Nucleosome plasticity is a critical element of chromatin liquid–liquid phase separation and multivalent nucleosome interactions

Stephen E. Farr, Esmae J. Woods, Jerelle A. Joseph, Adiran Garaizar, Rosana Collepardo-Guevara

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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.

Original languageEnglish (US)
Article number2883
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 1 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology

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