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Cited by 676Genomics and Chromatin DynamicsRNA Research and SplicingNuclear Structure and Function

Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome

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Shin, Yongdae, Chang, Yi-Che, Lee, Daniel S.W., Berry, Joel, Sanders, David W., Ronceray, Pierre, Wingreen, Ned S., Haataja, Mikko +1 more·2018·Cell
DOI 10.1016/j.cell.2018.10.057PMC PMC6724728
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Abstract

Phase transitions involving biomolecular liquids are a fundamental mechanism underlying intracellular organization. In the cell nucleus, liquid-liquid phase separation of intrinsically disordered proteins (IDPs) is implicated in assembly of the nucleolus, as well as transcriptional clusters, and other nuclear bodies. However, it remains unclear whether and how physical forces associated with nucleation, growth, and wetting of liquid condensates can directly restructure chromatin. Here, we use CasDrop, a novel CRISPR-Cas9-based optogenetic technology, to show that various IDPs phase separate into liquid condensates that mechanically exclude chromatin as they grow and preferentially form in low-density, largely euchromatic regions. A minimal physical model explains how this stiffness sensitivity arises from lower mechanical energy associated with deforming softer genomic regions. Targeted genomic loci can nonetheless be mechanically pulled together through surface tension-driven coalescence. Nuclear condensates may thus function as mechano-active chromatin filters, physically pulling in targeted genomic loci while pushing out non-targeted regions of the neighboring genome. VIDEO ABSTRACT.

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  • The solution reaches supersaturation more rapidly, facilitating widespread nucleation of multiple nuclei that then grow limited by diffusion, rather than growth of some seeding droplets, and the measured growth rate is lower.

    “The solution reaches supersaturation more rapidly, which facilitates widespread nucleation of multiple nuclei that then grow limited by diffusion, rather than growth of some seeding droplets, and the measured growth rate is lower34.”

    From Active coacervate droplets are protocells that grow and resist Ostwald ripening (2021) · cites this paper as [34]

    The Results section on pre-seeding and activation reports that rapid blue-light activation quickly produces deep supersaturation and widespread nucleation, whereas gradual activation favors growth at seeded sites. The STAR Methods describe diffusion-limited droplet growth in the simulations. Neither passage reports a measured lower growth rate for the rapidly activated droplets. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The fuel-driven active droplet grows by diffusion, in a classical nucleation-growth fashion, but the rate is determined by the ATP-forming reaction.

    “Based on individual droplet traces, we found that our fuel-driven active droplet grows by diffusion, in a classical nucleation-growth fashion34, but that the rate is determined by the ATP-forming reaction.”

    From Active coacervate droplets are protocells that grow and resist Ostwald ripening (2021) · cites this paper as [34]

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Authors
Shin, Y., Chang, Y.-C., Lee, D. S. W., Berry, J., Sanders, D. W., Ronceray, P., Wingreen, N. S., Haataja, M., & Brangwynne, C. P.
Affiliations
  • Seoul National University (KR)
  • Princeton University (US)
  • University of Pennsylvania (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Brangwynne, Clifford P.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2018-11
Volume
175
Issue
6
Pages
1481-1491.e13
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2018.10.057
PMC
PMC6724728
OpenAlex
W2903264039
Cited by
676
References
4
Citations by year
2026: 59 · 2025: 73 · 2024: 82 · 2023: 68 · 2022: 98 · 2021: 123 · 2020: 97 · 2019: 71 · 2018: 3
FWCI
26.02
Type
journal article
Language
en
Update notices
erratum (2019-03-07)
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • NIH 4D Nucleome Program (U01 DA040601)
  • DARPA (HR0011-17-2-0010)
  • Princeton Center for Complex Materials
  • NSF (PHY-1607612)
  • MRSEC (DMR 1420541)
  • NSF CAREER award (1253035)
  • NSF Graduate Research Fellowship Program (DCE-1656466)
  • Research Resettlement Fund
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
liquid-liquid phase separation, nuclear condensates, intrinsically disordered proteins, nuclear mechanics, chromatin stiffness, euchromatin, nucleolus, transcriptional clusters, nuclear bodies, mechanotransduction
MeSH terms
Animals, Cell Nucleolus, Chromatin, Cytoplasm, Female, Humans, Male, Genome, Human, NIH 3T3 Cells, Phase Transition, Cell Line, Tumor, Mice, HEK293 Cells, Intrinsically Disordered Proteins

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