Mapping chromatin structure at base-pair resolution unveils a unified model of cis-regulatory element interactions
Chromatin structure is a key determinant of gene expression in eukaryotes, but it has not been possible to define the structure of cis-regulatory elements at the scale of the proteins that bind them. Here, we generate multidimensional chromosome conformation capture (3C) maps at base-pair resolution using Micro Capture-C ultra (MCCu). This can resolve contacts between individual transcription factor motifs within cis-regulatory elements. Using degron systems, we show that removal of Mediator complex components alters fine-scale promoter structure and that nucleosome depletion plays a key role in transcription factor-driven enhancer-promoter contacts. We observe that chromatin is partitioned into nanoscale domains by nucleosome-depleted regions. This structural conformation is reproduced by chemically specific coarse-grained molecular dynamics simulations of the physicochemical properties of chromatin. Combining MCCu with molecular dynamics simulations and super-resolution microscopy allows us to propose a unified model in which the biophysical properties of chromatin orchestrate contacts between cis-regulatory elements.
Authors
- Thomas A. Milne (ORCID: https://orcid.org/0000-0002-0413-4271)
- Weijiao Zhang (ORCID: https://orcid.org/0009-0003-6493-8751)
- Douglas R. Higgs (ORCID: https://orcid.org/0000-0003-3579-8705)
- Joseph C. Hamley (ORCID: https://orcid.org/0000-0002-6524-1257)
- Lance D. Hentges (ORCID: https://orcid.org/0000-0001-6327-6774)
- James O. J. Davies (ORCID: https://orcid.org/0000-0002-4108-4357)
- Mira T. Kassouf (ORCID: https://orcid.org/0000-0002-9781-921X)
- Gianna Bloye (ORCID: https://orcid.org/0009-0006-3478-9937)
- Emilia Dimitrova (ORCID: https://orcid.org/0000-0001-5669-1240)
- Edward Tunnacliffe (ORCID: https://orcid.org/0000-0003-3939-744X)
- Maria Julia Maristany (ORCID: https://orcid.org/0009-0009-8875-9225)
- Lior Pytowski (ORCID: https://orcid.org/0000-0002-8530-5123)
- Michela Maresca (ORCID: https://orcid.org/0000-0003-3207-6563)
- Gulielma Lister
- Nicholas Denny (ORCID: https://orcid.org/0000-0002-5351-9581)
- Rosana Collepardo‐Guevara (ORCID: https://orcid.org/0000-0003-1781-7351)
- Robert J. Klose (ORCID: https://orcid.org/0000-0002-8726-7888)
- Hangpeng Li (ORCID: https://orcid.org/0000-0002-4895-0115)
- Elzo de Wit (ORCID: https://orcid.org/0000-0003-2883-1415)
- Lothar Schermelleh (ORCID: https://orcid.org/0000-0002-1612-9699)
- James L. T. Dalgleish (ORCID: https://orcid.org/0000-0002-2053-8786)
- Ana M. Dopico-Fernandez (ORCID: https://orcid.org/0009-0007-7314-3319)
- Ye Wei (ORCID: https://orcid.org/0009-0001-4191-260X)
- Jan Huertas (ORCID: https://orcid.org/0000-0003-2607-5214)
- Richard Doll
Institutions
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- University of Cambridge (GB)
- The Netherlands Cancer Institute (NL)
- University of Oxford (GB)
- Bridge University (SS)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Oncode Institute (NL)
- MRC Human Immunology Unit (GB)
Publication Details
- Journal
- Cell
- Published
- 2025-11-05
- DOI
- https://doi.org/10.1016/j.cell.2025.10.013
- Citations
- 7
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 5.64