Generation of dynamic three-dimensional genome structure through phase separation of chromatin

Fujishiro, Shin; Sasai, Masaki

doi:10.1101/2021.05.06.443035

Cited by 6 publications

(2 citation statements)

References 69 publications

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“…S1, rather than a lack of parameter fine tuning. Indeed, as recognized in previous studies, explicit interactions with nuclear lamina, 19,32,65,66 separate treatment of intra- and inter-chromosome interactions, 17 or assuming repulsive interactions between the compartments, 18 might be necessary to position B compartments towards the nuclear envelope.…”

Section: Resultsmentioning

confidence: 77%

Phase Separation and Correlated Motions in Motorized Genome

Jiang

Kamat

et al. 2022

Preprint

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The human genome is arranged in the cell nucleus non-randomly, and phase separation has been proposed as an important driving force for genome organization. However, the cell nucleus is an active system, and the contribution of non-equilibrium activities to phase separation and genome structure and dynamics remains to be explored. We simulated the genome using an energy function parameterized with chromosome conformation capture (Hi-C) data with the presence of active, nondirectional forces that break the detailed balance. We found that active forces that may arise from transcription and chromatin remodeling can dramatically impact the spatial localization of heterochromatin. When applied to euchromatin, active forces can drive heterochromatin to the nuclear envelope and compete with passive interactions among heterochromatin that tend to pull them in opposite directions. Furthermore, active forces induce long-range spatial correlations among genomic loci beyond single chromosome territories. We further showed that the impact of active forces could be understood from the effective temperature defined as the fluctuation-dissipation ratio. Our study suggests that non-equilibrium activities can significantly impact genome structure and dynamics, producing unexpected collective phenomena.

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Section: Resultsmentioning

confidence: 77%

Phase Separation and Correlated Motions in Motorized Genome

Jiang

Kamat

et al. 2022

Preprint

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“…The expansion of effective chromatin regions increases the volume fraction of chromosomes in the nucleus. Additionally, elements with different physical characteristics such as volume, shape, and rigidity tend to segregate with each other in space under crowded situations by various elements, which may be explained by the entropy effects and a similar mechanism to the depletion force [28][29][30][31][32][33][34][35] (note that the excluded volumes of rigid particles were effectively larger than those of soft particles even if the volumes of particles were uniform). Here, the chromatin regions containing DSB-induced damaged loci were expected to be more rigid than other regions due to the accumulation of DNA-binding repair-related proteins; these regions were implemented by rigid particles in the present model.…”

Section: Discussionmentioning

confidence: 99%

Mathematical model of chromosomal dynamics during DNA double strand break repair in budding yeast

Nakahata

Fujii

Awazu

2022

Preprint

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During the repair of double-strand breaks (DSBs) in DNA, active mobilizations for conformational changes in chromosomes have been widely observed in eukaryotes, from yeast to animal and plant cells. DSB-damaged loci in the yeast genome showed increased mobility and relocation to the nuclear periphery. However, the driving forces behind DSB-induced chromatin dynamics remain unclear. In this study, mathematical models of normal and DSB-damaged yeast chromosomes were developed to simulate their structural dynamics. The effects of histone degradation in the whole nucleus and the change in the physical properties of damaged loci due to the binding of SUMOylated repair proteins were considered in the model of DSB-induced chromosomes based on recent experimental results. The simulation results reproduced DSB-induced changes to structural and dynamical features by which the combination of whole nuclear histone degradation and the rigid structure formation of repair protein accumulations on damaged loci were suggested to be primary contributors to the process by which damaged loci are relocated to the nuclear periphery.

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Genome Compartmentalization with Nuclear Landmarks: Random yet Precise

Kamat

Wang

et al. 2021

Preprint

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The three-dimensional (3D) organization of eukaryotic genomes plays an important role in genome function. While significant progress has been made in deciphering the folding mechanisms of individual chromosomes, the principles of the dynamic large-scale spatial arrangement of all chromosomes inside the nucleus are poorly understood. We use polymer simulations to model the diploid human genome compartmentalization relative to nuclear bodies such as nuclear lamina, nucleoli, and speckles. We show that a self-organization process based on a co-phase separation between chromosomes and nuclear bodies can capture various features of genome organization, including the formation of chromosome territories, phase separation of A/B compartments, and the liquid property of nuclear bodies. The simulated 3D structures quantitatively reproduce both sequencing-based genomic mapping and imaging assays that probe chromatin interaction with nuclear bodies. Importantly, our model captures the heterogeneous distribution of chromosome positioning across cells, while simultaneously producing well-defined distances between active chromatin and nuclear speckles. Such heterogeneity and preciseness of genome organization can coexist due to the non-specificity of phase separation and the slow chromosome dynamics. Together, our work reveals that the co-phase separation provides a robust mechanism for encoding functionally important 3D contacts without requiring thermodynamic equilibration that can be difficult to achieve.

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Generation of dynamic three-dimensional genome structure through phase separation of chromatin

Cited by 6 publications

References 69 publications

Phase Separation and Correlated Motions in Motorized Genome

Phase Separation and Correlated Motions in Motorized Genome

Mathematical model of chromosomal dynamics during DNA double strand break repair in budding yeast

Genome Compartmentalization with Nuclear Landmarks: Random yet Precise

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