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Cell. 2018 Nov 29;175(6):1481-1491.e13. doi: 10.1016/j.cell.2018.10.057.

Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome.

Author information

1
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA; Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul 08826, South Korea.
2
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
3
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
4
Department of Materials Science and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.
6
Princeton Center for Theoretical Science, Princeton University, Princeton, NJ 08544, USA.
7
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
8
Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ 08544, USA.
9
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Howard Hughes Medical Institute, Princeton University, Princeton, NJ 08544, USA. Electronic address: cbrangwy@princeton.edu.

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.

KEYWORDS:

chromatin; condensates; gene regulation; mechanobiology; nuclear mechanics; nuclear organization; optogenetics; phase immiscibility; phase separation

PMID:
30500535
PMCID:
PMC6724728
[Available on 2019-11-29]
DOI:
10.1016/j.cell.2018.10.057
[Indexed for MEDLINE]

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