ArticleProceedings of the National Academy of Sciences of the United States of America2020
Nonequilibrium models of optimal enhancer function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed.
- Stable epigenetic states set single-cell activation thresholds in mammalian expression systems.bioRxiv : the preprint server for biology · 2026Article
- Invariant nonequilibrium dynamics in gene regulation optimize information flow.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A fundamental trade-off among noise suppression, response sensitivity and speed in biological feedback networks.NPJ systems biology and applications · 2026Article
- Highly Constrained Kinetic Models for Single-Cell Gene Expression Analysis.bioRxiv : the preprint server for biology · 2026Article
- Emergence of activation or repression in transcriptional control under a fixed molecular context.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Timing is everything: transcription bursting in development.Genes & development · 2025Review
- Deriving a genetic regulatory network from an optimization principle.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Chromatin enables precise and scalable gene regulation with factors of limited specificity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Flexibility and sensitivity in gene regulation out of equilibrium.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Energy Aware Technology Mapping of Genetic Logic Circuits.ACS synthetic biology · 2024Article
- Energy Aware Technology Mapping of Genetic Logic Circuits.bioRxiv : the preprint server for biology · 2024Article
- Governing principles of transcriptional logic out of equilibrium.Biophysical journal · 2024Article
- Shadow enhancers mediate trade-offs between transcriptional noise and fidelity.PLoS computational biology · 2023Article
- Size limits the sensitivity of kinetic schemes.Nature communications · 2023Article
- Competing constraints shape the nonequilibrium limits of cellular decision-making.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The Mediator complex as a master regulator of transcription by RNA polymerase II.Nature reviews. Molecular cell biology · 2022Review
- Eukaryotic gene regulation at equilibrium, or non?Current opinion in systems biology · 2022Article
- Deciphering enhancer sequence using thermodynamics-based models and convolutional neural networks.Nucleic acids research · 2021Article
- Allosteric conformational ensembles have unlimited capacity for integrating information.eLife · 2021Article
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3 authors.
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Abstract
In prokaryotes, thermodynamic models of gene regulation provide a highly quantitative mapping from promoter sequences to gene-expression levels that is compatible with in vivo and in vitro biophysical measurements. Such concordance has not been achieved for models of enhancer function in eukaryotes. In equilibrium models, it is difficult to reconcile the reported short transcription factor (TF) residence times on the DNA with the high specificity of regulation. In nonequilibrium models, progress is difficult due to an explosion in the number of parameters. Here, we navigate this complexity by looking for minimal nonequilibrium enhancer models that yield desired regulatory phenotypes: low TF residence time, high specificity, and tunable cooperativity. We find that a single extra parameter, interpretable as the "linking rate," by which bound TFs interact with Mediator components, enables our models to escape equilibrium bounds and access optimal regulatory phenotypes, while remaining consistent with the reported phenomenology and simple enough to be inferred from upcoming experiments. We further find that high specificity in nonequilibrium models is in a trade-off with gene-expression noise, predicting bursty dynamics-an experimentally observed hallmark of eukaryotic transcription. By drastically reducing the vast parameter space of nonequilibrium enhancer models to a much smaller subspace that optimally realizes biological function, we deliver a rich class of models that could be tractably inferred from data in the near future.
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