Abstract

Liquid–liquid phase separation (LLPS) is an important mechanism that helps explain the membraneless compartmentalization of the nucleus. Because chromatin compaction and LLPS are collective phenomena, linking their modulation to the physicochemical features of nucleosomes is challenging. Here, we develop an advanced multiscale chromatin model—integrating atomistic representations, a chemically-specific coarse-grained model, and a minimal model—to resolve individual nucleosomes within sub-Mb chromatin domains and phase-separated systems. To overcome the difficulty of sampling chromatin at high resolution, we devise a transferable enhanced-sampling Debye-length replica-exchange molecular dynamics approach. We find that nucleosome thermal fluctuations become significant at physiological salt concentrations and destabilize the 30-nm fiber. Our simulations show that nucleosome breathing favors stochastic folding of chromatin and promotes LLPS by simultaneously boosting the transient nature and heterogeneity of nucleosome–nucleosome contacts, and the effective nucleosome valency. Our work puts forward the intrinsic plasticity of nucleosomes as a key element in the liquid-like behavior of nucleosomes within chromatin, and the regulation of chromatin LLPS.

Resolving nucleosomes with chemical accuracy inside sub-Mb chromatin provides molecular insight into the modulation of chromatin structure and its liquid–liquid phase separation (LLPS). By developing a multiscale chromatin model, the authors find that DNA breathing enhances the valency, heterogeneity, and dynamics of nucleosomes, promoting disordered folding and LLPS.

Details

Title
Nucleosome plasticity is a critical element of chromatin liquid–liquid phase separation and multivalent nucleosome interactions
Author
Farr, Stephen E 1 ; Woods, Esmae J 1   VIAFID ORCID Logo  ; Joseph Jerelle A 2   VIAFID ORCID Logo  ; Garaizar Adiran 1   VIAFID ORCID Logo  ; Collepardo-Guevara Rosana 2   VIAFID ORCID Logo 

 University of Cambridge, Maxwell Centre, Cavendish Laboratory, Department of Physics, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
 University of Cambridge, Maxwell Centre, Cavendish Laboratory, Department of Physics, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Yusuf Hamied Department of Chemistry, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Department of Genetics, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2528309754
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.