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

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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.


Acknowledgements: We thank T. Kretschmann for preparing the figures for publication, L. Lavis (Howard Hughes Medical Institute, Janelia Farm) for providing the JF549 dye, J. Wysocka (Stanford) for the Tbx3 constructs used for 2D enhancer tracking, A. Riddell for flow cytometry and the CSCI imaging (P. Humphreys and D. Clements) and DNA sequencing (M. Paramor and V. Murray) facilities. We thank K. Bowman, G. Brown and A. Crombie for preliminary computational analysis of NuRD-regulated genes and 2D enhancer tracking experiments, respectively. We thank the EU FP7 Integrated Project ‘4DCellFate’ (277899 E.D.L., B.D.H., I.B., C.S. and L.D.C.), the Medical Research Council (MR/P019471/1 E.D.L.) and the Wellcome Trust (206291/Z/17/Z E.D.L.) for program funding. We also thank the MRC (MR/R009759/1 B.D.H., and MR/M010082/1 E.D.L.), the Wellcome Trust (106115/Z/14/Z I.B. and 210701/Z/18/Z C.S.) and the Isaac Newton Trust (17.24(aa) B.D.H.) for project grant funding, and we thank the Wellcome Trust/MRC for core funding (203151/Z/16/Z) to the Cambridge Stem Cell Institute (including a starter grant to S.B.).


Nucleosomes, Chromatin, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Promoter Regions, Genetic, Enhancer Elements, Genetic

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Nat Struct Mol Biol

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Springer Science and Business Media LLC
European Commission (277899)
Wellcome Trust (206291/Z/17/Z)
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MC_PC_17230)
Medical Research Council (MR/P019471/1)
Medical Research Council (MR/M010082/1)