Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanics and functional consequences of nuclear deformations

Nature Reviews Molecular Cell Biology volume 23, pages 583–602 (2022)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The nuclear envelope and nucleo-skeletal interactions.
Fig. 2: Chromatin organization and its impact on nuclear mechanics.
Fig. 3: Physiological sources of nuclear deformations.
Fig. 4: Migration-associated nuclear deformations.
Fig. 5: Nuclear envelope rupture and repair.
Fig. 6: Examples of functional consequences of nuclear deformations.

Similar content being viewed by others

References

  1. Lammerding, J. Mechanics of the nucleus. Compr. Physiol. 1, 783–807 (2013).

    Google Scholar 

  2. Szczesny, S. E. & Mauck, R. L. The nuclear option: evidence implicating the cell nucleus in mechanotransduction. J. Biomech. Eng. 139, 0210061–02100616 (2017).

    Article  PubMed Central  Google Scholar 

  3. Long, J. T. & Lammerding, J. Nuclear deformation lets cells gauge their physical confinement. Dev. Cell 56, 156–158 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Thomas, C. H., Collier, J. H., Sfeir, C. S. & Healy, K. E. Engineering gene expression and protein synthesis by modulation of nuclear shape. Proc. Natl Acad. Sci. USA 99, 1972–1977 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Skinner, B. M. & Johnson, E. E. P. Nuclear morphologies: their diversity and functional relevance. Chromosoma 126, 195–212 (2017).

    Article  PubMed  Google Scholar 

  6. Gupta, S., Marcel, N., Sarin, A. & Shivashankar, G. V. Role of actin dependent nuclear deformation in regulating early gene expression. PLoS ONE 7, e53031 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Miroshnikova, Y. A., Nava, M. M. & Wickström, S. A. Emerging roles of mechanical forces in chromatin regulation. J. Cell Sci. 130, 2243–2250 (2017).

    CAS  PubMed  Google Scholar 

  8. Zink, D., Fischer, A. H. & Nickerson, J. A. Nuclear structure in cancer cells. Nat. Rev. Cancer 4, 677–687 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Clippinger, S. R. et al. Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy. Proc. Natl Acad. Sci. USA 116, 17831–17840 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Franke, W. W., Scheer, U., Krohne, G. & Jarasch, E. D. The nuclear envelope and the architecture of the nuclear periphery. J. Cell Biol. 91, 39s–50s (1981).

    Article  CAS  PubMed  Google Scholar 

  11. Kim, D.-H. et al. Volume regulation and shape bifurcation in the cell nucleus. J. Cell Sci. 128, 3375–3385 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Jevtić, P. et al. The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity. EMBO Rep. 20, e47283 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. García-González, A. et al. The effect of cell morphology on the permeability of the nuclear envelope to diffusive factors. Front. Physiol. 9, 925 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Donnaloja, F., Jacchetti, E., Soncini, M. & Raimondi, M. T. Mechanosensing at the nuclear envelope by nuclear pore complex stretch activation and its effect in physiology and pathology. Front. Physiol. 10, 896 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schuller, A. P. et al. The cellular environment shapes the nuclear pore complex architecture. Nature 598, 667–671 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nava, M. M. et al. Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell 181, 800–817.e22 (2020). This article demonstrates how cyclic strain application can induce transient chromatin modifications, which, together with slower realignment of cells perpendicular to the stretch direction, help protect the cells from mechanically induced DNA damage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lomakin, A. J. et al. The nucleus acts as a ruler tailoring cell responses to spatial constraints. Science 370, eaba2894 (2020). This article, together with concurrently published work by Venturini et al. (ref.127), demonstrates how physical confinement that compresses the nucleus triggers increased cell cortical contractility via recruitment of cPLA2 to the stretched nuclear membranes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Turgay, Y. et al. The molecular architecture of lamins in somatic cells. Nature 543, 261–264 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tenga, R. & Medalia, O. Structure and unique mechanical aspects of nuclear lamin filaments. Curr. Opin. Struct. Biol. 64, 152–159 (2020).

    Article  CAS  PubMed  Google Scholar 

  20. de Leeuw, R., Gruenbaum, Y. & Medalia, O. Nuclear lamins: thin filaments with major functions. Trends Cell Biol. 28, 34–45 (2018).

    Article  PubMed  CAS  Google Scholar 

  21. Shimi, T. et al. Structural organization of nuclear lamins A, C, B1, and B2 revealed by superresolution microscopy. Mol. Biol. Cell 26, 4075–4086 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kolb, T., Maass, K., Hergt, M., Aebi, U. & Herrmann, H. Lamin A and lamin C form homodimers and coexist in higher complex forms both in the nucleoplasmic fraction and in the lamina of cultured human cells. Nucleus 2, 425–433 (2011).

    Article  PubMed  Google Scholar 

  23. Nmezi, B. et al. Concentric organization of A- and B-type lamins predicts their distinct roles in the spatial organization and stability of the nuclear lamina. Proc. Natl Acad. Sci. USA 116, 4307–4315 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Naetar, N. et al. LAP2alpha maintains a mobile and low assembly state of A-type lamins in the nuclear interior. eLife 10, e63476 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pascual-Reguant, L. et al. Lamin B1 mapping reveals the existence of dynamic and functional euchromatin lamin B1 domains. Nat. Commun. 9, 3420 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Cho, S. et al. Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell-cycle arrest. Dev. Cell 49, 920–935 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Koushki, N. et al. Lamin A redistribution mediated by nuclear deformation determines dynamic localization of YAP. bioRxiv https://doi.org/10.1101/2020.03.19.998708 (2020).

    Article  Google Scholar 

  28. Zhu, L. & Brangwynne, C. P. Nuclear bodies: the emerging biophysics of nucleoplasmic phases. Curr. Opin. Cell Biol. 34, 23–30 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Buchwalter, A., Kaneshiro, J. M. & Hetzer, M. W. Coaching from the sidelines: the nuclear periphery in genome regulation. Nat. Rev. Genet. 20, 39–50 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bizhanova, A. & Kaufman, P. Close to the edge: heterochromatin at the nucleolar and nuclear peripheries. Biochim. Biophys. Acta 1864, 194666 (2021).

    Article  CAS  Google Scholar 

  31. Miron, E. et al. Chromatin arranges in chains of mesoscale domains with nanoscale functional topography independent of cohesin. Sci. Adv. 6, eaba8811 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cho, S., Irianto, J. & Discher, D. E. Mechanosensing by the nucleus: from pathways to scaling relationships. J. Cell Biol. 216, 305–315 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Maeshima, K., Tamura, S., Hansen, J. C. & Itoh, Y. Fluid-like chromatin: toward understanding the real chromatin organization present in the cell. Curr. Opin. Cell Biol. 64, 77–89 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Hansen, J. C., Maeshima, K. & Hendzel, M. J. The solid and liquid states of chromatin. Epigenetics Chromatin 14, 50 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jahed, Z., Domkam, N., Ornowski, J., Yerima, G. & Mofrad, M. R. K. Molecular models of LINC complex assembly at the nuclear envelope. J. Cell Sci. 134, jcs258194 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. Lombardi, M. L. et al. The interaction between nesprins and SUN proteins at the nuclear envelope is critical for force transmission between the nucleus and cytoskeleton. J. Biol. Chem. 286, 26743–26753 (2011). First function demonstration of force transmission from the cytoskeleton to the nucleus via the LINC complex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Denis, K. B. et al. The LINC complex is required for endothelial cell adhesion and adaptation to shear stress and cyclic stretch. Mol. Biol. Cell 32, 1654–1663 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Splinter, D. et al. Bicaudal D2, Tynein, and kinesin-1 associate with nuclear pore complexes and regulate centrosome and nuclear positioning during mitotic entry. PLoS Biol. 8, e1000350 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Salpingidou, G., Smertenko, A., Hausmanowa-Petrucewicz, I., Hussey, P. J. & Hutchison, C. J. A novel role for the nuclear membrane protein emerin in association of the centrosome to the outer nuclear membrane. J. Cell Biol. 178, 897–904 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sosa, B. A., Rothballer, A., Kutay, U. & Schwartz, T. U. LINC complexes form by binding of three KASH peptides to domain interfaces of trimeric SUN proteins. Cell 149, 1035–1047 (2012). First detailed structural characterization of the LINC complex, elucidating how forces can be transmitted across the nesprin–SUN protein interface.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cruz, V. E., Demircioglu, F. E. & Schwartz, T. U. Structural analysis of different LINC complexes reveals distinct binding modes. J. Mol. Biol. 432, 6028–6041 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Rajgor, D. & Shanahan, C. M. Nesprins: from the nuclear envelope and beyond. Expert Rev. Mol. Med. 15, e5 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Wilson, M. H. & Holzbaur, E. L. F. Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells. Development 142, 218–228 (2014).

    Article  CAS  Google Scholar 

  44. Fridolfsson, H. N., Ly, N., Meyerzon, M. & Starr, D. A. UNC-83 coordinates kinesin-1 and dynein activities at the nuclear envelope during nuclear migration. Dev. Biol. 338, 237–250 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Wilhelmsen, K. et al. Nesprin-3, a novel outer nuclear membrane protein, associates with the cytoskeletal linker protein plectin. J. Cell Biol. 171, 799–810 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Roux, K. J. et al. Nesprin 4 is an outer nuclear membrane protein that can induce kinesin-mediated cell polarization. Proc. Natl Acad. Sci. USA 106, 2194–2199 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Horn, H. F. et al. A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton. J. Cell Biol. 202, 1023–1039 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Agrawal, A. & Lele, T. P. Mechanics of nuclear membranes. J. Cell Sci. 132, jcs229245 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hoffman, L. M. et al. Mechanical stress triggers nuclear remodeling and the formation of transmembrane actin nuclear lines with associated nuclear pore complexes. Mol. Biol. Cell 31, 1774–1787 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Versaevel, M. et al. Super-resolution microscopy reveals LINC complex recruitment at nuclear indentation sites. Sci. Rep. 4, 7362 (2015).

    Article  CAS  Google Scholar 

  51. Davidson, P. M. et al. Nesprin-2 accumulates at the front of the nucleus during confined cell migration. EMBO Rep. 21, e49910 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lim, S. M., Cruz, V. E., Antoku, S., Gundersen, G. G. & Schwartz, T. U. Structures of FHOD1-nesprin1/2 complexes reveal alternate binding modes for the FH3 domain of formins. Structure 29, 540–552 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Saunders, C. A. et al. TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement. J. Cell Biol. 216, 657–674 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gudise, S., Figueroa, R. A., Lindberg, R., Larsson, V. & Hallberg, E. Samp1 is functionally associated with the LINC complex and A-type lamina networks. J. Cell Sci. 124, 2077–2085 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Zwerger, M. et al. Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling. Hum. Mol. Genet. 22, 2335–2349 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hao, H. et al. The nesprin-1/-2 ortholog ANC-1 regulates organelle positioning in C. elegans independently from its KASH or actin-binding domains. eLife 10, e61069 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Versaevel, M., Riaz, M., Grevesse, T. & Gabriele, S. Cell confinement: putting the squeeze on the nucleus. Soft Matter 9, 6665–6676 (2013).

    Article  CAS  Google Scholar 

  58. Guilak, F., Tedrow, J. R. & Burgkart, R. Viscoelastic properties of the cell nucleus. Biochem. Biophys. Res. Commun. 269, 781–786 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Hobson, C. M., Falvo, M. R. & Superfine, R. A survey of physical methods for studying nuclear mechanics and mechanobiology. Appl. Bioeng. 5, 041508 (2021).

    Article  CAS  Google Scholar 

  60. Pajerowski, J. D., Dahl, K. N., Zhong, F. L., Sammak, P. J. & Discher, D. E. Physical plasticity of the nucleus in stem cell differentiation. Proc. Natl Acad. Sci. USA 104, 15619–15624 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Davidson, P. M. et al. High-throughput microfluidic micropipette aspiration device to probe time-scale dependent nuclear mechanics in intact cells. Lab. Chip 19, 3652–3663 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rowat, A. C., Foster, L. J., Nielsen, M. M., Weiss, M. & Ipsen, J. H. Characterization of the elastic properties of the nuclear envelope. J. R. Soc. Interface 2, 63–69 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dahl, K. N., Engler, A. J., Pajerowski, J. D. & Discher, D. E. Power-law rheology of isolated nuclei with deformation mapping of nuclear substructures. Biophys. J. 89, 2855–2864 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Stephens, A. D., Banigan, E. J., Adam, S. A., Goldman, R. D. & Marko, J. F. Chromatin and lamin A determine two different mechanical response regimes of the cell nucleus. Mol. Biol. Cell 28, 1984–1996 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Grevesse, T., Dabiri, B. E., Parker, K. K. & Gabriele, S. Opposite rheological properties of neuronal microcompartments predict axonal vulnerability in brain injury. Sci. Rep. 5, 9475 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lammerding, J. et al. Lamins A and C but not lamin B1 regulate nuclear mechanics. J. Biol. Chem. 281, 25768–25780 (2006). This report establishes the important role of lamins A/C in determining nuclear deformability.

    Article  CAS  PubMed  Google Scholar 

  67. Neelam, S. et al. Direct force probe reveals the mechanics of nuclear homeostasis in the mammalian cell. Proc. Natl Acad. Sci. USA 112, 5720–5725 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lammerding, J. et al. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J. Clin. Invest. 113, 370–378 (2004). First report of a role of lamins A/C in mediating nuclear mechanotransduction and providing nuclear stability to allow cells to withstand mechanical stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lammerding, J. et al. Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells. J. Cell Biol. 170, 781–791 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cao, X. et al. A chemomechanical model for nuclear morphology and stresses during cell transendothelial migration. Biophys. J. 111, 1541–1552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Versaevel, M. et al. Probing cytoskeletal pre-stress and nuclear mechanics in endothelial cells with spatiotemporally controlled (de-)adhesion kinetics on micropatterned substrates. Cell Adhes. Migr. 11, 98–109 (2017).

    Article  CAS  Google Scholar 

  72. Ferrera, D. et al. Lamin B1 overexpression increases nuclear rigidity in autosomal dominant leukodystrophy fibroblasts. FASEB J. 28, 3906–3918 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen, N. Y. et al. An absence of lamin B1 in migrating neurons causes nuclear membrane ruptures and cell death. Proc. Natl Acad. Sci. USA 116, 25870–25879 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hatch, E. M. & Hetzer, M. W. Nuclear envelope rupture is induced by actin-based nucleus confinement. J. Cell Biol. 215, 27–36 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Raab, M. et al. ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science 352, 359–362 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. Denais, C. M. et al. Nuclear envelope rupture and repair during cancer cell migration. Science 352, 353–358 (2016). Together with the work by Raab et al. (ref. 75), this is the first report of migration-induced nuclear envelope rupture and DNA damage, while also identifying a role of ESCRT proteins in interphase nuclear envelope resealing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang, Q. et al. Local, transient tensile stress on the nuclear membrane causes membrane rupture. Mol. Biol. Cell 30, 899–906 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Furusawa, T. et al. Chromatin decompaction by the nucleosomal binding protein HMGN5 impairs nuclear sturdiness. Nat. Commun. 6, 6138 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Samwer, M. et al. DNA cross-bridging shapes a single nucleus from a set of mitotic chromosomes. Cell 170, 956–972 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang, P. et al. WDR5 modulates cell motility and morphology and controls nuclear changes induced by a 3D environment. Proc. Natl Acad. Sci. USA 115, 8581–8586 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Serra-Marques, A. et al. The mitotic protein NuMA plays a spindle-independent role in nuclear formation and mechanics. J. Cell Biol. 219, e202004202 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Tamashunas, A. C. et al. High-throughput gene screen reveals modulators of nuclear shape. Mol. Biol. Cell 31, 1392–1402 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Welsh, T. J., Shen, Y., Levin, A. & Knowles, T. P. J. Mechanobiology of protein droplets: force arises from disorder. Cell 175, 1457–1459 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Gibson, B. A. et al. Organization of chromatin by intrinsic and regulated phase separation. Cell 179, 470–484 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zidovska, A. The rich inner life of the cell nucleus: dynamic organization, active flows, and emergent rheology. Biophys. Rev. 12, 1093–1106 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Jord, A. A. et al. Cytoplasmic forces functionally reorganize nuclear condensates in oocytes. bioRxiv https://doi.org/10.1101/2021.03.15.434387 (2021).

    Article  Google Scholar 

  88. Bracha, D. et al. Mapping local and global liquid phase behavior in living cells using photo-oligomerizable seeds. Cell 175, 1467–1480 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Shin, Y. et al. Spatiotemporal control of intracellular phase transitions using light-activated optoDroplets. Cell 168, 159–171 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. Shin, Y. et al. Liquid nuclear condensates mechanically sense and restructure the genome. Cell 175, 1481–1491 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Stephens, A. D. et al. Physicochemical mechanotransduction alters nuclear shape and mechanics via heterochromatin formation. Mol. Biol. Cell 30, 2320–2330 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cantwell, H. & Nurse, P. Unravelling nuclear size control. Curr. Genet. 65, 1281–1285 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Versaevel, M., Grevesse, T. & Gabriele, S. Spatial coordination between cell and nuclear shape within micropatterned endothelial cells. Nat. Commun. 3, 671 (2012). This work demonstrates that actomyosin stress fibres regulate nuclear deformations in response to cell shape changes and report a drastic condensation of chromatin in deformed nuclei.

    Article  PubMed  CAS  Google Scholar 

  94. Seirin-Lee, S. et al. Role of dynamic nuclear deformation on genomic architecture reorganization. PLoS Comput. Biol. 15, e1007289 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Alisafaei, F., Jokhun, D. S., Shivashankar, G. V. & Shenoy, V. B. Regulation of nuclear architecture, mechanics, and nucleocytoplasmic shuttling of epigenetic factors by cell geometric constraints. Proc. Natl Acad. Sci. USA 116, 13200–13209 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Petrie, R. J., Koo, H. & Yamada, K. M. Generation of compartmentalized pressure by a nuclear piston governs cell motility in a 3D matrix. Science 345, 1062–1065 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mistriotis, P. et al. Confinement hinders motility by inducing RhoA-mediated nuclear influx, volume expansion, and blebbing. J. Cell Biol. 218, 4093–4111 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mitchison, T. J. Colloid osmotic parameterization and measurement of subcellular crowding. Mol. Biol. Cell 30, 173–180 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Deviri, D. & Safran, S. A. Balance of osmotic pressures determines the volume of the cell nucleus. bioRxiv https://doi.org/10.1101/2021.10.01.462771v1 (2021).

    Article  Google Scholar 

  100. Lemière, J., Real-Calderon, P., Holt, L. J., Fai, T. G. & Chang, F. Control of nuclear size by osmotic forces in Schizosaccharomyces pombe. bioRxiv https://doi.org/10.1101/2021.12.05.471221 (2021).

    Article  Google Scholar 

  101. Takata, H. et al. Chromatin compaction protects genomic DNA from radiation damage. PLoS ONE 8, e75622 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Holaska, J. M., Kowalski, A. K. & Wilson, K. L. Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the nuclear inner membrane. PLoS Biol. 2, e231 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Le, H. Q. et al. Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment. Nat. Cell Biol. 18, 864–875 (2016). This study identifies how mechanical stretch can result in emerin translocation to the ONM, where it facilitates perinuclear actin polymerization that results in depletion of intranuclear actin and changes in chromatin organization.

    Article  CAS  PubMed  Google Scholar 

  104. Davidson, P. M. & Cadot, B. Actin on and around the nucleus. Trends Cell Biol. 31, 211–223 (2020).

    Article  PubMed  CAS  Google Scholar 

  105. Buxboim, A. et al. Matrix elasticity regulates lamin-a,c phosphorylation and turnover with feedback to actomyosin. Curr. Biol. 24, 1909–1917 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Mattout, A. et al. An EDMD mutation in C. elegans lamin blocks muscle-specific gene relocation and compromises muscle integrity. Curr. Biol. 21, 1603–1614 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Solovei, I. et al. LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Cell 152, 584–598 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Shin, J.-W. et al. Lamins regulate cell trafficking and lineage maturation of adult human hematopoietic cells. Proc. Natl Acad. Sci. USA 110, 18892–18897 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Swift, J. et al. Nuclear lamin-a scales with tissue stiffness and enhances matrix-directed differentiation. Science 341, 1240104 (2013). Detailed proteomic analysis linking higher levels of lamins A/C (and collagen) to cells residing in stiff tissues, suggesting a mechano-adaptive role of lamin A/C expression.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Zuela, N., Dorfman, J. & Gruenbaum, Y. Global transcriptional changes caused by an EDMD mutation correlate to tissue specific disease phenotypes in C. elegans. Nucleus 8, 60–69 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Iyer, K. V. et al. Apico-basal cell compression regulates lamin A/C levels in epithelial tissues. Nat. Commun. 12, 1756 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Olins, D. E. & Olins, A. L. Granulocyte heterochromatin: defining the epigenome. BMC Cell Biol. 6, 39 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Rowat, A. C. et al. Nuclear envelope composition determines the ability of neutrophil-type cells to passage through micron-scale constrictions. J. Biol. Chem. 288, 8610–8618 (2013). One of the first reports providing functional evidence that nuclear envelope composition and deformability determine the ability of cells to transit through tight constrictions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Roberts, A. B. et al. Tumor cell nuclei soften during transendothelial migration. J. Biomech. 121, 110400 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Bell, E. S. et al. Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer. bioRxiv https://doi.org/10.1101/2021.07.12.451842v1 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Infante, E. et al. LINC complex–Lis1 interplay controls MT1–MMP matrix digest-on-demand response for confined tumor cell migration. Nat. Commun. 9, 2443 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Krause, M. et al. Cell migration through three-dimensional confining pores: speed accelerations by deformation and recoil of the nucleus. Philos. Trans. R. Soc. Lond. B Biol. Sci. 374, 20180225 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Gerlitz, G. The emerging roles of heterochromatin in cell migration. Front. Cell Dev. Biol. 8, 394 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Earle, A. J. et al. Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells. Nat. Mater. 19, 464–473 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Mitchell, M. J. et al. Lamin A/C deficiency reduces circulating tumor cell resistance to fluid shear stress. Am. J. Physiol. Cell Physiol. 309, C736–C746 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gundersen, G. G. & Worman, H. J. Nuclear positioning. Cell 152, 1376–1389 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Roman, W. & Gomes, E. R. Nuclear positioning in skeletal muscle. Semin. Cell Dev. Biol. 82, 51–56 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Collins, M. A. et al. Ensconsin-dependent changes in microtubule organization and LINC complex-dependent changes in nucleus-nucleus interactions result in quantitatively distinct myonuclear positioning defects. Mol. Biol. Cell 32, ar27 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lorber, D., Rotkopf, R. & Volk, T. A minimal constraint device for imaging nuclei in live Drosophila contractile larval muscles reveals novel nuclear mechanical dynamics. Lab. Chip 20, 2100–2112 (2020).

    Article  CAS  PubMed  Google Scholar 

  125. Davidson, P. M., Denais, C., Bakshi, M. C. & Lammerding, J. Nuclear deformability constitutes a rate-limiting step during cell migration in 3-D environments. Cell. Mol. Bioeng. 7, 293–306 (2014). This report, along with work by Harada et al. (ref. 175) and Wolf et al. (ref. 126), presents some of the first evidence that increased nuclear deformability caused by reduced lamin A/C expression enhances cell migration through confined environments.

    Article  CAS  PubMed  Google Scholar 

  126. Wolf, K. et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J. Cell Biol. 201, 1069–1084 (2013). This study demonstrates that nuclear deformability presents a rate-limiting factor in the ability of cells to migrate through constrictions smaller than ~10% of the undeformed nuclear cross-section.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Venturini, V. et al. The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science 370, eaba2644 (2020). As presented in work by Lomakin et al. (ref. 17), it was shown that the nuclear envelope provides a gauge of cell deformation and activates a mechanotransduction pathway that controls actomyosin contractility via mechanically induced recruitment of cPLA2 to the INM.

    Article  CAS  PubMed  Google Scholar 

  128. Smith, E. R. et al. Nuclear envelope structural proteins facilitate nuclear shape changes accompanying embryonic differentiation and fidelity of gene expression. BMC Cell Biol. 18, 8 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Spear, P. C. & Erickson, C. A. Interkinetic nuclear migration: a mysterious process in search of a function. Dev. Growth Differ. 54, 306–316 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Tsukamoto, S. et al. Compressive forces driven by lateral actin fibers are a key to the nuclear deformation under uniaxial cell-substrate stretching. Biochem. Biophys. Res. Commun. 597, 37–43 (2022).

    Article  CAS  PubMed  Google Scholar 

  131. Alam, S. G. et al. The nucleus is an intracellular propagator of tensile forces in NIH 3T3 fibroblasts. J. Cell Sci. 128, 1901–1911 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Aureille, J. et al. Nuclear envelope deformation controls cell cycle progression in response to mechanical force. EMBO Rep. 20, e48084 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Lammerding, J. & Wolf, K. Nuclear envelope rupture: actin fibers are putting the squeeze on the nucleus. J. Cell Biol. 215, 5–8 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hatch, E. M. Nuclear envelope rupture: little holes, big openings. Curr. Opin. Cell Biol. 52, 66–72 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Khatau, S. B. et al. A perinuclear actin cap regulates nuclear shape. Proc. Natl Acad. Sci. USA 106, 19017–19022 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lovett, D. B., Shekhar, N., Nickerson, J. A., Roux, K. J. & Lele, T. P. Modulation of nuclear shape by substrate rigidity. Cell. Mol. Bioeng. 6, 230–238 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. Gupta, M. et al. Adaptive rheology and ordering of cell cytoskeleton govern matrix rigidity sensing. Nat. Commun. 6, 7525 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Nagayama, K., Yahiro, Y. & Matsumoto, T. Apical and basal stress fibers have different roles in mechanical regulation of the nucleus in smooth muscle cells cultured on a substrate. Cell. Mol. Bioeng. 6, 473–481 (2013).

    Article  CAS  Google Scholar 

  139. Bruyère, C. et al. Actomyosin contractility scales with myoblast elongation and enhances differentiation through YAP nuclear export. Sci. Rep. 9, 15565 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Azevedo, M. & Baylies, M. K. Getting into position: nuclear movement in muscle cells. Trends Cell Biol. 30, 303–316 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Roman, W. et al. Muscle repair after physiological damage relies on nuclear migration for cellular reconstruction. Science 374, 355–359 (2021).

    Article  CAS  PubMed  Google Scholar 

  142. Gimpel, P. et al. Nesprin-1α-dependent microtubule nucleation from the nuclear envelope via Akap450 is necessary for nuclear positioning in muscle cells. Curr. Biol. 27, 2999–3009.e9 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Roman, W. et al. Myofibril contraction and crosslinking drive nuclear movement to the periphery of skeletal muscle. Nat. Cell Biol. 19, 1189–1201 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Wu, Y. K., Umeshima, H., Kurisu, J. & Kengaku, M. Nesprins and opposing microtubule motors generate a point force that drives directional nuclear motion in migrating neurons. Development 145, dev158782 (2018).

    Article  PubMed  CAS  Google Scholar 

  145. Picariello, H. S. et al. Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner. Proc. Natl Acad. Sci. USA 116, 15550–15559 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Vargas, J. D., Hatch, E. M., Anderson, D. J. & Hetzer, M. W. Transient nuclear envelope rupturing during interphase in human cancer cells. Nucleus 3, 88–100 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Chai, R. J. et al. Disrupting the LINC complex by AAV mediated gene transduction prevents progression of lamin induced cardiomyopathy. Nat. Commun. 12, 4722 (2021). First report showing that LINC complex disruption can improve disease progression in a laminopathy mouse model of dilated cardiomyopathy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Piccus, R. & Brayson, D. The nuclear envelope: LINCing tissue mechanics to genome regulation in cardiac and skeletal muscle. Biol. Lett. 16, 20200302 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Razafsky, D., Potter, C. & Hodzic, D. Validation of a mouse model to disrupt LINC complexes in a cell-specific manner. J. Vis. Exp. 106, e53318 (2015).

    Google Scholar 

  150. Hampoelz, B. et al. Microtubule-induced nuclear envelope fluctuations control chromatin dynamics in Drosophila embryos. Development 138, 3377–3386 (2011).

    Article  CAS  PubMed  Google Scholar 

  151. Schulze, S. R. et al. A comparative study of Drosophila and human A-type lamins. PLoS ONE 4, e7564 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Bone, C. R., Chang, Y.-T., Cain, N. E., Murphy, S. P. & Starr, D. A. Nuclei migrate through constricted spaces using microtubule motors and actin networks in C. elegans hypodermal cells. Development 143, 4193–4202 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Driver, E. C., Northrop, A. & Kelley, M. W. Cell migration, intercalation and growth regulate mammalian cochlear extension. Development 144, 3766–3776 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Mohammed, D. et al. Substrate area confinement is a key determinant of cell velocity in collective migration. Nat. Phys. 15, 858–866 (2019).

    Article  CAS  Google Scholar 

  155. Yanakieva, I., Erzberger, A., Matejčić, M., Modes, C. D. & Norden, C. Cell and tissue morphology determine actin-dependent nuclear migration mechanisms in neuroepithelia. J. Cell Biol. 218, 3272–3289 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Norden, C., Young, S., Link, B. A. & Harris, W. A. Actomyosin is the main driver of interkinetic nuclear migration in the retina. Cell 138, 1195–1208 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Tsai, L.-H. & Gleeson, J. G. Nucleokinesis in neuronal migration. Neuron 46, 383–388 (2005).

    Article  CAS  PubMed  Google Scholar 

  158. Cooper, J. A. Mechanisms of cell migration in the nervous system. J. Cell Biol. 202, 725–734 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Young, S. G., Jung, H.-J., Lee, J. M. & Fong, L. G. Nuclear lamins and neurobiology. Mol. Cell Biol. 34, 2776–2785 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Wolf, K. et al. Collagen-based cell migration models in vitro and in vivo. Semin. Cell Dev. Biol. 20, 931–941 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Yamada, K. M. & Sixt, M. Mechanisms of 3D cell migration. Nat. Rev. Mol. Cell Biol. 20, 738–752 (2019).

    Article  CAS  PubMed  Google Scholar 

  162. Renkawitz, J. et al. Nuclear positioning facilitates amoeboid migration along the path of least resistance. Nature 568, 546–550 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Maciejowski, J. & Hatch, E. M. Nuclear membrane rupture and its consequences. Annu. Rev. Cell Dev. Biol. 36, 85–114 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Thiam, H.-R. et al. Perinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments. Nat. Commun. 7, 10997 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Fridolfsson, H. N. & Starr, D. A. Kinesin-1 and dynein at the nuclear envelope mediate the bidirectional migrations of nuclei. J. Cell Biol. 191, 115–128 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Marks, P. C. & Petrie, R. J. Push or pull: how cytoskeletal crosstalk facilitates nuclear movement through 3D environments. Phys. Biol. 19, 021003 (2022).

    Article  Google Scholar 

  167. de Noronha, C. M. C. et al. Dynamic disruptions in nuclear envelope architecture and integrity induced by HIV-1 Vpr. Science 294, 1105–1108 (2001).

    Article  PubMed  Google Scholar 

  168. Vos, W. H. D. et al. Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum. Mol. Genet. 20, 4175–4186 (2011). First report of spontaneous nuclear envelope rupture in laminopathy cells.

    Article  PubMed  CAS  Google Scholar 

  169. Srivastava, N. et al. Nuclear fragility, blaming the blebs. Curr. Opin. Cell Biol. 70, 100–108 (2021).

    Article  CAS  PubMed  Google Scholar 

  170. Pfeifer, C. R. et al. Gaussian curvature dilutes the nuclear lamina, favoring nuclear rupture, especially at high strain rate. Nucleus 13, 129–143 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Pfeifer, C. R., Vashisth, M., Xia, Y. & Discher, D. E. Nuclear failure, DNA damage, and cell cycle disruption after migration through small pores: a brief review. Essays Biochem. 63, 569–577 (2019).

    Article  CAS  PubMed  Google Scholar 

  172. Goldman, R. D. et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 101, 8963–8968 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Muchir, A. et al. Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations. Muscle Nerve 30, 444–450 (2004).

    Article  CAS  PubMed  Google Scholar 

  174. Karoutas, A. et al. The NSL complex maintains nuclear architecture stability via lamin A/C acetylation. Nat. Cell Biol. 21, 1248–1260 (2019).

    Article  CAS  PubMed  Google Scholar 

  175. Harada, T. et al. Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival. J. Cell Biol. 204, 669–682 (2014). Study demonstrating that increased nuclear deformability caused by reduced lamin A/C expression enhances cell migration through confined environments but renders cells more susceptible to mechanically induced damage and cell death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Rowat, A. C., Lammerding, J. & Ipsen, J. H. Mechanical properties of the cell nucleus and the effect of emerin deficiency. Biophys. J. 91, 4649–4664 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Berre, M. L., Aubertin, J. & Piel, M. Fine control of nuclear confinement identifies a threshold deformation leading to lamina rupture and induction of specific genes. Integr. Biol. 4, 1406–1414 (2012).

    Article  CAS  Google Scholar 

  178. Takaki, T. et al. Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability. Nat. Commun. 8, 16013 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Jain, N. & Vogel, V. Spatial confinement downsizes the inflammatory response of macrophages. Nat. Mater. 17, 1134–1144 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Isermann, P. & Lammerding, J. Consequences of a tight squeeze: nuclear envelope rupture and repair. Nucleus 8, 268–274 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Deviri, D. et al. Scaling laws indicate distinct nucleation mechanisms of holes in the nuclear lamina. Nat. Phys. 15, 823–829 (2019).

    Article  CAS  Google Scholar 

  182. Irianto, J. et al. DNA damage follows repair factor depletion and portends genome variation in cancer cells after pore migration. Curr. Biol. 27, 210–223 (2017). This study reports increasing DNA damage and chromosomal abnormalities in tumour cells after repeated migration through small constrictions.

    Article  CAS  PubMed  Google Scholar 

  183. Halfmann, C. T. et al. Repair of nuclear ruptures requires barrier-to-autointegration factor. J. Cell Biol. 218, 2136–2149 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Penfield, L. et al. Dynein pulling forces counteract lamin-mediated nuclear stability during nuclear envelope repair. Mol. Biol. Cell 29, 852–868 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Young, A. M., Gunn, A. L. & Hatch, E. M. BAF facilitates interphase nuclear membrane repair through recruitment of nuclear transmembrane proteins. Mol. Biol. Cell 31, 1551–1560 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Nader, G. P. et al. Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion. Cell 184, 5230–5246 (2021).

    Article  CAS  PubMed  Google Scholar 

  187. Shah, P. et al. Nuclear deformation causes DNA damage by increasing replication stress. Curr. Biol. 31, 753–765 (2021).

    Article  CAS  PubMed  Google Scholar 

  188. Kidiyoor, G. R. et al. ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration. Nat. Commun. 11, 4828 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Jiang, Y. N. et al. Interleukin 6-triggered ataxia-telangiectasia mutated kinase activation facilitates epithelial-to-mesenchymal transition in lung cancer by upregulating vimentin expression. Exp. Cell Res. 381, 165–171 (2019).

    Article  CAS  PubMed  Google Scholar 

  190. Peng, B., Ortega, J., Gu, L., Chang, Z. & Li, G.-M. Phosphorylation of proliferating cell nuclear antigen promotes cancer progression by activating the ATM/Akt/GSK3β/Snail signaling pathway. J. Biol. Chem. 294, 7037–7045 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Enyedi, B., Jelcic, M. & Niethammer, P. The cell nucleus serves as a mechanotransducer of tissue damage-induced inflammation. Cell 165, 1160–1170 (2016). First demonstration that increased nuclear membrane tension can trigger recruitment of cPLA2 to the, where it can induce further downstream signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Shen, Z. et al. A synergy between mechanosensitive calcium- and membrane-binding mediates tension-sensing by C2-like domains. Proc. Natl Acad. Sci. USA 119, e2112390119 (2022).

  194. Niethammer, P. Components and mechanisms of nuclear mechanotransduction. Annu. Rev. Cell Dev. Biol. 37, 233–256 (2021).

    Article  CAS  PubMed  Google Scholar 

  195. Shen, Z. & Niethammer, P. A cellular sense of space and pressure. Science 370, 295–296 (2020).

    Article  CAS  PubMed  Google Scholar 

  196. Katayama, T. et al. Stimulatory effects of arachidonic acid on myosin ATPase activity and contraction of smooth muscle via myosin motor domain. Am. J. Physiol. Heart Circ. Physiol. 298, H505–H514 (2010).

    Article  CAS  PubMed  Google Scholar 

  197. Brown, M., Roulson, J.-A., Hart, C. A., Tawadros, T. & Clarke, N. W. Arachidonic acid induction of Rho-mediated transendothelial migration in prostate cancer. Br. J. Cancer 110, 2099–2108 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171, 1397–1410 (2017). First report of mechanically induced opening of NPCs, mediating import of the mechanoresponsive transcription factor YAP.

    Article  CAS  PubMed  Google Scholar 

  199. Zimmerli, C. E. et al. Nuclear pores dilate and constrict in cellulo. Science 374, eabd9776 (2021).

    Article  CAS  PubMed  Google Scholar 

  200. Driscoll, T. P., Cosgrove, B. D., Heo, S.-J., Shurden, Z. E. & Mauck, R. L. Cytoskeletal to nuclear strain transfer regulates YAP signaling in mesenchymal stem cells. Biophys. J. 108, 2783–2793 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Moya, I. M. & Halder, G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat. Rev. Mol. Cell Biol. 20, 211–226 (2019).

    Article  CAS  PubMed  Google Scholar 

  202. Luciano, M. et al. Cell monolayers sense curvature by exploiting active mechanics and nuclear mechanoadaptation. Nat. Phys. 17, 1382–1390 (2021).

    Article  CAS  Google Scholar 

  203. Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).

    Article  CAS  PubMed  Google Scholar 

  204. Tajik, A. et al. Transcription upregulation via force-induced direct stretching of chromatin. Nat. Mater. 15, 1287–1296 (2016). First report of mechanically induced chromosome stretching and increased gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Sun, J., Chen, J., Mohagheghian, E. & Wang, N. Force-induced gene up-regulation does not follow the weak power law but depends on H3K9 demethylation. Sci. Adv. 6, eaay9095 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Almonacid, M. et al. Active fluctuations of the nuclear envelope shape the transcriptional dynamics in oocytes. Dev. Cell 51, 145–157.e10 (2019).

    Article  CAS  PubMed  Google Scholar 

  207. Hsia, C.-R. et al. Confined migration induces heterochromatin formation and alters chromatin accessibility. bioRxiv https://doi.org/10.1101/2021.09.22.461293 (2021).

    Article  Google Scholar 

  208. Jacobson, E. C. et al. Migration through a small pore disrupts inactive chromatin organization in neutrophil-like cells. BMC Biol. 16, 142 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Golloshi, R. et al. Constricted migration is associated with stable 3D genome structure differences in melanoma cells. bioRxiv https://doi.org/10.1101/856583 (2020).

    Article  Google Scholar 

  210. Damodaran, K. et al. Compressive force induces reversible chromatin condensation and cell geometry-dependent transcriptional response. Mol. Biol. Cell 29, 3039–3051 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Ho, C. Y., Jaalouk, D. E., Vartiainen, M. K. & Lammerding, J. Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics. Nature 497, 507–511 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Killaars, A. R., Walker, C. J. & Anseth, K. S. Nuclear mechanosensing controls MSC osteogenic potential through HDAC epigenetic remodeling. Proc. Natl Acad. Sci. USA 117, 21258–21266 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Walker, C. J. et al. Nuclear mechanosensing drives chromatin remodelling in persistently activated fibroblasts. Nat. Biomed. Eng. 5, 1485–1499 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Seelbinder, B. et al. Nuclear deformation guides chromatin reorganization in cardiac development and disease. Nat. Biomed. Eng. 5, 1500–1516 (2021).

    Article  CAS  PubMed  Google Scholar 

  215. Heo, S.-J. et al. Mechanically induced chromatin condensation requires cellular contractility in mesenchymal stem cells. Biophys. J. 111, 864–874 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Heo, S.-J. et al. Biophysical regulation of chromatin architecture instills a mechanical memory in mesenchymal stem cells. Sci. Rep. 5, 16895 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Hannezo, E. & Heisenberg, C.-P. Mechanochemical feedback loops in development and disease. Cell 178, 12–25 (2019).

    Article  CAS  PubMed  Google Scholar 

  218. Kirby, T. J. & Lammerding, J. Emerging views of the nucleus as a cellular mechanosensor. Nat. Cell Biol. 20, 373–381 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Miroshnikova, Y. A. & Wickström, S. A. Mechanical forces in nuclear organization. Cold Spring Harb. Perspect. Biol. 14, a039685 (2022).

    Article  CAS  PubMed  Google Scholar 

  220. Swift, J. & Discher, D. E. The nuclear lamina is mechano-responsive to ECM elasticity in mature tissue. J. Cell Sci. 127, 3005–3015 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Ihalainen, T. O. et al. Differential basal-to-apical accessibility of lamin A/C epitopes in the nuclear lamina regulated by changes in cytoskeletal tension. Nat. Mater. 14, 1252–1261 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Sapra, K. T. et al. Nonlinear mechanics of lamin filaments and the meshwork topology build an emergent nuclear lamina. Nat. Commun. 11, 6205 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Guilluy, C. et al. Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus. Nat. Cell Biol. 16, 376–381 (2014). First report of mechano-adaptive changes in isolated nuclei, indicating a nucleus-intrinsic ability to respond to mechanical forces.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Zwerger, M., Ho, C. Y. & Lammerding, J. Nuclear mechanics in disease. Annu. Rev. Biomed. Eng. 13, 397–428 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Nyirenda, N., Farkas, D. L. & Ramanujan, V. K. Preclinical evaluation of nuclear morphometry and tissue topology for breast carcinoma detection and margin assessment. Breast Cancer Res. Treat. 126, 345–354 (2011).

    Article  PubMed  Google Scholar 

  226. Mueller, J. L. et al. Rapid staining and imaging of subnuclear features to differentiate between malignant and benign breast tissues at a point-of-care setting. J. Cancer Res. Clin. Oncol. 142, 1475–1486 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Somech, R., Shaklai, S., Amariglio, N., Rechavi, G. & Simon, A. J. Nuclear envelopathies — raising the nuclear veil. Pediatr. Res. 57, 8–15 (2005).

    Article  Google Scholar 

  228. Hershberger, R. E., Hedges, D. J. & Morales, A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat. Rev. Cardiol. 10, 531–547 (2013).

    Article  CAS  PubMed  Google Scholar 

  229. Wong, X. & Stewart, C. L. The laminopathies and the insights they provide into the structural and functional organization of the nucleus. Annu. Rev. Genomics Hum. Genet. 21, 263–288 (2020).

    Article  CAS  PubMed  Google Scholar 

  230. Bonne, G. et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery–Dreifuss muscular dystrophy. Nat. Genet. 21, 285–288 (1999).

    Article  CAS  PubMed  Google Scholar 

  231. Sandre-Giovannoli, A. D. et al. Lamin a truncation in Hutchinson-Gilford progeria. Science 300, 2055 (2003).

    Article  PubMed  Google Scholar 

  232. Folker, E. S., Ostlund, C., Luxton, G. W. G., Worman, H. J. & Gundersen, G. G. Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement. Proc. Natl Acad. Sci. USA 108, 131–136 (2011).

    Article  CAS  PubMed  Google Scholar 

  233. Méjat, A. & Misteli, T. LINC complexes in health and disease. Nucleus 1, 40–52 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Fischer, M., Rikeit, P., Knaus, P. & Coirault, C. YAP-mediated mechanotransduction in skeletal muscle. Front. Physiol. 7, 41 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Owens, D. J. et al. Lamin mutations cause increased YAP nuclear entry in muscle stem cells. Cells 9, 816 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  236. Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293–298 (2003).

    Article  CAS  PubMed  Google Scholar 

  237. Verstraeten, V. L. R. M., Ji, J. Y., Cummings, K. S., Lee, R. T. & Lammerding, J. Increased mechanosensitivity and nuclear stiffness in Hutchinson-Gilford progeria cells: effects of farnesyltransferase inhibitors. Aging Cell 7, 383–393 (2008).

    Article  CAS  PubMed  Google Scholar 

  238. Booth, E. A., Spagnol, S. T., Alcoser, T. A. & Dahl, K. N. Nuclear stiffening and chromatin softening with progerin expression leads to an attenuated nuclear response to force. Soft Matter 11, 6412–6418 (2015).

    Article  CAS  PubMed  Google Scholar 

  239. Kim, P. H. et al. Disrupting the LINC complex in smooth muscle cells reduces aortic disease in a mouse model of Hutchinson-Gilford progeria syndrome. Sci. Transl. Med. 10, eaat7163 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  240. Dahl, K. N. et al. Distinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 103, 10271–10276 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Columbaro, M. et al. Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment. Cell. Mol. Life Sci. 62, 2669–2678 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Coffinier, C. et al. Deficiencies in lamin B1 and lamin B2 cause neurodevelopmental defects and distinct nuclear shape abnormalities in neurons. Mol. Biol. Cell 22, 4683–4693 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Young, S. G., Jung, H.-J., Coffinier, C. & Fong, L. G. Understanding the roles of nuclear A- and B-type lamins in brain development. J. Biol. Chem. 287, 16103–16110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Coffinier, C., Fong, L. G. & Young, S. G. LINCing lamin B2 to neuronal migration: growing evidence for cell-specific roles of B-type lamins. Nucleus 1, 407–411 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  245. Vortmeyer-Krause, M. et al. Lamin B2 follows lamin A/C- mediated nuclear mechanics and cancer cell invasion efficacy. bioRxiv https://doi.org/10.1101/2020.04.07.028969 (2020).

    Article  Google Scholar 

  246. Padiath, Q. S. et al. Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat. Genet. 38, 1114–1123 (2006).

    Article  CAS  PubMed  Google Scholar 

  247. Ballatore, C., Lee, V. M.-Y. & Trojanowski, J. Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci. 8, 663–672 (2007).

    Article  CAS  PubMed  Google Scholar 

  248. Sergent, C., Baillet, S. & Dehaene, S. Timing of the brain events underlying access to consciousness during the attentional blink. Nat. Neurosci. 8, 1391–1400 (2005).

    Article  CAS  PubMed  Google Scholar 

  249. Fernández-Nogales, M. et al. Huntington’s disease is a four-repeat tauopathy with tau nuclear rods. Nat. Med. 20, 881–885 (2014).

    Article  PubMed  CAS  Google Scholar 

  250. Crisp, M. et al. Coupling of the nucleus and cytoplasm: role of the LINC complex. J. Cell Biol. 172, 41–53 (2006). First description of the LINC complex and its role in connecting the cytoskeleton and nuclear interior.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Paonessa, F. et al. Microtubules deform the nuclear membrane and disrupt nucleocytoplasmic transport in tau-mediated frontotemporal dementia. Cell Rep. 26, 582–593.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Fernández-Nogales, M. & Lucas, J. J. Altered levels and isoforms of tau and nuclear membrane invaginations in Huntington’s disease. Front Cell. Neurosci. 13, 574 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  253. von Appen, A. et al. LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation. Nature 582, 115–118 (2020).

    Article  CAS  Google Scholar 

  254. Stephens, A. D., Banigan, E. J. & Marko, J. F. Separate roles for chromatin and lamins in nuclear mechanics. Nucleus 9, 119–124 (2018).

    Article  PubMed  Google Scholar 

  255. Bronshtein, I. et al. Loss of lamin A function increases chromatin dynamics in the nuclear interior. Nat. Commun. 6, 8044 (2015).

    Article  CAS  PubMed  Google Scholar 

  256. Corne, T. D. J. et al. Deregulation of focal adhesion formation and cytoskeletal tension due to loss of A-type lamins. Cell Adhes. Migr. 11, 447–463 (2017).

    Article  CAS  Google Scholar 

  257. Nikolova, V. et al. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J. Clin. Invest. 113, 357–369 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Puckelwartz, M. J. et al. Nesprin-1 mutations in human and murine cardiomyopathy. J. Mol. Cell. Cardiol. 48, 600–608 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

  1. University of Mons, Soft Matter & Biomaterials Group, Interfaces and Complex Fluids Laboratory, Research Institute for Biosciences, CIRMAP, Mons, Belgium

    Yohalie Kalukula & Sylvain Gabriele

  2. Biology Department, University of Massachusetts Amherst, Amherst, MA, USA

    Andrew D. Stephens

  3. Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA

    Jan Lammerding

  4. Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA

    Jan Lammerding

Authors
  1. Yohalie Kalukula
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew D. Stephens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan Lammerding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sylvain Gabriele
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.K., J.L. and S.G. conceptualized the article. J.L. and S.G. contributed equally to the editing of the text. Figure designs were generated by Y.K. and S.G. and further edited by J.L., Y.K. and S.G. All authors contributed substantially to the discussion of the content and approved the final content.

Corresponding authors

Correspondence to Jan Lammerding or Sylvain Gabriele.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Molecular Cell Biology thanks Matthieu Piel, Pere Roca-Cusachs who co-reviewed with Zanetta Kechagia, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Mechanotransduction

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.

Mechanosensing

Molecular process through which cells or cellular components translate mechanical forces or deformations into biochemical signals.

Stress

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).

Rhabdomyosarcoma

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.

Farnesylation

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.

Nucleokinesis

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.

Viscoelastic

Rheological property of natural or synthetic materials with viscous and elastic properties that allows for timescale-dependent deformation when subjected to mechanical stress.

Elastic

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).

Viscous

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).

Strain

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.

Blebbing

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.

BAF

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.

Laminopathy

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.

TREX1

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.

Micronuclei

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.

Chromocentres

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-022-00480-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing