Surface Fluctuations and Coalescence of Nucleolar Droplets in the Human Cell Nucleus

Caragine, Christina M.; Haley, Shannon; Zidovska, Alexandra

doi:10.1103/physrevlett.121.148101

Cited by 129 publications

(138 citation statements)

References 30 publications

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“…3). These experiments are performed in room-temperature water with viscosity ∼ 10 −3 Pa · s; cellular interiors are 10 5 − 10 6 × more viscous [32,40], sufficiently suppressing the diffusivity of typical cellular cargo such that we would predict increased motor precision. A comparison of step-number Fano factor between a cargo-less motor and an identical motor with low-diffusivity cargo, both in high-viscosity conditions, would distinguish intrinsic motor behavior from the cargo-induced Fano factor decrease our work predicts, but we are unaware of any existing studies with such data.…”

Section: Discussionmentioning

confidence: 99%

Pulling cargo increases the precision of molecular motor progress

Brown

Sivak

2019

EPL

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Biomolecular motors use free energy to drive a variety of cellular tasks, including the transport of cargo, such as vesicles and organelles. We find that the widely-used 'constant-force' approximation for the effect of cargo on motor dynamics leads to a much larger variance of motor step number compared to explicitly modeling diffusive cargo, suggesting the constant-force approximation may be misapplied in some cases. We also find that, with cargo, motor progress is significantly more precise than suggested by a recent result. For cargo with a low relative diffusivity, the dynamics of continuous cargo motion-rather than discrete motor steps-dominate, leading to a new, more permissive bound on the precision of motor progress which is independent of the number of stages per motor cycle.

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Section: Discussionmentioning

confidence: 99%

Pulling cargo increases the precision of molecular motor progress

Brown

Sivak

2019

EPL

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“…[73][74][75] Water has a viscosity of 10 −3 Pa · s, while viscosity measurements inside the cell reach as high as 10 3 Pa · s, a million-fold higher. 76 This higher intracellular viscosity is due to macromolecular crowding, i.e. the high concentrations of macromolecules which occupy 10-40% of the cell volume.…”

Section: Case Studiesmentioning

confidence: 99%

Theory of Nonequilibrium Free Energy Transduction by Molecular Machines

2019

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Biomolecular machines are protein complexes that convert between different forms of free energy. They are utilized in nature to accomplish many cellular tasks. As isothermal nonequilibrium stochastic objects at low Reynolds number, they face a distinct set of challenges compared to more familiar human-engineered macroscopic machines. Here we review central questions in their performance as free energy transducers, outline theoretical and modeling approaches to understand these questions, identify both physical limits on their operational characteristics and design principles for improving performance, and discuss emerging areas of research.

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“…3A,B). Finally, the comparison with experiments probing in vivo nucleoplasm (65) shows that liquid state model of chromatin in MELON framework accurately capture the nuclear coalescence profiles as well as surface profiles and sequence of steps on time-lapse nuclear domain coalescence events (Fig. 3B,C).…”

mentioning

confidence: 77%

“…In this section, we study the roles of heterochromatin droplet diffusion, fluctuations and nuclear heterochromatin fraction on the kinetics of phase separation in the idealized nucleus during interphase and senescent phases. The setup of the first set of simulation is mimicking the rapid liquid-like nucleo-protein droplet fusion events during interphase the dynamics of which have been observed and quantified in multiple recent experiments (31,32,65). It is acknowledged that within In vivo nucleoplasm environment, heterochromatin droplets display shape and size fluctuations as a result of thermal fluctuations and active, ATP-driven motor activity (66).…”

Section: Impact Of Diffusion Fluctuations and Heterochromatin Contenmentioning

confidence: 99%

Mesoscale liquid model of chromatin recapitulates nuclear order of eukaryotes

Laghmach

Pierro

Potoyan

2019

Preprint

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The nuclear envelope segregates the genome of Eukaryota from the cytoplasm. Within the nucleus, chromatin is further compartmentalized into architectures that change throughout the lifetime of the cell. Epigenetic patterns along the chromatin polymer strongly correlate with chromatin compartmentalization and, accordingly, also change during the cell life cycle and at differentiation. Recently, it has been suggested that sub-nuclear chromatin compartmentalization might result from a process of liquid-liquid phase separation orchestrated by the epigenetic marking and operated by proteins that bind to chromatin. Here, we translate these observations into a diffuse interface model of chromatin, which we named MEsoscale Liquid mOdel of Nucleus (MELON). Using this streamlined continuum model of the genome, we study the large-scale rearrangements of chromatin that happen at different stages of the growth and senescence of the cell, and during nuclear inversion events. Particularly, we investigate the role of droplet diffusion, fluctuations, and heterochromatin-lamina interactions during nuclear remodeling. Our results indicate that the physical process of liquid-liquid phase separation, together with surface effects is sufficient to recapitulate much of the large-scale morphology and dynamics of chromatin along the life cycle of cells. SIGNIFICANCE STATEMENTEukaryotic chromatin occupies a few micrometers of nuclear space while remaining dynamic and accessible for gene regulation. The physical state of nuclear chromatin is shaped by the juxtaposition of complex, out of equilibrium processes on one hand and intrinsic polymeric aspect of the genome on the other. Recent experiments have revealed a remarkable ability of disordered nuclear proteins to drive liquid-liquid phase separation of chromatin domains. We have built a mesoscale liquid model of nuclear chromatin which allows dissecting the contribution of liquid behavior of chromatin to nuclear order of eukaryotes. Our results show that liquid-liquid phase separation, together with surface effects is sufficient for recapitulating large-scale morphology and dynamics of chromatin at many stages of the nuclear cycle. Laghmach et alClear evidence of hierarchical compartmentalization in chromatin at multiple scales has emerged through studies employing DNA-DNA proximity ligation assays. First, two genomic compartments were observed (3), named A and B, which were then refined through higher resolution experiments to reveal the existence of even smaller sub-compartments (10). The A and B compartments appear to be enriched in epigenetic markings correlating with transcriptional activation and silencing respectively. Several studies have suggested that chromatin compartmentalization may result from a process of liquid-liquid phase separation orchestrated by the epigenetic markings which collectively act to remodel chromosomal loci (15)(16)(17)(18)(19). The epigenetically driven phase segregation events have shown to emerge right at the nucleosome resolution mediated by protein b...

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Surface Fluctuations and Coalescence of Nucleolar Droplets in the Human Cell Nucleus

Cited by 129 publications

References 30 publications

Pulling cargo increases the precision of molecular motor progress

Pulling cargo increases the precision of molecular motor progress

Theory of Nonequilibrium Free Energy Transduction by Molecular Machines

Mesoscale liquid model of chromatin recapitulates nuclear order of eukaryotes

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