Live-cell three-dimensional single-molecule tracking reveals modulation of enhancer dynamics by NuRD

• Published in: Nature structural & molecular biology Vol. 30; no. 11; pp. 1628 - 1639
• Main Authors: Basu, S., Shukron, O., Hall, D., Parutto, P., Ponjavic, A., Shah, D., Boucher, W., Lando, D., Zhang, W., Reynolds, N., Sober, L. H., Jartseva, A., Ragheb, R., Ma, X., Cramard, J., Floyd, R., Balmer, J., Drury, T. A., Carr, A. R., Needham, L.-M., Aubert, A., Communie, G., Gor, K., Steindel, M., Morey, L., Blanco, E., Bartke, T., Di Croce, L., Berger, I., Schaffitzel, C., Lee, S. F., Stevens, T. J., Klenerman, D., Hendrich, B. D., Holcman, D., Laue, E. D.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2023; Nature Publishing Group
• Subjects: 631/337/100/101; 631/337/100/102; 631/532/2064; 631/80/2373; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Chromatin; Cohesin; Diffusion rate; Enhancer Elements, Genetic; Experiments; Genomes; Life Sciences; Membrane Biology; Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism; Molecular biology; Nucleosomes; Parameters; Promoter Regions, Genetic; Protein Structure; Proteins; RNA polymerase; Segments
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/s41594-023-01095-4

To understand how the nucleosome remodeling and deacetylase (NuRD) complex regulates enhancers and enhancer–promoter interactions, we have developed an approach to segment and extract key biophysical parameters from live-cell three-dimensional single-molecule trajectories. Unexpectedly, this has revealed that NuRD binds to chromatin for minutes, decompacts chromatin structure and increases enhancer dynamics. We also uncovered a rare fast-diffusing state of enhancers and found that NuRD restricts the time spent in this state. Hi-C and Cut&Run experiments revealed that NuRD modulates enhancer–promoter interactions in active chromatin, allowing them to contact each other over longer distances. Furthermore, NuRD leads to a marked redistribution of CTCF and, in particular, cohesin. We propose that NuRD promotes a decondensed chromatin environment, where enhancers and promoters can contact each other over longer distances, and where the resetting of enhancer–promoter interactions brought about by the fast decondensed chromatin motions is reduced, leading to more stable, long-lived enhancer–promoter relationships. This study describes an approach to segment and extract key biophysical parameters from live-cell three-dimensional single-molecule imaging trajectories. The authors use this approach to study how NuRD assembles on chromatin and how it regulates enhancer dynamics.