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Peer-reviewedCC BYNature Genetics

Cumulative transcription factor binding and p300-mediated histone acetylation drive enhancer activation frequency

  • Valentina Baderna1,2,3
  • Guido Barzaghi4,1,2
  • Rozemarijn Kleinendorst2
  • Kasit Chatsirisupachai5,2
  • Laura Moniot-Perron2
  • Colm Doyle2
  • Meike Schopp6
  • Tino Hochepied7,8
  • Claude Libert7,8
  • Duncan T. Odom6
  • Judith B. Zaugg9,10
  • Arnaud Regis Krebs11
11 affiliations
  1. 1Faculty of Biosciences, Collaboration for Joint PhD Degree between EMBL and Heidelberg University, Heidelberg, Germany
  2. 2Genome Biology Unit, EMBL Heidelberg, Heidelberg, Germany
  3. 3Institut Imagine, Paris, France
  4. 4Division of Precision Medicine, NYU Grossman School of Medicine, New York City, NY, USA
  5. 5Division of Medical Bioinformatics, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
  6. 6German Cancer Research Center (DKFZ), Division of Regulatory Genomics and Cancer Evolution, Heidelberg, Germany
  7. 7Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
  8. 8VIB Center for Inflammation Research, Ghent, Belgium
  9. 9Department of Biomedicine, University of Basel, Basel, Switzerland. [email protected]
  10. 10Structural and Computational Biology Unit, EMBL Heidelberg, Heidelberg, Germany. [email protected]
  11. 11Genome Biology Unit, EMBL Heidelberg, Heidelberg, Germany. [email protected]
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Abstract

In eukaryotes, transcription factors (TFs) must continuously compete with nucleosomes to access their binding sites, leading to cell-to-cell variability in chromatin accessibility at regulatory regions. Although critical to understand enhancer function in transcription, the mechanisms that define how frequently an enhancer is active in a cell population remain unclear. Here we used single-molecule footprinting to quantify the frequency at which chromatin is accessible at enhancers in response to TF perturbations and changes in their chromatin environment. We find that, individually, most TFs open chromatin in a small fraction of cells, and that cumulative TF binding controls enhancer activation frequency. Moreover, testing the functionality of hundreds of enhancers when inserted at an ectopic genomic location indicates that p300 activity is required for their full activation. Our data support a model in which enhancer activation frequency depends on the cumulative function of multiple TFs and is modulated by p300 activity.

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Cite

BibTeXRIS
BibTeX
@article{baderna2026cumulative,
  title = {{Cumulative transcription factor binding and p300-mediated histone acetylation drive enhancer activation frequency}},
  author = {Valentina Baderna and Guido Barzaghi and Rozemarijn Kleinendorst and Kasit Chatsirisupachai and Laura Moniot-Perron and Colm Doyle and Meike Schopp and Tino Hochepied and Claude Libert and Duncan T. Odom and Judith B. Zaugg and Arnaud Regis Krebs},
  journal = {Nature Genetics},
  year = {2026},
  month = jul,
  doi = {10.1038/s41588-026-02703-x},
  url = {https://doi.org/10.1038/s41588-026-02703-x},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Cumulative transcription factor binding and p300-mediated histone acetylation drive enhancer activation frequency
AU  - Valentina Baderna
AU  - Guido Barzaghi
AU  - Rozemarijn Kleinendorst
AU  - Kasit Chatsirisupachai
AU  - Laura Moniot-Perron
AU  - Colm Doyle
AU  - Meike Schopp
AU  - Tino Hochepied
AU  - Claude Libert
AU  - Duncan T. Odom
AU  - Judith B. Zaugg
AU  - Arnaud Regis Krebs
PY  - 2026
DA  - 2026/07/31
JO  - Nature Genetics
DO  - 10.1038/s41588-026-02703-x
UR  - https://doi.org/10.1038/s41588-026-02703-x
AB  - In eukaryotes, transcription factors (TFs) must continuously compete with nucleosomes to access their binding sites, leading to cell-to-cell variability in chromatin accessibility at regulatory regions. Although critical to understand enhancer function in transcription, the mechanisms that define how frequently an enhancer is active in a cell population remain unclear. Here we used single-molecule footprinting to quantify the frequency at which chromatin is accessible at enhancers in response to TF perturbations and changes in their chromatin environment. We find that, individually, most TFs open chromatin in a small fraction of cells, and that cumulative TF binding controls enhancer activation frequency. Moreover, testing the functionality of hundreds of enhancers when inserted at an ectopic genomic location indicates that p300 activity is required for their full activation. Our data support a model in which enhancer activation frequency depends on the cumulative function of multiple TFs and is modulated by p300 activity.
SN  - 1061-4036
SN  - 1546-1718
ER  -