Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation

Stephens, Andrew D.; Liu, Patrick Z.; Kandula, Viswajit; Chen, Haimei; Almassalha, Luay M.; Herman, Cameron; Backman, Vadim; O’Halloran, Thomas V.; Adam, Stephen A.; Goldman, Robert D.; Banigan, Edward J.; Marko, John F.

doi:10.1091/mbc.e19-05-0286

Cited by 86 publications

(121 citation statements)

References 66 publications

(93 reference statements)

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“…Increased amounts of heterochromatin lead to increased elastic stiffness [32]: if the heterochromatic B regions were liquid, there would be no change in elasticity. Experiments demonstrating that the nuclear envelope is stabilized (destabilized) against spontaneous rupture by increased (decreased) heterochromatinization further support this conclusion [33].…”

Section: Liquid Versus Solid Versus Something In Betweenmentioning

confidence: 80%

Physics and Biology (of Chromosomes)

Marko

2020

Journal of Molecular Biology

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Advances in molecular biology, optics, genetics and bioinformatics have opened the door to mapping, in molecular detail, processes inside living cells. With the ability to observe the individual moving parts of cellular machinery, concepts formerly confined to physics are entering mainstream biology. This article discusses a few ideas of this sort related to chromosome biology, to illustrate what kinds of insights physics might yet bring to our understanding of living systems.

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Section: Liquid Versus Solid Versus Something In Betweenmentioning

confidence: 80%

Physics and Biology (of Chromosomes)

Marko

2020

Journal of Molecular Biology

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“…Our results demonstrate the dynamical equivalence between the diffusing behavior of the chromatin granules tracked in both isolated and in situ nuclei; although MPT-SURF analysis determined that osmotic stress in living cells promoted smaller mechanical changes than in isolated nuclei. Probably, this is due to regulation mechanisms in the whole cell, through mechanosensitive ion channels able to regulate the nuclear compaction and heterochromatin formation due to changes in the composition of the extracellular medium 41 . Also, we cannot discard the contribution of the cytoskeleton in living cells, which is a major actor in nuclear deformation and strain recovery 56 .…”

Section: Discussionmentioning

confidence: 99%

“…3a). To address whether these osmotic effects on intact cells might promote in situ nuclear changes detected by MPT-SURF, we cultured Jurkat cells in high (Mg 2+ ) or low (EDTA) levels of divalent cations, which have been reported to increase heterochromatin levels in breast cancer cells 41 . Firstly, we demonstrated that www.nature.com/scientificreports www.nature.com/scientificreports/ Mg 2+ addition did not alter the nuclear area of Jurkat cells, whilst EDTA treatment significantly increased it (Fig.…”

Section: Chromatin Mobility By Multiple Particle Tracking Enhanced Upmentioning

confidence: 99%

Multiple particle tracking analysis in isolated nuclei reveals the mechanical phenotype of leukemia cells

Herráez-Aguilar

Madrazo

López-Menéndez

et al. 2020

Sci Rep

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The nucleus is fundamentally composed by lamina and nuclear membranes that enclose the chromatin, nucleoskeletal components and suspending nucleoplasm. the functional connections of this network integrate external stimuli into cell signals, including physical forces to mechanical responses of the nucleus. Canonically, the morphological characteristics of the nucleus, as shape and size, have served for pathologists to stratify and diagnose cancer patients; however, novel biophysical techniques must exploit physical parameters to improve cancer diagnosis. By using multiple particle tracking (Mpt) technique on chromatin granules, we designed a SURF (Speeded Up Robust Features)-based algorithm to study the mechanical properties of isolated nuclei and in living cells. We have determined the apparent shear stiffness, viscosity and optical density of the nucleus, and how the chromatin structure influences on these biophysical values. Moreover, we used our MPT-SURF analysis to study the apparent mechanical properties of isolated nuclei from patients of acute lymphoblastic leukemia. We found that leukemia cells exhibited mechanical differences compared to normal lymphocytes. Interestingly, isolated nuclei from high-risk leukemia cells showed increased viscosity than their counterparts from normal lymphocytes, whilst nuclei from relapsed-patient's cells presented higher density than those from normal lymphocytes or standard-and high-risk leukemia cells. Taken together, here we presented how MPT-SURF analysis of nuclear chromatin granules defines nuclear mechanical phenotypic features, which might be clinically relevant. The nucleus is a central cellular organelle that must alter its physical properties during cellular functions, including gene expression, cell migration, and development in homeostasis and human diseases 1. The nucleus is composed by the nuclear envelope, nucleoskeletal components, and the nucleoplasm, which contains the DNA and its associated molecules forming the chromatin 2. The nuclear envelope is mainly composed by nuclear membranes, A-(lamin A and C) and B-(lamin B) lamin types, and other structural proteins that connect the nucleus with the cytoskeleton as LINC complexes 3. Lamin A/C levels and its ratio to lamin B levels control nuclear deformability and stiffness 4,5. It has been reported that other nuclear components, as LINC and F-actin binding proteins, control nuclear shape and rigidity 6. In general, these nuclear changes correlate with more invasive phenotype of tumor cells and higher genomic instability upon cell migration 7,8. Chromatin organization is modulated by epigenetic changes that promote chromatin compaction and decondensation according to electrostatic interactions and configurational entropy 9-11. Several biophysical techniques support that the chromatin conformation alterations contributes to the morphology and the biophysical behavior of the nucleus 12-16 Abnormalities in nuclear shape and organization occur in a wide range of human pathologies,

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“…In addition to the cellular mechanical support, lamins cover a multitude of other functions, related to chromatin organization, gene regulation, and cell fate determination. The substrate stiffness correlates to the amount of A-type lamins and the phenotype of the cells [154,156,157]. For example, Heo et al showed that compliant external stimuli favor the MSC differentiation into adipocytes, induced by scarce cell focal adhesions and therefore, soft nuclei and inhibited A-type lamin production [157].…”

Section: Lamin A/c Roles In Cell Mechanotransductionmentioning

confidence: 99%

Lamin A/C Mechanotransduction in Laminopathies

Donnaloja

Carnevali

Jacchetti

et al. 2020

Cells

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Mechanotransduction translates forces into biological responses and regulates cell functionalities. It is implicated in several diseases, including laminopathies which are pathologies associated with mutations in lamins and lamin-associated proteins. These pathologies affect muscle, adipose, bone, nerve, and skin cells and range from muscular dystrophies to accelerated aging. Although the exact mechanisms governing laminopathies and gene expression are still not clear, a strong correlation has been found between cell functionality and nuclear behavior. New theories base on the direct effect of external force on the genome, which is indeed sensitive to the force transduced by the nuclear lamina. Nuclear lamina performs two essential functions in mechanotransduction pathway modulating the nuclear stiffness and governing the chromatin remodeling. Indeed, A-type lamin mutation and deregulation has been found to affect the nuclear response, altering several downstream cellular processes such as mitosis, chromatin organization, DNA replication-transcription, and nuclear structural integrity. In this review, we summarize the recent findings on the molecular composition and architecture of the nuclear lamina, its role in healthy cells and disease regulation. We focus on A-type lamins since this protein family is the most involved in mechanotransduction and laminopathies.

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Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation

Cited by 86 publications

References 66 publications

Physics and Biology (of Chromosomes)

Physics and Biology (of Chromosomes)

Multiple particle tracking analysis in isolated nuclei reveals the mechanical phenotype of leukemia cells

Lamin A/C Mechanotransduction in Laminopathies

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