Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin

By A. Larson, D. Elnatan, Madeline M. Keenen, Michael J. Trnka, J. B. Johnston, Alma Burlingame, David A. Agard, S. Redding, G. Narlikar. Nature, 2017

1,508 citations recorded by the source corpus.

Gene silencing by heterochromatin is proposed to occur in part as a result of the ability of heterochromatin protein 1 (HP1) proteins to spread across large regions of the genome, compact the underlying chromatin and recruit diverse ligands. Here we identify a new property of the human HP1α protein: the ability to form phase-separated droplets. While unmodified HP1α is soluble, either phosphorylation of its N-terminal extension or DNA binding promotes the formation of phase-separated droplets. Phosphorylation-driven phase separation can be promoted or reversed by specific HP1α ligands. Known components of heterochromatin such as nucleosomes and DNA preferentially partition into the HP1α droplets, but molecules such as the transcription factor TFIIB show no preference. Using a single-molecule DNA curtain assay, we find that both unmodified and phosphorylated HP1α induce rapid compaction of DNA strands into puncta, although with different characteristics. We show by direct protein delivery into mammalian cells that an HP1α mutant incapable of phase separation in vitro forms smaller and fewer nuclear puncta than phosphorylated HP1α. These findings suggest that heterochromatin-mediated gene silencing may occur in part through sequestration of compacted chromatin in phase-separated HP1 droplets, which are dissolved or formed by specific ligands on the basis of nuclear context.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fae44f4d14b647f36c5bd1a0539939a6e35f9e4d

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Citations in the corpus

Coactivator condensation at super-enhancers links phase separation and gene control (2018, neutral): “Why do some proteins, such as HP1a, contribute to phase-separated heterochromatin condensates (59, 60) and others contribute to euchromatic condensates? The rules that govern partitioning into specific types of condensates have begun to be studied (61–65) andwill need to be defined for proteins invo”
Chromatin organization by an interplay of loop extrusion and compartmental segregation (2017, methodology): “Conversely, perturbations altering the nuclear volume or the compartmental interaction, e.g. by changing the epigenetic landscape or mediators of compartment interactions, possibly HP1 (44, 45), are expected to affect compartmentalization, while leaving TADs unaffected.”
Physical Principles Underlying the Complex Biology of Intracellular Phase Transitions (2020, background): “Finally, dimerization of HP1a/α plays a key role in forming a species with the requisite multivalence to undergo phase separation (84, 159).”
Competing protein-RNA interaction networks control multiphase intracellular organization (2020, positive): “Several studies suggest that dimerization of substrate-binding domains might be sufficient for assembly of certain condensates (Larson et al., 2017; Strom et al., 2017).”
Liquid-Liquid Phase Separation in Disease. (2019, background): “Phase separation is now thought to underlie many biological processes, including heterochromatin formation (93, 141); nucleocytoplasmic transport (136); and the formation of membraneless compartments, such as nucleoli (50, 107).”