1.
Mechanical Frustration of Phase Separation in the Cell Nucleus by Chromatin.
Abstract:
Liquid-liquid phase separation is a fundamental mechanism underlying subcellular organization. Motivated by the striking observation that optogenetically generated droplets in the nucleus display suppressed coarsening dynamics, we study the impact of chromatin mechanics on droplet phase separation. We combine theory and simulation to show that cross-linked chromatin can mechanically suppress droplets' coalescence and ripening, as well as quantitatively control their number, size, and placement. Our results highlight the role of the subcellular mechanical environment on condensate regulation.
2.
Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome.
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 mechanoactive
chromatin filters, physically pulling in targeted
genomic loci while pushing out non-targeted regions
of the neighboring genome.
