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Regulation of genome organization and gene expression by nuclear mechanotransduction

Nature Reviews Molecular Cell Biology volume 18, pages 717–727 (2017)Cite this article

Subjects

Key Points

  • Cellular mechanical states modulate cytoskeleton–nucleus links and trigger the translocation of regulatory molecules to the nucleus.

  • The remodelling of cytoskeleton–nucleus links results in distinct morphological as well as mechanical and dynamic properties of the cell nucleus.

  • The cell type-specific organization of chromosomes and their intermingling is modulated by the mechanical state of a cell.

  • The recruitment of transcription factors to their target genes is facilitated by the nuclear mechanical state through the establishment of particular chromosome neighbourhoods and functional gene clusters.

  • Such cell type-specific chromosome neighbourhoods and gene clusters are established during cell differentiation.

  • The spatial organization of chromosomes and their intermingling are crucial for mechanoregulation of gene expression, and alterations thereof can result in the onset of various diseases.

Abstract

It is well established that cells sense chemical signals from their local microenvironment and transduce them to the nucleus to regulate gene expression programmes. Although a number of experiments have shown that mechanical cues can also modulate gene expression, the underlying mechanisms are far from clear. Nevertheless, we are now beginning to understand how mechanical cues are transduced to the nucleus and how they influence nuclear mechanics, genome organization and transcription. In particular, recent progress in super-resolution imaging, in genome-wide application of RNA sequencing, chromatin immunoprecipitation and chromosome conformation capture and in theoretical modelling of 3D genome organization enables the exploration of the relationship between cell mechanics, 3D chromatin configurations and transcription, thereby shedding new light on how mechanical forces regulate gene expression.

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Figure 1: Nuclear mechanotransduction.
Figure 2: Crosstalk between the serum response pathway, the NF-κB pathway and global chromatin remodelling.
Figure 3: The modulation of chromosome intermingling and gene neighbourhoods is induced by cell mechanical constraints.
Figure 4: The modularity in chromosome organization and gene expression depends on nuclear mechanical state.

References

  1. Discher, D. E., Janmey, P. & Wang, Y. L. Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Petridou, N. I., Spiró, Z. & Heisenberg, C. P. Multiscale force sensing in development. Nat. Cell Biol. 19, 581–588 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Kutys, M. L. & Chen, C. S. Forces and mechanotransduction in 3D vascular biology. Curr. Opin. Cell Biol. 42, 73–79 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Humphrey, J. D., Dufresne, E. R. & Schwartz, M. A. Mechanotransduction and extracellular matrix homeostasis. Nat. Rev. Mol. Cell Biol. 15, 802–812 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schreiber, T. H., Shinder, V., Cain, D. W., Alon, R. & Sackstein, R. Shear flow-dependent integration of apical and subendothelial chemokines in T-cell transmigration: implications for locomotion and the multistep paradigm. Blood 109, 1381–1386 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vogel, V. & Sheetz, M. Local force and geometry sensing regulate cell functions. Nat. Rev. Mol. Cell Biol. 7, 265–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Chen, C. S., Mrksich, M., Huang, S., Whitesides, G. M. & Ingber, D. E. Geometric control of cell life and death. Science 276, 1425–1428 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Przybyla, L., Muncie, J. M. & Weaver, V. M. Mechanical control of epithelial-to-mesenchymal transitions in development and cancer. Annu. Rev. Cell Dev. Biol. 32, 527–554 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Chin, L., Xia, Y., Discher, D. E. & Janmey, P. A. Mechanotransduction in cancer. Curr. Opin. Chem. Eng. 11, 77–84 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Brock, A., Krause, S. & Ingber, D. E. Control of cancer formation by intrinsic genetic noise and microenvironmental cues. Nat. Rev. Cancer 15, 499–509 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Sun, Z., Guo, S. S. & Fässler, R. Integrin-mediated mechanotransduction. J. Cell Biol. 215, 445–456 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Roca-Cusachs, P., Conte, V. & Trepat, X. Quantifying forces in cell biology. Nat. Cell Biol. 19, 742–751 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Stutchbury, B., Atherton, P., Tsang, R., Wang, D. Y. & Ballestrem, C. Distinct focal adhesion protein modules control different aspects of mechanotransduction. J. Cell Sci. 130, 1612–1624 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Coste, B. et al. Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 483, 176–181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Collins, C., Denisin, A. K., Pruitt, B. L. & Nelson, W. J. Changes in E-cadherin rigidity sensing regulate cell adhesion. Proc. Natl Acad. Sci. USA 114, E5835–E5844 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Luca, V. C. et al. Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science 355, 1320–1324 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mattila, P. K., Batista, F. D. & Treanor, B. Dynamics of the actin cytoskeleton mediates receptor cross talk: an emerging concept in tuning receptor signaling. J. Cell Biol. 212, 267–280 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Moore, S. W., Roca-Cusachs, P. & Sheetz, M. P. Stretchy proteins on stretchy substrates: the important elements of integrin-mediated rigidity sensing. Dev. Cell 19, 194–206 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Engler, A. J. et al. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006). This study demonstrates that mesenchymal stem cells can be differentiated into different lineages by changing the substrate rigidity.

    Article  CAS  PubMed  Google Scholar 

  20. Kilian, K. A., Bugarija, B., Lahn, B. T. & Mrksich, M. Geometric cues for directing the differentiation of mesenchymal stem cells. Proc. Natl Acad. Sci. USA 107, 4872–4877 (2010). This study identifies surface topography as a regulator of stem cell differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Adamo, L. et al. Biomechanical forces promote embryonic haematopoiesis. Nature 459, 1131–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fernández- Sánchez, M. E. et al. Mechanical induction of the tumorigenic β-catenin pathway by tumor growth pressure. Nature 523, 92–95 (2015).

    Article  CAS  Google Scholar 

  23. Jain, R. K., Martin, J. D. & Stylianopoulos, T. The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng. 16, 321–346 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shivashankar, G. V. Mechanosignaling to the cell nucleus and gene regulation. Annu. Rev. Biophys. 40, 361–378 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Panciera, T., Azzolin, L., Cordenonsi, M. & Piccolo, S. Mechanobiology of YAP and TAZ in physiology and disease. Nat. Rev. Mol. Cell Biol. http://dx.doi.org/10.1038/nrm.2017.87 (2017).

  26. Lanctôt, C. et al. Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nat. Rev. Genet. 8, 104–115 (2007).

    Article  PubMed  CAS  Google Scholar 

  27. Dekker, J. & Mirny, L. The 3D genome as moderator of chromosomal communication. Cell 164, 1110–1121 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mammoto, A., Mammoto, T. & Ingber, D. E. Mechanosensitive mechanisms in transcriptional regulation. J. Cell Sci. 125, 3061–3073 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang, N., Tytell, J. D. & Ingber, D. E. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat. Rev. Mol. Cell Biol. 10, 75–82 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Kadrmas, J. L. & Beckerle, M. C. The LIM domain: from the cytoskeleton to the nucleus. Nat. Rev. Mol. Cell Biol. 5, 920–931 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Pawłowski, R. et al. An actin-regulated importin α/β-dependent extended bipartite NLS directs nuclear import of MRTF-A. EMBO J. 29, 3448–3458 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Starr, D. A. & Fridolfsson, H. N. Interactions between nuclei and the cytoskeleton are mediated by SUN-KASH nuclear-envelope bridges. Annu. Rev. Cell Dev. Biol. 26, 421–444 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Crisp, M. et al. Coupling of the nucleus and cytoplasm: role of the LINC complex. J. Cell Biol. 172, 41–53 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Alam, S. G. et al. The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity. Sci. Rep. 6, 38063 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Arsenovic, P. T. et al. Nesprin-2G, a component of the nuclear LINC complex, is subject to Myosin-dependent tension. Biophys. J. 110, 34–43 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 

  38. Zhang, Q. et al. Nesprin-1 and -2 are involved in the pathogenesis of Emery-Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum. Mol. Genet. 16, 2816–2833 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Sosa, B. A., Kutay, U. & Schwartz, T. U. Structural insights into LINC complexes. Curr. Opin. Struct. Biol. 23, 285–291 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Iyer, K. V. et al. Mechanical activation of cells induces chromatin remodeling preceding MKL nuclear transport. Biophys. J. 103, 1416–1428 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tajik, A. et al. Transcription upregulation via force-induced direct stretching of chromatin. Nat. Mater. 15, 1287–1296 (2016). This study demonstrates the direct mechanical coupling between plasma membrane and chromatin for transcription control.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li, Q., Makhija, E., Hameed, F. M. & Shivashankar, G. V. Micropillar displacements by cell traction forces are mechanically correlated with nuclear dynamics. Biochem. Biophys. Res. Commun. 461, 372–377 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Guilluy, C. et al. Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus. Nat. Cell Biol. 16, 376–381 (2014). This paper shows that the inner nuclear membrane protein emerin can be activated by mechanical forces.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kumar, A. et al. ATR mediates a checkpoint at the nuclear envelope in response to mechanical stress. Cell 158, 633–646 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Enyedi, B., Jelcic, M. & Niethammer, P. The cell nucleus serves as a mechanotransducer of tissue damage-induced inflammation. Cell 165, 1160–1170 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    CAS  PubMed  Google Scholar 

  47. Denais, C. M. et al. Nuclear envelope rupture and repair during cancer cell migration. Science 352, 353–358 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. Kaunas, R., Nguyen, P., Usami, S. & Chien, S. Cooperative effects of Rho and mechanical stretch on stress fiber organization. Proc. Natl Acad. Sci. USA 102, 15895–15900 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Khatau, S. B. et al. A perinuclear actin cap regulates nuclear shape. Proc. Natl Acad. Sci. USA 106, 19017–19022 (2009). This paper identifies the role of apical actin stress fibres in regulating the shape of the cell nucleus, a process dependent on cell–extracellular matrix interactions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li, Q. et al. The regulation of dynamic mechanical coupling between actin cytoskeleton and nucleus by matrix geometry. Biomaterials 35, 961–969 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Shao, X., Li, Q., Mogilner, A., Bershadsky, A. D. & Shivashankar, G. V. Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim. Proc. Natl Acad. Sci. USA 112, E2595–E2601 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ramabhadran, V., Hatch, A. L. & Higgs, H. N. Actin monomers activate inverted formin 2 by competing with its autoinhibitory interaction. J. Biol. Chem. 288, 26847–26855 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Versaevel, M., Grevesse, T. & Gabriele, S. Spatial coordination between cell and nuclear shape within micropatterned endothelial cells. Nat. Commun. 3, 671 (2012).

    Article  PubMed  CAS  Google Scholar 

  55. 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 

  56. Gruenbaum, Y. & Foisner, R. Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annu. Rev. Biochem. 84, 131–164 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Thorpe, S. D. & Lee, D. A. Dynamic regulation of nuclear architecture and mechanics-a rheostatic role for the nucleus in tailoring cellular mechanosensitivity. Nucleus 8, 287–300 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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 

  59. Kim, D. H. & Wirtz, D. Cytoskeletal tension induces the polarized architecture of the nucleus. Biomaterials 48, 161–172 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mazumder, A. & Shivashankar, G. V. Gold-nanoparticle-assisted laser perturbation of chromatin assembly reveals unusual aspects of nuclear architecture within living cells. Biophys. J. 93, 2209–2216 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ramdas, N. M. & Shivashankar, G. V. Cytoskeletal control of nuclear morphology and chromatin organization. J. Mol. Biol. 427, 695–706 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Swift, J. et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341, 1240104 (2013). This study shows, using a proteomic screen, that nuclear lamin A levels increase with increased tissue stiffness.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Burke, B. & Stewart, C. L. The nuclear lamins: flexibility in function. Nat. Rev. Mol. Cell Biol. 14, 13–24 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. 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 

  65. 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 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bascom, G. & Schlick, T. Linking chromatin fibers to gene folding by hierarchical looping. Biophys. J. 112, 434–445 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mazumder, A. et al. Dynamics of chromatin decondensation reveals the structural integrity of a mechanically prestressed nucleus. Biophys. J. 95, 3028–3035 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17, 487–500 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. Gesson, K. et al. A-Type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha. Genome Res. 26, 462–473 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Schreiner, S. M., Koo, P. K., Zhao, Y., Mochrie, S. G. & King, M. C. The tethering of chromatin to the nuclear envelope supports nuclear mechanics. Nat. Commun. 6, 7159 (2015).

    Article  PubMed  Google Scholar 

  71. 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 

  72. Hanson, L. et al. Vertical nanopillars for in situ probing of nuclear mechanics in adherent cells. Nat. Nanotechnol. 10, 554–562 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Radhakrishnan, A. V., Jokhun, D. S., Venkatachalapathy, S. & Shivashankar, G. V. Nuclear positioning and its translational dynamics are regulated by cell geometry. Biophys. J. 112, 1920–1928 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kumar, A., Maitra, A., Sumit, M., Ramaswamy, S. & Shivashankar, G. V. Actomyosin contractility rotates the cell nucleus. Sci. Rep. 4, 3781 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Makhija, E., Jokhun, D. S. & Shivashankar, G. V. Nuclear deformability and telomere dynamics are regulated by cell geometric constraints. Proc. Natl Acad. Sci. USA 113, E32–E40 (2016). This paper demonstrates that the cell–matrix interactions regulate nuclear and chromatin dynamics.

    Article  CAS  PubMed  Google Scholar 

  76. Ji, J. Y. et al. Cell nuclei spin in the absence of lamin b1. J. Biol. Chem. 282, 20015–20026 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Toh, K. C., Ramdas, N. M. & Shivashankar, G. V. Actin cytoskeleton differentially alters the dynamics of lamin A, HP1α and H2B core histone proteins to remodel chromatin condensation state in living cells. Integr. Biol. (Camb.) 7, 1309–1317 (2015).

    Article  CAS  Google Scholar 

  78. Jain, N., Iyer, K. V., Kumar, A. & Shivashankar, G. V. Cell geometric constraints induce modular gene-expression patterns via redistribution of HDAC3 regulated by actomyosin contractility. Proc. Natl Acad. Sci. USA 110, 11349–11354 (2013). This study exemplifies the coupling between cell shape and modular gene expression patterns by analysing transcriptome maps in polarized and isotropic cell shapes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 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 

  80. Meshorer, E. et al. Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. Dev. Cell 10, 105–116 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bhattacharya, D., Talwar, S., Mazumder, A. & Shivashankar, G. V. Spatio-temporal plasticity in chromatin organization in mouse cell differentiation and during Drosophila embryogenesis. Biophys. J. 96, 3832–3839 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Talwar, S., Kumar, A., Rao, M., Menon, G. I. & Shivashankar, G. V. Correlated spatio-temporal fluctuations in chromatin compaction states characterize stem cells. Biophys. J. 104, 553–564 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mazumder, A. & Shivashankar, G. V. Emergence of a prestressed eukaryotic nucleus during cellular differentiation and development. J. R. Soc. Interface 7, S321–S330 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Heo, S. J. et al. Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity. eLife 5, e18207 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Wang, Y. et al. Visualizing the mechanical activation of Src. Nature 434, 1040–1045 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Vartiainen, M. K., Guettler, S., Larijani, B. & Treisman, R. Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL. Science 316, 1749–1752 (2007). This study shows that cytoplasmic-to-nuclear shuttling of the transcription cofactor MAL (also known as MRTF) is regulated by the actin polymerization state.

    Article  CAS  PubMed  Google Scholar 

  87. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011). This study demonstrates the importance of YAP–TAZ transcription factors in cellular nuclear mechanosensing and the downstream differential regulation of transcriptional programmes.

    Article  CAS  PubMed  Google Scholar 

  88. Totaro, A. et al. YAP/TAZ link cell mechanics to Notch signalling to control epidermal stem cell fate. Nat. Commun. 8, 15206 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Le, H. Q. et al. Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment. Nat. Cell Biol. 18, 864–875 (2016).

    Article  CAS  PubMed  Google Scholar 

  90. Speight, P., Kofler, M., Szászi, K. & Kapus, A. Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFβ-regulated Smad3. Nat. Commun. 7, 11642 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Qi, Y. X. et al. Nuclear envelope proteins modulate proliferation of vascular smooth muscle cells during cyclic stretch application. Proc. Natl Acad. Sci. USA 113, 5293–5298 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nakazawa, N. et al. Matrix mechanics controls FHL2 movement to the nucleus to activate p21 expression. Proc. Natl Acad. Sci. USA 113, E6813–E6822 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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 

  94. Tang, R. H. et al. Myocardin inhibits cellular proliferation by inhibiting NF-κB(p65)-dependent cell cycle progression. Proc. Natl Acad. Sci. USA 105, 3362–3367 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mitra, A. et al. Cell geometry dictates TNFα-induced genome response. Proc. Natl Acad. Sci. USA 114, E3882–E3891 (2017). This study exemplifies the role of the cellular and nuclear mechanical state for integrating biochemical signals to regulate gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Maharana, S. et al. Chromosome intermingling-the physical basis of chromosome organization in differentiated cells. Nucleic Acids Res. 44, 5148–5160 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Wang, Y., Nagarajan, M., Uhler, C. & Shivashankar, G. V. Orientation and repositioning of chromosomes correlate with cell geometry-dependent gene expression. Mol. Biol. Cell 28, 1997–2009 (2017). This study demonstrates that altering the mechanical state of the cell induces chromosome repositioning and orientation to regulate gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang, Y., Ratna, P. & Shivashankar, G. V. Superresolution imaging of nanoscale chromosome contacts. Sci. Rep. 7, 42422 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Osborne, C. S. et al. Active genes dynamically colocalize to shared sites of ongoing transcription. Nat. Genet. 36, 1065–1071 (2004). This study exemplifies the role of spatial gene clustering for co-regulation.

    Article  CAS  PubMed  Google Scholar 

  100. Noordermeer, D. et al. The dynamic architecture of Hox gene clusters. Science 334, 222–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Jin, F. et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503, 290–294 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Gialitakis, M., Arampatzi, P., Makatounakis, T. & Papamatheakis, J. Gamma interferon-dependent transcriptional memory via relocalization of a gene locus to PML nuclear bodies. Mol. Cell. Biol. 30, 2046–2056 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Fanucchi, S., Shibayama, Y., Burd, S., Weinberg, M. S. & Mhlanga, M. M. Chromosomal contact permits transcription between coregulated genes. Cell 155, 606–620 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Noordermeer, D. et al. Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci. eLife 3, e02557 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Letsou, W. & Cai, L. Noncommutative biology: sequential regulation of complex networks. PLoS Comput. Biol 12, e1005089 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Thévenin, A. et al. Functional gene groups are concentrated within chromosomes, among chromosomes and in the nuclear space of the human genome. Nucleic Acids Res. 42, 9854–9861 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Zhu, Y. et al. Constructing 3D interaction maps from 1D epigenomes. Nat. Commun. 7, 10812 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Capurso, D., Bengtsson, H. & Segal, M. R. Discovering hotspots in functional genomic data superposed on 3D chromatin configuration reconstructions. Nucleic Acids Res. 44, 2028–2035 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Cisse, I. I. et al. Real-time dynamics of RNA polymerase II clustering in live human cells. Science 341, 664–667 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Virtanen, J. A. & Vartiainen, M. K. Diverse functions for different forms of nuclear actin. Curr. Opin. Cell Biol. 46, 33–38 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Spichal, M. & Fabre, E. The emerging role of the cytoskeleton in chromosome dynamics. Front. Genet. 8, 60 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Leight, J. L., Wozniak, M. A., Chen, S., Lynch, M. L. & Chen, C. S. Matrix rigidity regulates a switch between TGF-β1-induced apoptosis and epithelial-mesenchymal transition. Mol. Biol. Cell 23, 781–791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bonev, B. & Cavalli, G. Organization and function of the 3D genome. Nat. Rev. Genet. 17, 661–678 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Sun, S. & Irvine, K. D. Cellular organization and cytoskeletal regulation of the Hippo signaling network. Trends Cell Biol. 26, 694–704 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sun, S. C. The non-canonical NF-κB pathway in immunity and inflammation. Nat. Rev. Immunol. 17, 545–558 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Schreiber, K. H. & Kennedy, B. K. When lamins go bad: nuclear structure and disease. Cell 152, 1365–1375 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hatch, E. & Hetzer, M. Breaching the nuclear envelope in development and disease. J. Cell Biol. 205, 133–141 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Scaffidi, P. & Misteli, T. Lamin A-dependent nuclear defects in human aging. Science 312, 1059–1063 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Frost, B. Alzheimer's disease: an acquired neurodegenerative laminopathy. Nucleus 7, 275–283 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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 

  121. Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Roukos, V. et al. Spatial dynamics of chromosome translocations in living cells. Science 341, 660–664 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Graham, D. M. & Burridge, K. Mechanotransduction and nuclear function. Curr. Opin. Cell Biol. 40, 98–105 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  125. McGregor, A. L., Hsia, C. R. & Lammerding, J. Squish and squeeze-the nucleus as a physical barrier during migration in confined environments. Curr. Opin. Cell Biol. 40, 32–40 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Jorgens, D. M. et al. Deep nuclear invaginations are linked to cytoskeletal filaments — integrated bioimaging of epithelial cells in 3D culture. J. Cell Sci. 130, 177–189 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Harr, J. C., Gonzalez-Sandoval, A. & Gasser, S. M. Histones and histone modifications in perinuclear chromatin anchoring: from yeast to man. EMBO Rep. 17, 139–155 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Branco, M. R. & Pombo, A. Intermingling of chromosome territories in interphase suggests role in translocations and transcription-dependent associations. PLoS Biol. 4, e138 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  130. Grys, B. T. et al. Machine learning and computer vision approaches for phenotypic profiling. J. Cell Biol. 216, 65–71 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. LeCun, Y., Bengio, Y. & Hinton, G. Deep learning. Nature 521, 436–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Yu, K. et al. Predicting non-small cell lung cancer prognosis by fully automated microscopic pathology image features. Nat. Commun. 7, 12474 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mahamid, J. et al. Visualizing the molecular sociology at the HeLa cell nuclear periphery. Science 351, 969–972 (2016).

    Article  CAS  PubMed  Google Scholar 

  134. Li, G. & Reinberg, D. Chromatin higher-order structures and gene regulation. Curr. Opin. Genet. Dev. 21, 175–186 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Gonzalez-Sandoval, A. & Gasser, S. M. On TADs and LADs: spatial control over gene expression. Trends Genet. 32, 485–495 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Feuerborn, A. & Cook, P. R. Why the activity of a gene depends on its neighbors. Trends Genet. 31, 483–490 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Bolzer, A. et al. Three-dimensional maps of all chromosomes in human male fibroblast nuclei and prometaphase rosettes. PLoS Biol. 3, e157 (2005). This paper demonstrates that chromosomes are nonrandomly organized within the cell nucleus.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Bickmore, W. A. & van Steensel, B. Genome architecture: domain organization of interphase chromosomes. Cell 152, 1270–1284 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Iyer, K. V. et al. Modeling and experimental methods to probe the link between global transcription and spatial organization of chromosomes. PLoS ONE 7, e46628 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Cook, P. R. A model for all genomes: the role of transcription factories. J. Mol. Biol. 395, 1–10 (2010).

    Article  CAS  PubMed  Google Scholar 

  141. Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009). This study identifies genome-wide chromosome contacts by use of chromosome capture assays.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Chen, H. et al. Functional organization of the human 4D nucleome. Proc. Natl Acad. Sci. USA 112, 8002–8007 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Schmitt, A. D., Hu, M. & Ren, B. Genome-wide mapping and analysis of chromosome architecture. Nat. Rev. Mol. Cell Biol. 17, 743–755 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Norton, H. K. & Phillips Cremins, J. E. Crossed wires: 3D genome misfolding in human disease. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201611001 (2017).

  146. Uhler, C. & Wright, S. J. Packing ellipsoids with overlap. SIAM Rev. 55, 671–706 (2013).

    Article  Google Scholar 

  147. Boettiger, A. N. et al. Super-resolution imaging reveals distinct chromatin folding for different epigenetic states. Nature 529, 418–422 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Dong, B. et al. Super-resolution intrinsic fluorescence imaging of chromatin utilizing native, unmodified nucleic acids for contrast. Proc. Natl Acad. Sci. USA 113, 9716–9721 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Chen, B. et al. Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. Cell 155, 1479–1491 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ma, H. et al. Multicolor CRISPR labeling of chromosomal loci in human cells. Proc. Natl Acad. Sci. USA 112, 3002–3007 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ramani, V. et al. Massively multiplex single-cell Hi-C. Nat. Methods 14, 263–266 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

C.U. was partially supported by the US Defense Advanced Research Projects Agency (DARPA) (W911NF-16-1-0551), the National Science Foundation (NSF) (1651995) and the US Office of Naval Research (N00014-17-1-2147). G.V.S. was funded by the Mechanobiology Institute, Singapore, the MOE-Tier 3 grant, Singapore, and the Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology (IFOM), Milan, Italy. The authors thank members of the Uhler and Shivashankar laboratories for useful discussions.

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Authors and Affiliations

  1. Department of Electrical Engineering and Computer Science, Laboratory of Information and Decision Systems, Institute for Data, Systems and Society, Massachusetts Institute of Technology (MIT), Cambridge, 02139, Massachusetts, USA

    Caroline Uhler

  2. Mechanobiology Institute, National University of Singapore, 119077, Singapore

    G. V. Shivashankar

  3. Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology (IFOM), Milan, 20139, Italy

    G. V. Shivashankar

Authors
  1. Caroline Uhler
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  2. G. V. Shivashankar
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Both authors contributed to researching data for the article, discussion of the content and writing, reviewing and editing of the manuscript.

Corresponding author

Correspondence to G. V. Shivashankar.

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The authors declare no competing financial interests.

PowerPoint slides

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The process in which a somatic cell is transformed into another type of somatic cell.

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Cell surface transmembrane receptors involved in mechanosensing.

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Cell membrane protein complexes that connect the actin cytoskeleton with the extracellular matrix.

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A transmembrane receptor that bridges cell–cell junctions.

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Protein complexes comprising actin and myosin; they form contractile units.

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Proteins that bridge the cytoskeleton of two neighbouring cells through the cell–cell junction.

Magnetic twisting cytometry

A technique for applying precise forces to single cells.

Visco-elastic coupling

The propensity of materials to exhibit viscous and elastic responses when deformed.

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The globular form of monomeric actin.

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Forces generated by the intrinsic thermodynamic tendency to increase entropy.

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A genetic disorder of premature ageing.

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Uhler, C., Shivashankar, G. Regulation of genome organization and gene expression by nuclear mechanotransduction. Nat Rev Mol Cell Biol 18, 717–727 (2017). https://doi.org/10.1038/nrm.2017.101

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