Single-Molecule Dynamics of Enhanceosome Assembly in Embryonic Stem Cells
Open accessAbstract
Enhancer-binding pluripotency regulators (Sox2 and Oct4) play a seminal role in embryonic stem (ES) cell-specific gene regulation. Here, we combine in vivo and in vitro single-molecule imaging, transcription factor (TF) mutagenesis, and ChIP-exo mapping to determine how TFs dynamically search for and assemble on their cognate DNA target sites. We find that enhanceosome assembly is hierarchically ordered with kinetically favored Sox2 engaging the target DNA first, followed by assisted binding of Oct4. Sox2/Oct4 follow a trial-and-error sampling mechanism involving 84-97 events of 3D diffusion (3.3-3.7 s) interspersed with brief nonspecific collisions (0.75-0.9 s) before acquiring and dwelling at specific target DNA (12.0-14.6 s). Sox2 employs a 3D diffusion-dominated search mode facilitated by 1D sliding along open DNA to efficiently locate targets. Our findings also reveal fundamental aspects of gene and developmental regulation by fine-tuning TF dynamics and influence of the epigenome on target search parameters.
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Transcription factor binding to DNA appears to be very transient.
“While it is clear that enhancers typically favour the more flexible models of sequence organisation, the degree of necessary cooperation between TFs is less obvious, particularly since TF binding to DNA appears to be very transient [113–117].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [115]
Regulatory processes at the interface between enhancers and promoters have been estimated to occur in the order of tens of seconds.
“Regulatory processes at the interface between enhancers and promoters have been estimated to occur in the order of tens of seconds41,43,46, consistent with the condition that intermediate regulatory steps should be faster than bursting kinetics (Fig. 3f).”
From Nonlinear control of transcription through enhancer–promoter interactions (2022) · cites this paper as [46]
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- Authors
- Chen, J., Zhang, Z., Li, L., Chen, B.-C., Revyakin, A., Hajj, B., Legant, W., Dahan, M., Lionnet, T., Betzig, E., Tjian, R., & Liu, Z.
- Affiliations
- Howard Hughes Medical Institute (US)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Liu, Zhe
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 156
- Issue
- 6
- Pages
- 1274-1285
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4040518
- OpenAlex
- W2028200156
- Cited by
- 602
- References
- 48
- Citations by year
- 2026: 29 · 2025: 38 · 2024: 46 · 2023: 40 · 2022: 57 · 2021: 63 · 2020: 57 · 2019: 40 · 2018: 50 · 2017: 56 · 2016: 49 · 2015: 55 · 2014: 22
- FWCI
- 25.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- SOX2, Oct4, embryonic stem cells, enhancer binding, ChIP-exo
- MeSH terms
- Animals, DNA, Enhancer Elements, Genetic, Kinetics, Epigenesis, Genetic, Chromatin Immunoprecipitation, Octamer Transcription Factor-3, Mice, Embryonic Stem Cells, Genome-Wide Association Study, SOXB1 Transcription Factors, Single-Cell Analysis
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