As the home of cellular genetic information, the nucleus has a critical role in determining cell fate and function in response to various signals and stimuli. In addition to biochemical inputs, the nucleus is constantly exposed to intrinsic and extrinsic mechanical forces that trigger dynamic changes in nuclear structure and morphology. Emerging data suggest that the physical deformation of the nucleus modulates many cellular and nuclear functions. These functions have long been considered to be downstream of cytoplasmic signalling pathways and dictated by gene expression. In this Review, we discuss an emerging perspective on the mechanoregulation of the nucleus that considers the physical connections from chromatin to nuclear lamina and cytoskeletal filaments as a single mechanical unit. We describe key mechanisms of nuclear deformations in time and space and provide a critical review of the structural and functional adaptive responses of the nucleus to deformations. We then consider the contribution of nuclear deformations to the regulation of important cellular functions, including muscle contraction, cell migration and human disease pathogenesis. Collectively, these emerging insights shed new light on the dynamics of nuclear deformations and their roles in cellular mechanobiology.
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The authors apologize to all authors whose work could not be included owing to space constraints. A.D.S. is supported by the Pathway to Independence Award (R00GM123195) and 4D Nucleome 2 centre grant (1UM1HG011536). S.G. acknowledges funding from FEDER Prostem Research Project no. 1510614 (Wallonia DG06), the F.R.S.-FNRS Epiforce Project no. T.0092.21 and the Interreg MAT(T)ISSE project, which is financially supported by Interreg France-Wallonie-Vlaanderen (Fonds Européen de Développement Régional, FEDER-ERDF). Y.K. is financially supported by FRIA (F.R.S.-FNRS) and FRMH (Fonds pour la Recherche Médicale dans le Hainaut). J.L. is supported by awards from the National Institutes of Health (R01HL082792, R01GM137605, U54CA210184), the National Science Foundation (URoL-2022048) and the VolkswagenStiftung (Az. 96733).
The authors declare no competing interests.
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In its literal sense, mechanotransduction refers to the molecular process in which mechanical stimuli are converted (or transduced) into biochemical signals, that is, equivalent to the ‘mechanosensing’ defined below. However, mechanotransduction is commonly used to more broadly refer to cellular responses to changes in the mechanical environment, including forces, deformations or mechanical properties. In this article, we use this broader definition of mechanotransduction.
Molecular process through which cells or cellular components translate mechanical forces or deformations into biochemical signals.
Expression of the mechanical loading in terms of force applied per cross-sectional area of an object. Units of stress are N m−2 (or Pa).
Highly aggressive form of cancer mostly observed in children and adolescents that usually develops in soft tissues, such as the muscles, from mesenchymal cells that have failed to fully differentiate.
- Segmental premature ageing disease
Pathological condition that reflects some but not other phenotypes of the normal ageing process at a much earlier age. For example, children with Hutchinson–Gilford progeria syndrome develop severe cardiovascular disease (heart attacks and strokes) in their early teens but lack neurodegenerative defects such as dementia and are not more prone to cancer.
- Intermediate filaments
Large family of nuclear and cytoskeletal filaments that includes keratins (types I and II), desmin and vimentin (type III), neurofilaments (type IV) and lamins (type V). Intermediate filaments form dimers that then assemble into larger nonpolar filament structures that are characterized by their ability to extend substantially under mechanical stress.
Post-translational modification of proteins catalysed by the enzyme farnesyltransferase, which adds a 15-carbon unsaturated hydrocarbon chain to a cysteine residue via a thioether linkage, thus anchoring the protein to a lipid membrane.
- Lamina-associated polypeptide 2α
One of six alternatively spliced isoforms of the mammalian LAP2 gene that is functionally and structurally different. LAP2α shares only the NH2 terminus with the other isoforms and contains a unique COOH terminus. LAP2α is localized throughout the nucleus and is a specific binding partner of nucleoplasmic A-type lamins.
- Topologically associating domains
(TADs). Self-interacting megabase-scale genomic blocks in which DNA sequences exhibit significantly higher interaction frequencies with other DNA sequences within the domain than with those outside of the block.
- Liquid–liquid phase separation
Physicochemical process leading to the formation of membraneless compartments or cell structures. This process is based on multivalent macromolecular interactions, including π–π interactions, cation–anion interactions, dipole–dipole interactions and π–cation interactions, that drive the transition of some proteins into another phase with different physiochemical properties to induce the formation of membraneless organelles or cell structures.
Translation of the nucleus within the cell, often neurons, which may or may not be coupled to cell migration.
- Stress fibres
Actin filament assembly resulting from the interaction and merging of pre-existing radial fibres and transverse arcs (10–30 filaments). Stress fibres can reach a diameter of several hundreds of nanometres and are under constant tensile stress owing to actomyosin contractility.
- Focal adhesions
Integrin-mediated cell–substrate adhesion structure anchoring the ends of stress fibres. Focal adhesions mediate strong attachments to substrates and function as an integrin-based signalling platform.
- Tensile force
Pulling force resulting in the extension of an object.
Rheological property of natural or synthetic materials with viscous and elastic properties that allows for timescale-dependent deformation when subjected to mechanical stress.
Property of a material that instantaneously deforms in response to a stress and recovers its size and shape after deformation. It is usually represented by a spring that stores energy in the form of elastic potential energy. Units of an elastic modulus are Pa (or N m−2).
Property of liquid of high viscosity, which corresponds to the resistance of a fluid to deform under either shear or extensional stress, defined as the ratio of shear stress to shear flow. Viscous fluids are usually depicted by a dashpot, which represents the internal friction within the fluid that dissipates energy over time. Units of viscosity are Pa s (or N s m−2).
Geometric measure of the amount of deformation in the direction of the applied force divided by the initial length of the object (unitless number).
- Strain stiffening
Mechanical material property corresponding to a sudden increase of the elastic modulus under strain, that is, an increase in resistance to further deformation.
- Plastic deformation
Ability of a solid material to undergo permanent deformation (that is, irreversible change of shape) without rupture in response to applied forces.
- Linker histone H1
Histone protein family responsible for DNA compaction, whose members are located at the base of a nucleosome adjacent to the DNA entry/exit site to regulate the higher-order chromatin structure.
Dynamic protrusion of the plasma or nuclear membrane, often characterized by a spherical morphology. At the cytoplasm, blebbing results from actomyosin contraction of the cortex that causes either transient detachment of the cell membrane from the actin cortex or a rupture in the actin cortex. The cytosol streams out and inflates the bleb. Nuclear blebs arise from increased intranuclear pressure and detachment of the nuclear membranes from the nuclear lamina.
Barrier-to-autointegration factor is an essential 10 kDa chromatin-binding protein that is highly conserved in metazoa and helps DNA anchoring to the nuclear envelope. BAF is involved in multiple pathways, including nuclear envelope reassembly (after mitosis and nuclear envelope rupture), chromatin epigenetics and DNA damage response. BAF function is controlled by phosphorylation/dephosphorylation waves that drive nuclear envelope disassembly.
- Biomolecular condensates
Micron-scale compartments often formed by liquid–liquid phase separation that lack surrounding membranes and concentrate functionally related components such as proteins and nucleic acids.
- Colloid osmotic pressure
Pressure generated by solutions of macromolecules in contact with pores that are permeable to water and ions but not to macromolecules. Colloid osmotic pressure generates depletion forces that push macromolecules together in crowded solutions and thus promotes aggregation and phase separation.
- Confocal Brillouin microscopy
Optical technique combining Brillouin spectroscopy with confocal microscopy to provide a non-contact and direct readout of the mechanical properties of a material (that is, stiffness, temperature or strain) at the micrometre scale. Spontaneous Brillouin light scattering arises from the interaction between photons and acoustic phonons (that is, propagation of thermodynamic fluctuations) and permits quantification of the intracellular longitudinal modulus without disturbing the cell.
- Interkinetic nuclear migration
Periodic movement of the nucleus between apical and basal surfaces of neuroepithelial progenitor cells as they progress through the cell cycle. Interkinetic nuclear migration results in all mitoses taking place at the apical side of the neuroepithelium. As a consequence, most newborn neurons resulting from division of neuroepithelial progenitors must move their soma from the apical side to more basal locations where they function.
- Cerebellar granule cells
Among the smallest and the most numerous neuron type that form dense and distinct layers of the cerebellar cortex.
Over 450 mutations have been reported in the genes encoding lamins, in particular the LMNA gene, causing diseases termed laminopathies. The number of identified laminopathies has steadily increased in recent years, currently including 13 known conditions. Most of these diseases are rare but LMNA mutations are the second most common cause of congenital dilated cardiomyopathy. Although lamins are nearly ubiquitously expressed, many of the laminopathies exhibit tissue-specific phenotypes, for example, primarily affecting striated muscles and tendons, hence the suggestion of a mechanical connection.
- LEM-domain proteins
The LAP2, emerin and MAN1 (LEM) domain is a ~40-residue helix–loop–helix fold conserved both in eukaryotes and in prokaryotic DNA/RNA-binding proteins. Except for LAP2 proteins, which have a second LEM domain that binds DNA, the function of a eukaryotic LEM domain is to directly bind the conserved chromatin protein BAF.
Three prime repair exonuclease 1 is the major 3′ → 5′ DNA exonuclease in mammalian cells and metabolizes preferentially single-stranded DNA. It cleans the cytosol from DNA fragments coming from endogenous elements. Unless degraded, the accumulation of these DNA fragments can activate innate immune signalling.
- ATR kinase
Serine/threonine protein kinase activated in S phase and involved in sensing DNA damage and activating DNA damage checkpoint upon genotoxic stresses (for example, ionizing radiation or ultraviolet light), thereby acting as a DNA damage sensor.
- Epithelial–mesenchymal transition
Transcriptionally governed process over which epithelial cells establish a front-rear polarity while acquiring a mesenchymal and motile phenotype.
- ATM kinase
Serine/threonine protein kinase that is recruited and activated to sites of DNA double-strand breaks and signals to various downstream targets to initiate cell cycle arrest and DNA repair.
- Sterile inflammation
Immune response that is typically associated with the recognition of intracellular contents released from damaged and necrotic cells by inflammatory signalling receptors or triggered by exogenous material that can injure cells. This process occurs in the absence of microorganisms.
- cGAS–STING DNA-sensing pathway
Cellular cytosolic double-stranded DNA sensor, allowing innate immune response to infections, inflammation and cancer.
Small DNA-containing nuclear structures that are spatially isolated from the main nucleus. Micronuclei form from lagging chromosomes or chromosome fragments following mitotic errors or DNA damage, respectively.
Dense aggregation of heterochromatin formed during interphase.
- Facultative heterochromatin
Condensed, transcriptionally silent chromatin region that can decondense and adapt to allow transcription within temporal and spatial contexts. Facultative heterochromatin is not characterized by repetitive sequences so, at the DNA sequence level, it is entirely different from constitutive heterochromatin.
- Polycomb repressive complex 2
(PRC2). Major repressive chromatin complex formed by Polycomb group (PcG) proteins.
- Serum response factor
(SRF). Transcription factor that plays a key role in the transduction of mechanical signals from cytoplasmic actin and extracellular matrix proteins to the nucleus. SRF is involved in various cellular processes, from cell proliferation to differentiation and development.
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Kalukula, Y., Stephens, A.D., Lammerding, J. et al. Mechanics and functional consequences of nuclear deformations. Nat Rev Mol Cell Biol 23, 583–602 (2022). https://doi.org/10.1038/s41580-022-00480-z
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