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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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Flagged first, then by citations
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Research works printed but not linked: 1
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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
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.
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