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How subtle changes in 3D structure can create large changes in transcription
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Abstract
Animal genomes are organized into topologically associated domains (TADs). TADs are thought to contribute to gene regulation by facilitating enhancer-promoter (E-P) contacts within a TAD and preventing these contacts across TAD borders. However, the absolute difference in contact frequency across TAD boundaries is usually less than 2-fold, even though disruptions of TAD borders can change gene expression by 10-fold. Existing models fail to explain this hypersensitive response. Here, we propose a futile cycle model of enhancer-mediated regulation that can exhibit hypersensitivity through bistability and hysteresis. Consistent with recent experiments, this regulation does not exhibit strong correlation between E-P contact and promoter activity, even though regulation occurs through contact. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of E-P biochemical specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile apparently contradictory results from recent global TAD disruption with local TAD boundary deletion experiments. Together, these analyses advance our understanding of cis-regulatory contacts in controlling gene expression and suggest new experimental directions.
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“By reducing the dose of dox, we tuned the effective rTetR-VP48 concentration36 as measured in vitro by an Electrophoretic Mobility Shift Assay (Fig. S4L–O)”
From Single-molecule states link transcription factor binding to gene expression (2024) · cites this paper as [36]
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Cites
A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping
Rao, S. S. P., Huntley, M. H., Durand, N. C., Stamenova, E. K., Bochkov, I. D., Robinson, J. T., Sanborn, A. L., Machol, I., Omer, A. D., Lander, E. S., et al. (2014) · Cell · doi:10.1016/j.cell.2014.11.021 · Cited by 9,212
Alberts, B., Johnson, A., Lewis, J. H., Morgan, D. O., RAFF, M. C., Roberts, K. J., & Walter, P. (2017) · W.W. Norton eBooks · doi:10.1201/9781315735368 · Cited by 7,937
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829
Spatial partitioning of the regulatory landscape of the X-inactivation centre
Nora, E. P., Lajoie, B. R., Schulz, E. G., Giorgetti, L., Okamoto, I., Servant, N., Piolot, T., van Berkum, N. L., Meisig, J., Sedat, J., et al. (2012) · Nature · doi:10.1038/nature11049 · Cited by 2,895
Coactivator condensation at super-enhancers links phase separation and gene control
Sabari, B. R., Dall’Agnese, A., Boija, A., Klein, I. A., Coffey, E. L., Shrinivas, K., Abraham, B. J., Hannett, N. M., Zamudio, A. V., Manteiga, J. C., et al. (2018) · Science · doi:10.1126/science.aar3958 · Cited by 2,595
Juicebox Provides a Visualization System for Hi-C Contact Maps with Unlimited Zoom
Durand, N. C., Robinson, J., Shamim, M. S., Machol, I., Mesirov, J. P., Lander, E. S., & Aiden, E. L. (2016) · Cell Systems · doi:10.1016/j.cels.2015.07.012 · Cited by 2,421
Strogatz, S. H. (2018) · CRC Press eBooks · doi:10.1201/9780429492563 · Cited by 2,247
Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions
Lupiáñez, D. G., Kraft, K., Heinrich, V., Krawitz, P., Brancati, F., Klopocki, E., Horn, D., Kayserili, H., Opitz, J. M., Laxova, R., et al. (2015) · Cell · doi:10.1016/j.cell.2015.04.004 · Cited by 2,132
Mediator and cohesin connect gene expression and chromatin architecture
Kagey, M. H., Newman, J. J., Bilodeau, S., Zhan, Y., Orlando, D. A., van Berkum, N. L., Ebmeier, C. C., Goossens, J., Rahl, P. B., Levine, S. S., et al. (2010) · Nature · doi:10.1038/nature09380 · Cited by 1,939
Cohesin Loss Eliminates All Loop Domains
Rao, S. S. P., Huang, S.-C., Glenn St Hilaire, B., Engreitz, J. M., Perez, E. M., Kieffer-Kwon, K.-R., Sanborn, A. L., Johnstone, S. E., Bascom, G. D., Bochkov, I. D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.026 · Cited by 1,883
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Metadata
- Authors
- Xiao, J. Y., Hafner, A., & Boettiger, A. N.
- Affiliations
- Stanford University (US)
- Corresponding author
- Boettiger, Alistair N
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2021-07-09
- Volume
- 10
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8352591
- OpenAlex
- W3181995425
- Cited by
- 162
- References
- 109
- Citations by year
- 2026: 18 · 2025: 29 · 2024: 37 · 2023: 36 · 2022: 26 · 2021: 16
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (U01 DK127419)
- NIH (DGM132935A)
- Stanford University (GM008294, The Walter V. and Idun Berry Postdoctoral Fellowship Program)
- Burroughs Wellcome Fund (CASI)
- 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 › Protein Structure and Dynamics
- Keywords
- topologically associating domains, TAD boundaries, enhancer-promoter interactions, gene expression regulation, bistability, hysteresis, 3D genome organization, stochastic gene expression, promoter activity
- MeSH terms
- Animals, Chromatin, Gene Expression Regulation, Humans, Hypersensitivity, Promoter Regions, Genetic, Transcription, Genetic, Genome, Computational Biology, Mice
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