Nucleosome-mediated cooperativity between transcription factors
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Cooperativity between activation domains in controlling the transcription cycle is not required to explain the synergy between motif copy number and transcription.
“and cooperativity between activation domains in controlling the transcription cycle is not required to explain the synergy between motif copy number and transcription9.”
From Single-molecule states link transcription factor binding to gene expression (2024) · cites this paper as [9]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 13
- Lebrecht, D., Foehr, M., Smith, E., Lopes, F.J., Vanario-Alonso, C.E., Reinitz, J., Burz, D.S., and Hanes, S.D. (2005). Bicoid cooperative DNA binding is critical for embryonic patterning in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 102, 13176-13181.
- Pettersson, M., and Schaffner, W. (1990). Synergistic activation of transcription by multiple binding sites for NF-kappa B even in absence of co-operative factor binding to DNA. Journal of molecular biology 214, 373-380.
- Ptashne, M., and Gann, A. (2002). Genes & signals, (Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press).
- Polach, K.J., and Widom, J. (1995). Mechanism of protein access to specific DNA sequences in chromatin: a dynamic equilibrium model for gene regulation. Journal of molecular biology 254, 130-149.
- Anderson, J.D., and Widom, J. (2000). Sequence and position-dependence of the equilibrium accessibility of nucleosomal DNA target sites. Journal of molecular biology 296, 979-987.
- Polach, K.J., and Widom, J. (1996). A model for the cooperative binding of eukaryotic regulatory proteins to nucleosomal target sites. Journal of molecular biology 258, 800-812.
- Monod, J., Wyman, J., and Changeux, J.P. (1965). On the Nature of Allosteric Transitions: a Plausible Model. Journal of molecular biology 12, 88-118.
- Poirier, M.G., Bussiek, M., Langowski, J., and Widom, J. (2008). Spontaneous access to DNA target sites in folded chromatin fibers. Journal of molecular biology 379, 772-786.
- Sabo, P.J., Hawrylycz, M., Wallace, J.C., Humbert, R., Yu, M., Shafer, A., Kawamoto, J., Hall, R., Mack, J., Dorschner, M.O., et al. (2004). Discovery of functional noncoding elements by digital analysis of chromatin structure. Proceedings of the National Academy of Sciences of the United States of America 101, 16837-16842.
- Oliviero, S., and Struhl, K. (1991). Synergistic transcriptional enhancement does not depend on the number of acidic activation domains bound to the promoter. Proceedings of the National Academy of Sciences of the United States of America 88, 224-228.
- Xu, H.E., Kodadek, T., and Johnston, S.A. (1995). A single GAL4 dimer can maximally activate transcription under physiological conditions. Proceedings of the National Academy of Sciences of the United States of America 92, 7677-7680.
- Sekinger, E.A., Moqtaderi, Z., and Struhl, K. (2005). Intrinsic histone-DNA interactions and low nucleosome density are important for preferential accessibility of promoter regions in yeast. In Molecular Cell, Volume 18. pp. 735-748.
- Anderson, J.D., Lowary, P.T., and Widom, J. (2001). Effects of histone acetylation on the equilibrium accessibility of nucleosomal DNA target sites. Journal of molecular biology 307, 977-985.
Cited by
Sorted by citations
Chromatin accessibility and the regulatory epigenome
Klemm, S. L., Shipony, Z., & Greenleaf, W. J. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-018-0089-8 · Cited by 1,793 · see citing works
Transcriptional enhancers: from properties to genome-wide predictions
Shlyueva, D., Stampfel, G., & Stark, A. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3682 · Cited by 1,356 · see citing works
The 3D Genome as Moderator of Chromosomal Communication
Dekker, J., & Mirny, L. (2016) · Cell · doi:10.1016/j.cell.2016.02.007 · Cited by 937 · see citing works
Self-citationPioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming
Soufi, A., Garcia, M. F., Jaroszewicz, A., Osman, N., Pellegrini, M., & Zaret, K. S. (2015) · Cell · doi:10.1016/j.cell.2015.03.017 · Cited by 780 · see citing works
“Silent chromatin is packed with nucleosomes, acting as a barrier to targeting by most transcription factors (TFs) (Adams and Workman, 1995; Mirny, 2010).”
Absence of a simple code: how transcription factors read the genome
Slattery, M., Zhou, T., Yang, L., Dantas Machado, A. C., Gordân, R., & Rohs, R. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.07.002 · Cited by 537 · see citing works
Dynamic regulation of transcriptional states by chromatin and transcription factors
Voss, T. C., & Hager, G. L. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3623 · Cited by 504 · see citing works
The Genetics of Transcription Factor DNA Binding Variation
Deplancke, B., Alpern, D., & Gardeux, V. (2016) · Cell · doi:10.1016/j.cell.2016.07.012 · Cited by 390 · see citing works
Global reference mapping of human transcription factor footprints
Vierstra, J., Lazar, J., Sandstrom, R., Halow, J., Lee, K., Bates, D., Diegel, M., Dunn, D., Neri, F., Haugen, E., et al. (2020) · Nature · doi:10.1038/s41586-020-2528-x · Cited by 386 · see citing works
Grossman, S. R., Zhang, X., Wang, L., Engreitz, J., Melnikov, A., Rogov, P., Tewhey, R., Isakova, A., Deplancke, B., Bernstein, B. E., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1621150114 · Cited by 165 · see citing works
Chromatin loops as allosteric modulators of enhancer-promoter interactions
Doyle, B., Fudenberg, G., Imakaev, M., & Mirny, L. A. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003867 · Cited by 114 · see citing works
“We note that the concept of allostery has also been useful for understanding other systems, including nucleosome-mediated transcription factor binding cooperativity [46,47].”
Hold out the genome: a roadmap to solving the cis-regulatory code
de Boer, C. G., & Taipale, J. (2024) · Nature · doi:10.1038/s41586-023-06661-w · Cited by 107 · see citing works
Single-molecule states link transcription factor binding to gene expression
Doughty, B. R., Hinks, M. M., Schaepe, J. M., Marinov, G. K., Thurm, A. R., Rios-Martinez, C., Parks, B. E., Tan, Y., Marklund, E., Dubocanin, D., et al. (2024) · Nature · doi:10.1038/s41586-024-08219-w · Cited by 42 · see citing works
Allosteric conformational ensembles have unlimited capacity for integrating information
Biddle, J. W., Martinez-Corral, R., Wong, F., & Gunawardena, J. (2021) · eLife · doi:10.7554/elife.65498 · Cited by 41 · see citing works
Human genetic variation within neural crest enhancers: molecular and phenotypic implications
Rada-Iglesias, A., Prescott, S. L., & Wysocka, J. (2013) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2012.0360 · Cited by 24 · see citing works
Emergence of activation or repression in transcriptional control under a fixed molecular context
Martinez-Corral, R., Friedrich, D., Frömel, R., Velten, L., Gunawardena, J., & DePace, A. H. (2024) · doi:10.1101/2024.05.29.596388 · Cited by 18
- Authors
- Mirny, L. A.
- Affiliations
- Harvard–MIT Division of Health Sciences and Technology (US)
- Corresponding author
- Mirny, Leonid A.
- ORCID
- Mirny, Leonid A.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-12-13
- Volume
- 107
- Issue
- 52
- Pages
- 22534-22539
- ISSN
- 1756-0357 (ISSN-L)
- 0027-8424
- 1091-6490
- PMC
- PMC3012490
- OpenAlex
- W2111846924
- Cited by
- 349
- References
- 0
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 24 · 2023: 20 · 2022: 22 · 2021: 26 · 2020: 23 · 2019: 28 · 2018: 18 · 2017: 17 · 2016: 20 · 2015: 21 · 2014: 26 · 2013: 20 · 2012: 21
- Type
- posted content
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Nature Precedings (publishedVersion, cc-by)
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- arXiv (Cornell University) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Nature Precedings (submittedVersion)
- arXiv (Cornell University)
- Funders
- U.S. Forest Service
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Keywords
- transcription factor cooperativity, nucleosome positioning, cis-regulatory elements, hemoglobin cooperativity, Bohr effect, chromatin modification, gene expression regulation
- MeSH terms
- Algorithms, Binding Sites, DNA, Gene Expression Regulation, Histones, Models, Genetic, Nucleosomes, Protein Binding, Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
