Live-cell three-dimensional single-molecule tracking reveals modulation of enhancer dynamics by NuRD
Srinjan Basu, Ofir Shukron, Dominic Hall, Pierre Parutto, Aleks Ponjavic, Darshil U. Shah, Wayne Boucher, David Lando, Wenjuan Zhang, Nicola Reynolds, Louisa H. Sober, Aleksandra Jartseva, Ramy Ragheb, Xiao Ma, Julie Cramard, Robin Floyd, Jasmin Balmer, T. A. Drury, Alexander R. Carr, L.M. Needham, Alice Aubert, Guillaume Communie, Kavan Gor, M. Steindel, Lluís Morey, Enrique Blanco, Till Bartke, Luciano Di Croce, Imre Berger, Christiane Schaffitzel, Steven F. Lee, Tim J. Stevens, David Klenerman, Brian Hendrich, David Holcman, Ernest D. Laue
Abstract
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.