Nucleosome spacing can fine-tune higher-order chromatin assembly

Lifeng Chen, M. Julia Maristany, Stephen E. Farr, Jinyue Luo, Bryan A. Gibson, Lynda K. Doolittle, Jorge R. Espinosa, Jan Huertas, Sy Redding, Rosana Collepardo-Guevara () and Michael K. Rosen ()
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Lifeng Chen: University of Texas Southwestern Medical Center
M. Julia Maristany: Marine Biological Laboratory
Stephen E. Farr: University of Cambridge
Jinyue Luo: University of Massachusetts Chan Medical School
Bryan A. Gibson: University of Texas Southwestern Medical Center
Lynda K. Doolittle: University of Texas Southwestern Medical Center
Jorge R. Espinosa: Marine Biological Laboratory
Jan Huertas: Marine Biological Laboratory
Sy Redding: Marine Biological Laboratory
Rosana Collepardo-Guevara: Marine Biological Laboratory
Michael K. Rosen: University of Texas Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Cellular chromatin displays heterogeneous structure and dynamics, properties that control diverse nuclear processes. Models invoke phase separation of conformational ensembles of chromatin fibers as a mechanism regulating chromatin organization in vivo. Here we combine biochemistry and molecular dynamics simulations to examine, at single base-pair resolution, how nucleosome spacing controls chromatin phase separation. We show that as DNA linkers extend from 25 bp to 30 bp, as exemplars of 10 N + 5 and 10 N (integer N) bp lengths, chromatin condensates become less thermodynamically stable and nucleosome mobility increases. Simulations reveal that this is due to trade-offs between inter- and intramolecular nucleosome stacking, favored by rigid 10 N + 5 and 10 N bp linkers, respectively. A remodeler can induce or inhibit phase separation by moving nucleosomes, changing the balance between intra- and intermolecular stacking. The intrinsic phase separation capacity of chromatin enables fine tuning of compaction and dynamics, likely contributing to heterogeneous chromatin organization in vivo.

Date: 2025
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DOI: 10.1038/s41467-025-61482-x

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