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

Abstract

Liquid–liquid phase separation (LLPS) of chromatin is an important mechanism that helps explain the membrane-less compartmentalization of the nucleus. Because chromatin compaction and LLPS are collective phenomena, linking their modulation to biophysical features of individual nucleosomes is challenging. Here, we develop a novel multiscale chromatin model that integrates atomistic representations, a chemically-specific coarse-grained model, and a minimal model. In tandem, we devise a transferable Debye-length exchange molecular dynamics approach to achieve enhanced sampling of high-resolution chromatin. We find that nucleosome thermal fluctuations become significant at physiological salt concentrations and destabilize the 30-nm fiber. 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 results put forward the intrinsic plasticity of nucleosomes as a key element in the liquid-like behavior of chromatin, and help reconcile longstanding differences between fiber-based and in vivo chromatin models.

On the stability and layered organization of protein-DNA condensates

“…We represented protein and DNA molecules with one coarsegrained bead per amino acid or nucleotide. Models of similar resolutions have been widely used to study IDPs [64][65][66][67][68] and protein-DNA complexes [69][70][71][72][73][74][75][76][77] with great success. The MOFF force field for proteins 39 and molecular renormalization group coarse-graining model (MRG-CG) for the DNA 40 were combined together to describe protein-DNA interactions under implicit solvation.…”

Molecular Organization of the Early Stages of Nucleosome Phase Separation Visualized by Cryo-Electron Tomography

“…6E, blue dash line). These increased peak values relative to those found for the spinodal condensates probably indicate that the higher compaction in spherical condensates further discourage intra-array n / n +2 stacking in favor of inter-array NCPs interactions, a conclusion supported by chromatin dynamics simulations (Farr et al, 2021). The second peak position (Fig.…”

Quantifying epigenetic modulation of nucleosome breathing by high-throughput AFM imaging

“…Work in drosophila suggests that H3K36me3 is enriched in gene bodies, in particular, in the region of transcribed genes distal to the transcription start site 53,54 . The increased proneness of H3K36me3 nucleosomes to partially unwrap suggests that H3K36me3 can directly affect higher order chromatin structure by increasing the heterogeneity of nucleosome-nucleosome contacts as well as the effective nucleosome valency 11 .…”

“…Post-translational modifications (PTMs) of histones play a key role in the formation of higher order chromatin structure 3,[9][10][11][12][13] , the recruitment of proteins and complexes with specific enzymatic activities 14 , and the maintenance of DNA repair 15 and replication 16 . Numerous histone variants and PTMs alter histone-histone and histone-DNA interactions [17][18][19] to yield nucleosomal structures with varying degrees of stability and DNA wrapping.…”