Compartmentalization with nuclear landmarks yields random, yet precise, genome organization

Kamat, Kartik; Lao, Zhuohan; Qi, Yifeng; Wang, Yuchuan; Ma, Jian; Zhang, Bin

doi:10.1016/j.bpj.2023.03.003

Cited by 21 publications

(6 citation statements)

References 107 publications

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“…Computer modeling shows that to approach the experimentally observed parameters of chromosomal territories, the size of the loops must be comparable to the sizes of topologically associated domains (TADs) [97]. The organization of the cell nucleus can be modeled quite well by adding contacts of active chromosome regions with speckles and inactive ones -with nuclear lamina [98].…”

Section: The Role Of Physicochemical Processes In the Formation Of A ...mentioning

confidence: 99%

The role of physicochemical processes in the formation of the 3D genome and compartmentalization of the cell nucleus

Razin

2024

Postepy Biochem

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The review analyzes the role of physicochemical processes in the formation of the function-dependent architecture of the cell nucleus, built on the platform of a folded genome. The main attention is paid to various forms of the phase separation process, primarily the processes of liquid-liquid phase separation and polymer-polymer phase separation. The role of these processes in the formation of chromatin compartments and maintenance of three-dimensional genome architecture is discussed in detail. The relationship between genome activity and the creation of functional compartments in the cell nucleus is also analyzed.

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Section: The Role Of Physicochemical Processes In the Formation Of A ...mentioning

confidence: 99%

The role of physicochemical processes in the formation of the 3D genome and compartmentalization of the cell nucleus

Razin

2024

Postepy Biochem

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“…We present an open-source implementation of a computational framework that facilitates the structural and dynamical characterization of the human nucleus. This framework builds upon a previous investigation 64 but incorporates several significant modifications. Firstly, we enhance the model resolution by a factor of ten, enabling the precise determination of the spatial positioning of each chromatin segment measuring 100 KB in length.…”

Section: Non-equilibrium Nucleus Model At 100 Kb Resolutionmentioning

confidence: 99%

“…These simulation techniques aid in reconstructing structural ensembles that closely replicate experimental data, offering valuable insights into the mechanisms underlying chromosome folding. In recent studies, these approaches have also been employed to investigate the interplay between the genome and the nuclear lamina, [64][65][66][67] as well as nucleoli, 68 shedding light on their dynamic relationships.…”

Section: Introductionmentioning

confidence: 99%

OpenNucleome for high resolution nuclear structural and dynamical modeling

Lao,

Kamat,

Jiang

et al. 2023

Preprint

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The intricate structural organization of the human nucleus is fundamental to cellular function and gene regulation. Recent advancements in experimental techniques, including high-throughput sequencing and microscopy, have provided valuable insights into nuclear organization. Computational modeling has played significant roles in interpreting experimental observations by reconstructing high-resolution structural ensembles and uncovering organization principles. However, the absence of standardized modeling tools poses challenges for furthering nuclear investigations. We present OpenNucleome---an open-source software designed for conducting GPU-accelerated molecular dynamics simulations of the human nucleus. OpenNucleome offers particle-based representations of chromosomes at a resolution of 100 KB, encompassing nuclear lamina, nucleoli, and speckles. This software furnishes highly accurate structural models of nuclear architecture, affording the means for dynamic simulations of condensate formation, fusion, and exploration of non-equilibrium effects. We applied OpenNucleome to uncover the mechanisms driving the emergence of 'fixed points' within the nucleus signifying genomic loci robustly anchored in proximity to specific nuclear bodies for functional purposes. This anchoring remains resilient even amidst significant fluctuations in chromosome radial positions and nuclear shapes within individual cells. Our findings lend support to a nuclear zoning model that elucidates genome functionality. We anticipate OpenNucleome to serve as a valuable tool for nuclear investigations, streamlining mechanistic explorations and enhancing the interpretation of experimental observations.

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“…Protein molecules that recognize specific histone modifications have frequently been found to undergo liquid-liquid phase separation ( Larson et al, 2017 ; Kent et al, 2020 ; Xie et al, 2022 ; Leicher et al, 2022 ; Latham and Zhang, 2021 ; Lin et al, 2021a ; MacPherson et al, 2018 ), potentially contributing to chromatin demixing. Demixing can also arise from interactions between chromatin and various nuclear landmarks such as nuclear lamina and speckles ( Brahmachari et al, 2022 ; Falk et al, 2019 ; Mirny and Dekker, 2022 ; Kamat et al, 2023 ), as well as active transcriptional processes ( Hilbert et al, 2021 ; Jiang et al, 2022 ; Brahmachari et al, 2023 ; Goychuk et al, 2023 ). Furthermore, recent studies have revealed that nucleosome arrays alone can undergo spontaneous phase separation ( Gibson et al, 2019 ; Strickfaden et al, 2020 ; Zhang et al, 2022 ), indicating that compartmentalization may be an intrinsic property of chromatin driven by nucleosome-nucleosome interactions.…”

Section: Introductionmentioning

confidence: 99%

Explicit ion modeling predicts physicochemical interactions for chromatin organization

Lin,

Zhang

2024

eLife

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Molecular mechanisms that dictate chromatin organization in vivo are under active investigation, and the extent to which intrinsic interactions contribute to this process remains debatable. A central quantity for evaluating their contribution is the strength of nucleosome-nucleosome binding, which previous experiments have estimated to range from 2 to 14 kBT . We introduce an explicit ion model to dramatically enhance the accuracy of residue-level coarse-grained modeling approaches across a wide range of ionic concentrations. This model allows for de novo predictions of chromatin organization and remains computationally efficient, enabling large-scale conformational sampling for free energy calculations. It reproduces the energetics of protein-DNA binding and unwinding of single nucleosomal DNA, and resolves the differential impact of mono and divalent ions on chromatin conformations. Moreover, we showed that the model can reconcile various experiments on quantifying nucleosomal interactions, providing an explanation for the large discrepancy between existing estimations. We predict the interaction strength at physiological conditions to be 9 kBT , a value that is nonetheless sensitive to DNA linker length and the presence of linker histones. Our study strongly supports the contribution of physicochemical interactions to the phase behavior of chromatin aggregates and chromatin organization inside the nucleus.

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Compartmentalization with nuclear landmarks yields random, yet precise, genome organization

Cited by 21 publications

References 107 publications

The role of physicochemical processes in the formation of the 3D genome and compartmentalization of the cell nucleus

The role of physicochemical processes in the formation of the 3D genome and compartmentalization of the cell nucleus

OpenNucleome for high resolution nuclear structural and dynamical modeling

Explicit ion modeling predicts physicochemical interactions for chromatin organization

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