Organization of Chromatin by Intrinsic and Regulated Phase Separation

Eukaryotic chromatin is highly condensed but dynamically accessible to regulation and organized into subdomains. We demonstrate that reconstituted chromatin undergoes histone tail-driven liquid-liquid phase separation (LLPS) in physiologic salt and when microinjected into cell nuclei, producing dens...

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Bibliographic Details
Published in:Cell 2019-10, Vol.179 (2), p.470-484.e21
Main Authors: Gibson, Bryan A., Doolittle, Lynda K., Schneider, Maximillian W.G., Jensen, Liv E., Gamarra, Nathan, Henry, Lisa, Gerlich, Daniel W., Redding, Sy, Rosen, Michael K.
Format: Article
Language:English
Subjects:
Acetylation
Animals
BRD4
Cell Cycle Proteins - metabolism
Cell Nucleus - metabolism
Chromatin - metabolism
chromatin organization
E1A-Associated p300 Protein - metabolism
epigenetics
Escherichia coli - genetics
genome
HeLa Cells
histone
histone H1
Histones - metabolism
Humans
Nuclear Proteins - metabolism
nucleosome
nucleosome spacing
phase separation
Sf9 Cells
Transcription Factors - metabolism
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Summary:Eukaryotic chromatin is highly condensed but dynamically accessible to regulation and organized into subdomains. We demonstrate that reconstituted chromatin undergoes histone tail-driven liquid-liquid phase separation (LLPS) in physiologic salt and when microinjected into cell nuclei, producing dense and dynamic droplets. Linker histone H1 and internucleosome linker lengths shared across eukaryotes promote phase separation of chromatin, tune droplet properties, and coordinate to form condensates of consistent density in manners that parallel chromatin behavior in cells. Histone acetylation by p300 antagonizes chromatin phase separation, dissolving droplets in vitro and decreasing droplet formation in nuclei. In the presence of multi-bromodomain proteins, such as BRD4, highly acetylated chromatin forms a new phase-separated state with droplets of distinct physical properties, which can be immiscible with unmodified chromatin droplets, mimicking nuclear chromatin subdomains. Our data suggest a framework, based on intrinsic phase separation of the chromatin polymer, for understanding the organization and regulation of eukaryotic genomes. [Display omitted] •Chromatin undergoes liquid-liquid phase separation (LLPS) under physiologic conditions•Linker DNA length and patterning, histone H1, and acetylation modulate chromatin LLPS•Acetylated chromatin only phase separates upon binding multi-bromodomain proteins•LLPS could enable establishment and maintenance of distinct chromatin compartments Properties inherent to chromatin, including nucleosomal spacing, allow it to phase separate within the nucleoplasm, and this ability can be further modulated by regulatory factors.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2019.08.037