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Peer-reviewedCC BYScience Advances

Enhancer binding kinetics explain transcription factor hub formation

  • Samantha Fallacaro1,2,3
  • Manya Kapoor1,3,4
  • Lillian Encarnation1,3,5
  • Apratim Mukherjee2,3
  • Meghan A. Turner6
  • Hernan G. Garcia6,7,8,9,10
  • Mustafa Mir1,3,11,12
12 affiliations
  1. 1Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  2. 2Developmental, Stem Cell, and Regenerative Biology Graduate Group, Perelman School of Medicine, Philadelphia, PA 19104, USA.
  3. 3Center for Computational and Genomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  4. 4Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
  5. 5Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  6. 6Biophysics Graduate Group, University of California at Berkeley, Berkeley, CA 94720, USA.
  7. 7Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
  8. 8Department of Physics, University of California, Berkeley, CA 94720, USA.
  9. 9Institute for Quantitative Biosciences-QB3, University of California, Berkeley, CA 94720, USA.
  10. 10Chan Zuckerberg Biohub–San Francisco, San Francisco, CA 94158, USA.
  11. 11Howard Hughes Medical Institute, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  12. 12Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
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Abstract

Transcription factors (TFs) form dynamic, high-concentration clusters, condensates, or hubs, proposed to increase TF binding frequency at target enhancers. However, how enhancer sequence shapes hub properties remains unclear. We developed a live imaging-based framework to quantify the spatiotemporal relationship between TF hubs and actively transcribed genes in live Drosophila embryos. Examining hubs formed by the TF Dorsal across enhancers with defined binding site composition, we find that hub enrichment and persistence scale with the number of Dorsal binding motifs. However, these hub properties do not predict transcriptional bursts for a given enhancer. Combining quantitative imaging with computational modeling, we show that Dorsal hub formation can be explained by TF-DNA binding kinetics alone. These findings support a model in which TF hubs emerge from enhancer-encoded TF-DNA interactions rather than higher-order regulatory assemblies.

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Cite

BibTeXRIS
BibTeX
@article{fallacaro2026enhancer,
  title = {{Enhancer binding kinetics explain transcription factor hub formation}},
  author = {Samantha Fallacaro and Manya Kapoor and Lillian Encarnation and Apratim Mukherjee and Meghan A. Turner and Hernan G. Garcia and Mustafa Mir},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeh1086},
  url = {https://www.science.org/doi/10.1126/sciadv.aeh1086},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Enhancer binding kinetics explain transcription factor hub formation
AU  - Samantha Fallacaro
AU  - Manya Kapoor
AU  - Lillian Encarnation
AU  - Apratim Mukherjee
AU  - Meghan A. Turner
AU  - Hernan G. Garcia
AU  - Mustafa Mir
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aeh1086
UR  - https://www.science.org/doi/10.1126/sciadv.aeh1086
AB  - Transcription factors (TFs) form dynamic, high-concentration clusters, condensates, or hubs, proposed to increase TF binding frequency at target enhancers. However, how enhancer sequence shapes hub properties remains unclear. We developed a live imaging-based framework to quantify the spatiotemporal relationship between TF hubs and actively transcribed genes in live Drosophila embryos. Examining hubs formed by the TF Dorsal across enhancers with defined binding site composition, we find that hub enrichment and persistence scale with the number of Dorsal binding motifs. However, these hub properties do not predict transcriptional bursts for a given enhancer. Combining quantitative imaging with computational modeling, we show that Dorsal hub formation can be explained by TF-DNA binding kinetics alone. These findings support a model in which TF hubs emerge from enhancer-encoded TF-DNA interactions rather than higher-order regulatory assemblies.
SN  - 2375-2548
ER  -