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Open accessPosted ContentDOI: 10.1101/2021.03.02.433564

Chromatin Network Retards Droplet Coalescence

02 Mar 2021-bioRxiv (Cold Spring Harbor Laboratory)-
Abstract: Nuclear bodies are membraneless condensates that may form via liquid-liquid phase separation. The viscoelastic chromatin network could impact their stability and may hold the key for understanding experimental observations that defy predictions of classical theories. However, quantitative studies on the role of the chromatin network in phase separation have remained challenging. Using a diploid human genome model parameterized with chromosome conformation capture (Hi-C) data, we studied the thermodynamics and kinetics of droplet formation inside the nucleus. Dynamical simulations predicted the formation of multiple droplets for protein particles that experience specific interactions with nucleolus-associated domains (NADs). Coarsening dynamics, surface tension, and coalescence kinetics of the simulated droplets are all in quantitative agreements with experimental measurements for nucleoli. Free energy calculations further supported that a two-droplet state, which is often observed for nucleoli seen in somatic cells, is metastable and separated from the single-droplet state with an entropic barrier. Our study suggests that protein-chromatin interactions facilitate the nucleation of droplets, but hinders their coarsening due to the correlated motion between droplets and the chromatin network: as droplets coalesce, the chromatin network becomes increasingly constrained. Therefore, protein-chromatin interactions arrest phase separation in multi-droplet states and may drive the variation of nuclear body numbers across cell types.

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5 results found


Open accessJournal ArticleDOI: 10.1063/5.0044150
Abstract: Three-dimensional (3D) organization of the human genome plays an essential role in all DNA-templated processes, including gene transcription, gene regulation, and DNA replication. Computational modeling can be an effective way of building high-resolution genome structures and improving our understanding of these molecular processes. However, it faces significant challenges as the human genome consists of over 6 × 109 base pairs, a system size that exceeds the capacity of traditional modeling approaches. In this perspective, we review the progress that has been made in modeling the human genome. Coarse-grained models parameterized to reproduce experimental data via the maximum entropy optimization algorithm serve as effective means to study genome organization at various length scales. They have provided insight into the principles of whole-genome organization and enabled de novo predictions of chromosome structures from epigenetic modifications. Applications of these models at a near-atomistic resolution further revealed physicochemical interactions that drive the phase separation of disordered proteins and dictate chromatin stability in situ. We conclude with an outlook on the opportunities and challenges in studying chromosome dynamics.

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Topics: Genome (55%), Human genome (51%)

5 Citations


Open accessPosted ContentDOI: 10.1101/2021.11.16.468645
Sophia Liu1, Xingcheng Lin, Bo ZhangInstitutions (1)
18 Nov 2021-bioRxiv
Abstract: The arrangement of nucleosomes inside chromatin is of extensive interest. While in vitro experiments have revealed the formation of 30 nm fibers, most in vivo studies have failed to confirm their presence in cell nuclei. To reconcile the diverging experimental findings, we characterized chromatin organization using a near atomistic model. The computed force-extension curve matches well with measurements from single-molecule experiments. Notably, we found that a dodeca-nucleosome in the two-helix zigzag conformation breaks into structures with nucleosome clutches and a mix of trimers and tetramers under tension. Such unfolded configurations can also be stabilized through trans interactions with other chromatin chains. Our study supports a hypothesis that disordered, in vivo chromatin configurations arise as folding intermediates from regular fibril structures. We further revealed that chromatin segments with fibril or clutch structures engaged in distinct binding modes and discussed the implications of these inter-chain interactions for a potential sol-gel phase transition.

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Topics: Chromatin Fiber (69%), Chromatin (56%), Nucleosome (52%)

Open accessPosted ContentDOI: 10.1101/2021.10.04.463094
04 Oct 2021-bioRxiv
Abstract: The Polycomb group (PcG) complex PRC1 localizes in the nucleus in the form of condensed structures called Polycomb bodies. The PRC1 subunit Polyhomeotic (Ph) contains a polymerizing sterile alpha motif (SAM) that is implicated in both PcG body formation and chromatin organization in Drosophila and mammalian cells. A truncated version of Ph containing the SAM (mini-Ph), forms phase separated condensates with DNA or chromatin in vitro, suggesting PcG bodies may form by phase separation. In cells, Ph forms multiple condensates, while mini-Ph forms a single large nuclear condensate. We therefore hypothesize that sequences outside of mini-Ph are required for proper condensate formation. We identified three distinct Intrinsically Disordered Regions (IDRs) in Ph based on sequence composition and complexity. We tested the role of each IDR in Ph condensates using live imaging of transfected Drosophila S2 cells. We find that each IDR uniquely affects Ph SAM-dependent condensate size, number, and morphology.

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Topics: Polyhomeotic (65%), Sterile alpha motif (51%), Chromatin (51%)

Open accessPosted ContentDOI: 10.1101/2021.11.12.468401
Kartik Kamat1, Yifeng Qi1, Yuchuan Wang2, Jian Ma2  +1 moreInstitutions (2)
13 Nov 2021-bioRxiv
Abstract: 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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Topics: Nuclear lamina (55%), Chromosome Positioning (55%), Genome (54%) ... read more

Open accessPosted ContentDOI: 10.1101/2021.08.22.457249
Andrew P. Latham1, Bin Zhang1Institutions (1)
23 Aug 2021-bioRxiv
Abstract: Multi-component phase separation is emerging as a key mechanism for the formation of biological condensates that play essential roles in signal sensing and transcriptional regulation. The molecular factors that dictate these condensates9 stability and spatial organization are not fully understood, and it remains challenging to predict their microstructures. Using a near-atomistic, chemically accurate force field, we studied the phase behavior of chromatin regulators that are crucial for heterochromatin organization and their interactions with DNA. Our computed phase diagrams recapitulated previous experimental findings on different proteins. They revealed a strong dependence of condensate stability on the protein-DNA mixing ratio as a result of balancing protein-protein interactions and charge neutralization. Notably, a layered organization was observed in condensates formed by mixing HP1, histone H1, and DNA. This layered organization may be of biological relevance as it enables cooperative DNA packaging between the two chromatin regulators: histone H1 softens the DNA to facilitate the compaction induced by HP1 droplets. Our study supports near atomistic models as a valuable tool for characterizing the structure and stability of biological condensates.

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Topics: Heterochromatin organization (61%), Chromatin (54%)
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72 results found


Open accessJournal ArticleDOI: 10.1006/JCPH.1995.1039
Steven J. Plimpton1Institutions (1)
Abstract: Three parallel algorithms for classical molecular dynamics are presented. The first assigns each processor a fixed subset of atoms; the second assigns each a fixed subset of inter-atomic forces to compute; the third assigns each a fixed spatial region. The algorithms are suitable for molecular dynamics models which can be difficult to parallelize efficiently—those with short-range forces where the neighbors of each atom change rapidly. They can be implemented on any distributed-memory parallel machine which allows for message-passing of data between independently executing processors. The algorithms are tested on a standard Lennard-Jones benchmark problem for system sizes ranging from 500 to 100,000,000 atoms on several parallel supercomputers--the nCUBE 2, Intel iPSC/860 and Paragon, and Cray T3D. Comparing the results to the fastest reported vectorized Cray Y-MP and C90 algorithm shows that the current generation of parallel machines is competitive with conventional vector supercomputers even for small problems. For large problems, the spatial algorithm achieves parallel efficiencies of 90% and a 1840-node Intel Paragon performs up to 165 faster than a single Cray C9O processor. Trade-offs between the three algorithms and guidelines for adapting them to more complex molecular dynamics simulations are also discussed.

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Topics: Intel Paragon (64%), Intel iPSC (62%), Parallel algorithm (58%) ... read more

26,738 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.1181369
09 Oct 2009-Science
Abstract: We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.

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Topics: Chromosome conformation capture (56%), Chromatin Loop (52%), Genome (51%) ... read more

5,852 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2014.11.021
18 Dec 2014-Cell
Abstract: We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs "facing" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats.

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Topics: CTCF (55%), Chromatin Loop (53%), Chromosome conformation capture (51%) ... read more

4,386 Citations


Journal ArticleDOI: 10.1016/S0009-2614(99)01123-9
Yuji Sugita, Yuko Okamoto1Institutions (1)
Abstract: We have developed a formulation for molecular dynamics algorithm for the replica-exchange method. The effectiveness of the method for the protein-folding problem is tested with the penta-peptide Met-enkephalin. The method can overcome the multiple-minima problem by exchanging non-interacting replicas of the system at several temperatures. From only one simulation run, one can obtain probability distributions in canonical ensemble for a wide temperature range using multiple-histogram reweighting techniques, which allows the calculation of any thermodynamic quantity as a function of temperature in that range.

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Topics: Canonical ensemble (56%), Microcanonical ensemble (56%), Local Elevation (52%) ... read more

3,804 Citations


Journal ArticleDOI: 10.1038/35066075
Abstract: The expression of genes is regulated at many levels. Perhaps the area in which least is known is how nuclear organization influences gene expression. Studies of higher-order chromatin arrangements and their dynamic interactions with other nuclear components have been boosted by recent technical advances. The emerging view is that chromosomes are compartmentalized into discrete territories. The location of a gene within a chromosome territory seems to influence its access to the machinery responsible for specific nuclear functions, such as transcription and splicing. This view is consistent with a topological model for gene regulation.

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Topics: Chromosome Territory (61%), Regulation of gene expression (57%), Nuclear gene (57%) ... read more

1,988 Citations


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