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Transcriptional kinetic synergy: A complex landscape revealed by integrating modeling and synthetic biology

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Martinez-Corral, Rosa, Park, Minhee, Biette, Kelly M., Friedrich, Dhana, Scholes, Clarissa, Khalil, Ahmad S., Gunawardena, Jeremy, DePace, Angela H.·2023·Cell Systems
DOI 10.1016/j.cels.2023.02.003PMC PMC10472254

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Abstract

Transcription factors (TFs) control gene expression, often acting synergistically. Classical thermodynamic models offer a biophysical explanation for synergy based on binding cooperativity and regulated recruitment of RNA polymerase. Because transcription requires polymerase to transition through multiple states, recent work suggests that "kinetic synergy" can arise through TFs acting on distinct steps of the transcription cycle. These types of synergy are not mutually exclusive and are difficult to disentangle conceptually and experimentally. Here, we model and build a synthetic circuit in which TFs bind to a single shared site on DNA, such that TFs cannot synergize by simultaneous binding. We model mRNA production as a function of both TF binding and regulation of the transcription cycle, revealing a complex landscape dependent on TF concentration, DNA binding affinity, and regulatory activity. We use synthetic TFs to confirm that the transcription cycle must be integrated with recruitment for a quantitative understanding of gene regulation.

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  • Single-molecule footprinting methods that use methyltransferases to mark accessible sites can provide quantitative measurements of binding states across individual molecules.

    “single-molecule footprinting methods that use methyltransferases to mark accessible sites11–15 can provide quantitative measurements of these binding states across individual molecules”

    From Single-molecule states link transcription factor binding to gene expression (2024) · cites this paper as [13]

    The Results section on the synthetic platform discusses transcription-factor binding and unbinding kinetics, while STAR★METHODS describes flow cytometry and fluorescence measurements (pages unavailable). Searches for single-molecule footprinting and methyltransferases found no passage describing methyltransferase marking of accessible sites or quantitative binding-state measurements across individual molecules. (LLM, conf=0.76)

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Authors
Martinez-Corral, R., Park, M., Biette, K. M., Friedrich, D., Scholes, C., Khalil, A. S., Gunawardena, J., & DePace, A. H.
Affiliations
  • Harvard University (US)
  • Boston University (US)
Corresponding author
DePace, Angela H.
ORCID
Venue
Cell Systems
Publisher
Elsevier BV
Published
2023-04
Volume
14
Issue
4
Pages
324-339.e7
ISSN
2405-4712 (ISSN-L)
DOI
10.1016/j.cels.2023.02.003
PMC
PMC10472254
OpenAlex
W4366372506
Cited by
29
References
8
Citations by year
2026: 5 · 2025: 8 · 2024: 11 · 2023: 2 · 2022: 2 · 2021: 1
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Systems (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • National Science Foundation Division of Integrative Organismal Systems (IOS-1452557)
  • DARPA (D16AP00142)
  • Giovanni Armenise-Harvard Foundation
  • Lynch Foundation
  • National Science Foundation
  • National Institutes of Health (1R01GM122928, R01EB029483, IOS-1452557)
  • European Molecular Biology Organization (683\u20132019)
  • US Department of Defense (N00014-20-1-2825)
  • Harvard Medical School
  • National Science Foundation Division of Molecular and Cellular Biosciences (MCB-1715184, MCB-1713855)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
transcriptional synergy, transcription factors, transcription cycle, RNA polymerase recruitment, cooperative binding, synthetic transcription factors, gene expression regulation, mRNA production, thermodynamic modeling, synthetic gene circuits, DNA binding affinity
MeSH terms
DNA, Gene Expression Regulation, Protein Binding, Transcription Factors, Synthetic Biology

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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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