Structural reorganization and relaxation dynamics of axially stressed chromosomes

Ruben, Benjamin S; Brahmachari, Sumitabha; Contessoto, Vinícius G.; Cheng, Ryan R.; Oliveira, Antonio B.; Pierro, Michele Di; Onuchic, José N.

doi:10.1016/j.bpj.2023.03.029

Cited by 2 publications

(6 citation statements)

References 48 publications

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“…Recent work has proposed a viscoelastic model of chromosomes and their mechanical properties during interphase and mitosis. 29,31 This work used next-generation sequencing techniques and mathematic simulations to characterize the folding and structural conformations of individual chromosomes. Simulations generated force-extension curves demonstrating that mitotic chromosomes behave about 10-fold stiffer than interphase chromosomes.…”

Section: Resultsmentioning

confidence: 99%

“…Simulations generated force-extension curves demonstrating that mitotic chromosomes behave about 10-fold stiffer than interphase chromosomes. 29 We followed the results of this study to generate a representative Kelvin-Voigt model of viscoelasticity in MATLAB for evaluating the extension of each type of chromatin during cyclic sine and brachial mechanical loading. 32 We observed that, within the 10 cycles of 0.1 Hz simulated mechanical loading, interphase chromosomes reached oscillatory steady-state behavior in approximately 50 seconds ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that chromosomes mechanically unravel when extension reaches roughly double its native length, with damage occurring at approximately three times its native length. 29 Thus, strains around two-fold the initial length could be ideal for mechanically inducing strain We assumed that after reaching oscillatory steady state the cell adapts to only experience the strains applied each cycle and plotted the strain for each cycle under the various conditions ( Fig. 9E, F ).…”

Section: Resultsmentioning

confidence: 99%

“…Other recent work has used worm-like-chain models of DNA and computational tools to investigate the deformation of chromatin under mechanical forces and the resultant changes in histone binding complexes and chromosome-wide reorganization. 17,29 These works provided an excellent reference point for this study, enabling a deeper analysis into how different amplitudes and patterns of forces may result in altered nuclear re-organization. In this regard, our work provides a framework for understanding how applied dynamic mechanical strains to cells on flexible substrates is transferred to the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…28 Following previously described methods, we calculated E = 3.82 Pa and η = 68.81 N•s/m for interphase chromosomes, and E = 611.63 Pa and η = 733.95 N•s/m for mitotic chromosomes. 29 To calculate the input stress, we assumed perfect coupling and applied the elastic modulus of the nucleus in our model, 2010 Pa, the simulated average X strain in the nucleus values in Pa, to solve σ = ε *E for each waveform condition across 10 cycles of simulated loading. The model also assumes that all input stress is delivered directly to a chromosome in interphase or mitosis.…”

Section: Methodsmentioning

confidence: 99%

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A Computational Model of Mechanical Stretching of Cultured Cells on a Flexible Membrane

Massidda,

Ashirov,

Demkov

et al. 2024

Preprint

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Mechanical forces applied to cells are known to regulate a wide variety of biological processes. Recent studies have supported that mechanical forces can cause nuclear deformation, leading to significant alterations in the gene expression and chromatin landscape of the cell. While the stresses and strains applied to cells is it is often known or controlled experimentally on a macroscopic length scale, it is often unclear what the actual forces and displacements are at the microscopic level of the cell. In this work, we created a model of cell deformation during application of mechanical stretch to cultured cells growth on a flexible membrane. This configuration is commonly used is in experimental studies as a means to apply controlled mechanical strains to adherent cultured cells. The parameters used in the study were used for application of strain to a mesenchymal stem cell stretched on a membrane. computational model was created to simulate the stresses and strains within the cell under a variety of stain amplitudes, waveforms and frequencies of mechanical loading with the range of commonly used experimental systems. The results demonstrate the connection between mechanical loading parameters applied through the flexible membrane and the resulting stresses and strains within the cell and nucleus. Using a viscoelastic model of chromatin, we connected the results provide to a rough model of resulting deformation within chromatin from the forces applied to the nucleus. Overall, the model is useful in providing insight between experimentally applied mechanical forces and the actual forces within the cell to better interpret the results of experimental studies.Statement of SignificanceIn this work, we created a computational model of the mechanical stretching of cell on a flexible membrane under cyclic mechanical loading. This model provides insight into the forces and displacements inside of cell that result from that application of stretch. As many experiments use this set up, our work is relevant to interpreting many studies that use mechanical stretch to stimulate mechanotransduction.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

A Computational Model of Mechanical Stretching of Cultured Cells on a Flexible Membrane

Massidda,

Ashirov,

Demkov

et al. 2024

Preprint

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Bridging condensins mediate compaction of mitotic chromosomes

Forte,

Boteva,

Conforto

et al. 2023

Journal of Cell Biology

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Eukaryotic chromosomes compact during mitosis into elongated cylinders—and not the spherical globules expected of self-attracting long flexible polymers. This process is mainly driven by condensin-like proteins. Here, we present Brownian-dynamic simulations involving two types of such proteins with different activities. One, which we refer to as looping condensins, anchors long-lived chromatin loops to create bottlebrush structures. The second, referred to as bridging condensins, forms multivalent bridges between distant parts of these loops. We show that binding of bridging condensins leads to the formation of shorter and stiffer mitotic-like cylinders without requiring any additional energy input. These cylinders have several features matching experimental observations. For instance, the axial condensin backbone breaks up into clusters as found by microscopy, and cylinder elasticity qualitatively matches that seen in chromosome pulling experiments. Additionally, simulating global condensin depletion or local faulty condensin loading gives phenotypes seen experimentally and points to a mechanistic basis for the structure of common fragile sites in mitotic chromosomes.

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Structural reorganization and relaxation dynamics of axially stressed chromosomes

Cited by 2 publications

References 48 publications

A Computational Model of Mechanical Stretching of Cultured Cells on a Flexible Membrane

A Computational Model of Mechanical Stretching of Cultured Cells on a Flexible Membrane

Bridging condensins mediate compaction of mitotic chromosomes

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