.org/0000-0002-0785-5410 |
| work_keys_str_mv | AT mirnyleonida nucleosomemediatedcooperativitybetweentranscriptionfactors |