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Research Papers

The Nuclear Option: Evidence Implicating the Cell Nucleus in Mechanotransduction

[+] Author and Article Information
Spencer E. Szczesny

Department of Orthopaedic Surgery,
University of Pennsylvania,
424 Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104;
Translational Musculoskeletal Research Center,
Corporal Michael J. Crescenz Veterans Affairs
Medical Center,
3900 Woodland Avenue,
Philadelphia, PA 19104

Robert L. Mauck

Department of Orthopaedic Surgery,
University of Pennsylvania,
424 Stemmler Hall,
36th Street and Hamilton Walk,
Philadelphia, PA 19104;
Translational Musculoskeletal Research Center,
Corporal Michael J. Crescenz Veterans Affairs
Medical Center,
3900 Woodland Avenue,
Philadelphia, PA 19104;
Department of Bioengineering,
University of Pennsylvania,
240 Skirkanich Hall,
210 South 33rd Street,
Philadelphia, PA 19104
e-mail: lemauck@mail.med.upenn.edu

1Corresponding author.

Manuscript received June 30, 2016; final manuscript received November 1, 2016; published online January 19, 2017. Assoc. Editor: Victor H. Barocas.

J Biomech Eng 139(2), 021006 (Jan 19, 2017) (16 pages) Paper No: BIO-16-1276; doi: 10.1115/1.4035350 History: Received June 30, 2016; Revised November 01, 2016

Biophysical stimuli presented to cells via microenvironmental properties (e.g., alignment and stiffness) or external forces have a significant impact on cell function and behavior. Recently, the cell nucleus has been identified as a mechanosensitive organelle that contributes to the perception and response to mechanical stimuli. However, the specific mechanotransduction mechanisms that mediate these effects have not been clearly established. Here, we offer a comprehensive review of the evidence supporting (and refuting) three hypothetical nuclear mechanotransduction mechanisms: physical reorganization of chromatin, signaling at the nuclear envelope, and altered cytoskeletal structure/tension due to nuclear remodeling. Our goal is to provide a reference detailing the progress that has been made and the areas that still require investigation regarding the role of nuclear mechanotransduction in cell biology. Additionally, we will briefly discuss the role that mathematical models of cell mechanics can play in testing these hypotheses and in elucidating how biophysical stimulation of the nucleus drives changes in cell behavior. While force-induced alterations in signaling pathways involving lamina-associated polypeptides (LAPs) (e.g., emerin and histone deacetylase 3 (HDAC3)) and transcription factors (TFs) located at the nuclear envelope currently appear to be the most clearly supported mechanism of nuclear mechanotransduction, additional work is required to examine this process in detail and to more fully test alternative mechanisms. The combination of sophisticated experimental techniques and advanced mathematical models is necessary to enhance our understanding of the role of the nucleus in the mechanotransduction processes driving numerous critical cell functions.

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References

Engler, A. J. , Sen, S. , Sweeney, H. L. , and Discher, D. E. , 2006, “ Matrix Elasticity Directs Stem Cell Lineage Specification,” Cell, 126(4), pp. 677–689. [CrossRef] [PubMed]
McBeath, R. , Pirone, D. M. , Nelson, C. M. , Bhadriraju, K. , and Chen, C. S. , 2004, “ Cell Shape, Cytoskeletal Tension, and RhoA Regulate Stem Cell Lineage Commitment,” Dev. Cell, 6(4), pp. 483–495. [CrossRef] [PubMed]
Baker, B. M. , Trappmann, B. , Wang, W. Y. , Sakar, M. S. , Kim, I. L. , Shenoy, V. B. , Burdick, J. A. , and Chen, C. S. , 2015, “ Cell-Mediated Fibre Recruitment Drives Extracellular Matrix Mechanosensing in Engineered Fibrillar Microenvironments,” Nat. Mater., 14(12), pp. 1262–1268. [CrossRef] [PubMed]
Przybyla, L. , Muncie, J. M. , and Weaver, V. M. , 2016, “ Mechanical Control of Epithelial-to-Mesenchymal Transitions in Development and Cancer,” Annu. Rev. Cell Dev. Biol., 32, pp. 527–554. [CrossRef] [PubMed]
Duscher, D. , Maan, Z. N. , Wong, V. W. , Rennert, R. C. , Januszyk, M. , Rodrigues, M. , Hu, M. , Whitmore, A. J. , Whittam, A. J. , Longaker, M. T. , and Gurtner, G. C. , 2014, “ Mechanotransduction and Fibrosis,” J. Biomech., 47(9), pp. 1997–2005. [CrossRef] [PubMed]
Cui, Y. , Hameed, F. M. , Yang, B. , Lee, K. , Pan, C. Q. , Park, S. , and Sheetz, M. , 2015, “ Cyclic Stretching of Soft Substrates Induces Spreading and Growth,” Nat. Commun., 6, p. 6333. [CrossRef] [PubMed]
Kurpinski, K. , Chu, J. , Hashi, C. , and Li, S. , 2006, “ Anisotropic Mechanosensing by Mesenchymal Stem Cells,” Proc. Natl. Acad. Sci. U.S.A., 103(44), pp. 16095–16100. [CrossRef] [PubMed]
Johnson, B. D. , Mather, K. J. , and Wallace, J. P. , 2011, “ Mechanotransduction of Shear in the Endothelium: Basic Studies and Clinical Implications,” Vasc. Med., 16(5), pp. 365–377. [CrossRef] [PubMed]
Schwartz, M. A. , 2010, “ Integrins and Extracellular Matrix in Mechanotransduction,” Cold Spring Harbor Perspect. Biol., 2(12), p. a005066. [CrossRef]
Janmey, P. A. , Wells, R. G. , Assoian, R. K. , and McCulloch, C. A. , 2013, “ From Tissue Mechanics to Transcription Factors,” Differ. Res. Biol. Diversity, 86(3), pp. 112–120. [CrossRef]
Zaidel-Bar, R. , Itzkovitz, S. , Ma'ayan, A. , Iyengar, R. , and Geiger, B. , 2007, “ Functional Atlas of the Integrin Adhesome,” Nat. Cell Biol., 9(8), pp. 858–867. [CrossRef] [PubMed]
Kanchanawong, P. , Shtengel, G. , Pasapera, A. M. , Ramko, E. B. , Davidson, M. W. , Hess, H. F. , and Waterman, C. M. , 2010, “ Nanoscale Architecture of Integrin-Based Cell Adhesions,” Nature, 468(7323), pp. 580–584. [CrossRef] [PubMed]
Geiger, B. , Spatz, J. P. , and Bershadsky, A. D. , 2009, “ Environmental Sensing Through Focal Adhesions,” Nat. Rev. Mol. Cell Biol., 10(1), pp. 21–33. [CrossRef] [PubMed]
Yan, J. , Yao, M. , Goult, B. T. , and Sheetz, M. P. , 2015, “ Talin Dependent Mechanosensitivity of Cell Focal Adhesions,” Cell. Mol. Bioeng., 8(1), pp. 151–159. [CrossRef] [PubMed]
Harburger, D. S. , and Calderwood, D. A. , 2009, “ Integrin Signalling at a Glance,” J. Cell Sci., 122(2), pp. 159–163. [CrossRef] [PubMed]
Zhou, A.-X. , Hartwig, J. H. , and Akyürek, L. M. , 2010, “ Filamins in Cell Signaling, Transcription and Organ Development,” Trends Cell Biol., 20(2), pp. 113–123. [CrossRef] [PubMed]
Craig, D. H. , Haimovich, B. , and Basson, M. D. , 2007, “ α-Actinin-1 Phosphorylation Modulates Pressure-Induced Colon Cancer Cell Adhesion Through Regulation of Focal Adhesion Kinase-Src Interaction,” Am. J. Physiol. Cell Physiol., 293(6), pp. C1862–C1874. [CrossRef] [PubMed]
Sluchanko, N. N. , and Gusev, N. B. , 2010, “ 14-3-3 Proteins and Regulation of Cytoskeleton,” Biochem. Biokhimiia, 75(13), pp. 1528–1546. [CrossRef]
Schlegelmilch, K. , Mohseni, M. , Kirak, O. , Pruszak, J. , Rodriguez, J. R. , Zhou, D. , Kreger, B. T. , Vasioukhin, V. , Avruch, J. , Brummelkamp, T. R. , and Camargo, F. D. , 2011, “ Yap1 Acts Downstream of α-Catenin to Control Epidermal Proliferation,” Cell, 144(5), pp. 782–795. [CrossRef] [PubMed]
Jaalouk, D. E. , and Lammerding, J. , 2009, “ Mechanotransduction Gone Awry,” Nat. Rev. Mol. Cell Biol., 10(1), pp. 63–73. [CrossRef] [PubMed]
Martinac, B. , 2004, “ Mechanosensitive Ion Channels: Molecules of Mechanotransduction,” J. Cell Sci., 117(12), pp. 2449–2460. [CrossRef] [PubMed]
Anishkin, A. , Loukin, S. H. , Teng, J. , and Kung, C. , 2014, “ Feeling the Hidden Mechanical Forces in Lipid Bilayer Is an Original Sense,” Proc. Natl. Acad. Sci., 111(22), pp. 7898–7905. [CrossRef]
Matthews, B. D. , Thodeti, C. K. , Tytell, J. D. , Mammoto, A. , Overby, D. R. , and Ingber, D. E. , 2010, “ Ultra-Rapid Activation of TRPV4 Ion Channels by Mechanical Forces Applied to Cell Surface Beta1 Integrins,” Integr. Biol. Quant. Biosci. Nano Macro, 2(9), pp. 435–442.
Hayakawa, K. , Tatsumi, H. , and Sokabe, M. , 2008, “ Actin Stress Fibers Transmit and Focus Force to Activate Mechanosensitive Channels,” J. Cell Sci., 121(Pt. 4), pp. 496–503. [CrossRef] [PubMed]
Clapham, D. E. , 2007, “ Calcium Signaling,” Cell, 131(6), pp. 1047–1058. [CrossRef] [PubMed]
O'Conor, C. J. , Leddy, H. A. , Benefield, H. C. , Liedtke, W. B. , and Guilak, F. , 2014, “ TRPV4-Mediated Mechanotransduction Regulates the Metabolic Response of Chondrocytes to Dynamic Loading,” Proc. Natl. Acad. Sci., 111(4), pp. 1316–1321. [CrossRef]
Lee, W. , Leddy, H. A. , Chen, Y. , Lee, S. H. , Zelenski, N. A. , McNulty, A. L. , Wu, J. , Beicker, K. N. , Coles, J. , Zauscher, S. , Grandl, J. , Sachs, F. , Guilak, F. , and Liedtke, W. B. , 2014, “ Synergy Between Piezo1 and Piezo2 Channels Confers High-Strain Mechanosensitivity to Articular Cartilage,” Proc. Natl. Acad. Sci. U.S.A., 111(47), pp. E5114–5122. [CrossRef] [PubMed]
Pathak, M. M. , Nourse, J. L. , Tran, T. , Hwe, J. , Arulmoli, J. , Le, D. T. T. , Bernardis, E. , Flanagan, L. A. , and Tombola, F. , 2014, “ Stretch-Activated Ion Channel Piezo1 Directs Lineage Choice in Human Neural Stem Cells,” Proc. Natl. Acad. Sci., 111(45), pp. 16148–16153. [CrossRef]
Lierop, J. E. V. , Wilson, D. P. , Davis, J. P. , Tikunova, S. , Sutherland, C. , Walsh, M. P. , and Johnson, J. D. , 2002, “ Activation of Smooth Muscle Myosin Light Chain Kinase by Calmodulin ROLE OF LYS30 and GLY40,” J. Biol. Chem., 277(8), pp. 6550–6558. [CrossRef] [PubMed]
Munevar, S. , Wang, Y.-L. , and Dembo, M. , 2004, “ Regulation of Mechanical Interactions Between Fibroblasts and the Substratum by Stretch-Activated Ca2+ Entry,” J. Cell Sci., 117(Pt. 1), pp. 85–92. [CrossRef] [PubMed]
Khatau, S. B. , Hale, C. M. , Stewart-Hutchinson, P. J. , Patel, M. S. , Stewart, C. L. , Searson, P. C. , Hodzic, D. , and Wirtz, D. , 2009, “ A Perinuclear Actin Cap Regulates Nuclear Shape,” Proc. Natl. Acad. Sci. U.S.A., 106(45), pp. 19017–19022. [CrossRef] [PubMed]
Versaevel, M. , Grevesse, T. , and Gabriele, S. , 2012, “ Spatial Coordination Between Cell and Nuclear Shape Within Micropatterned Endothelial Cells,” Nat. Commun., 3, p. 671. [CrossRef] [PubMed]
Neelam, S. , Chancellor, T. J. , Li, Y. , Nickerson, J. A. , Roux, K. J. , Dickinson, R. B. , and Lele, T. P. , 2015, “ Direct Force Probe Reveals the Mechanics of Nuclear Homeostasis in the Mammalian Cell,” Proc. Natl. Acad. Sci. U.S.A., 112(18), pp. 5720–5725. [CrossRef] [PubMed]
Maniotis, A. J. , Chen, C. S. , and Ingber, D. E. , 1997, “ Demonstration of Mechanical Connections Between Integrins, Cytoskeletal Filaments, and Nucleoplasm That Stabilize Nuclear Structure,” Proc. Natl. Acad. Sci. U.S.A., 94(3), pp. 849–854. [CrossRef] [PubMed]
Guilak, F. , 1995, “ Compression-Induced Changes in the Shape and Volume of the Chondrocyte Nucleus,” J. Biomech., 28(12), pp. 1529–1541. [CrossRef] [PubMed]
Nathan, A. S. , Baker, B. M. , Nerurkar, N. L. , and Mauck, R. L. , 2011, “ Mechano-Topographic Modulation of Stem Cell Nuclear Shape on Nanofibrous Scaffolds,” Acta Biomater., 7(1), pp. 57–66. [CrossRef] [PubMed]
Poh, Y.-C. , Shevtsov, S. P. , Chowdhury, F. , Wu, D. C. , Na, S. , Dundr, M. , and Wang, N. , 2012, “ Dynamic Force-Induced Direct Dissociation of Protein Complexes in a Nuclear Body in Living Cells,” Nat. Commun., 3, p. 866. [CrossRef] [PubMed]
Booth-Gauthier, E. A. , Alcoser, T. A. , Yang, G. , and Dahl, K. N. , 2012, “ Force-Induced Changes in Subnuclear Movement and Rheology,” Biophys. J., 103(12), pp. 2423–2431. [CrossRef] [PubMed]
Thomas, C. H. , Collier, J. H. , Sfeir, C. S. , and Healy, K. E. , 2002, “ Engineering Gene Expression and Protein Synthesis by Modulation of Nuclear Shape,” Proc. Natl. Acad. Sci., 99(4), pp. 1972–1977. [CrossRef]
Heo, S.-J. , Nerurkar, N. L. , Baker, B. M. , Shin, J.-W. , Elliott, D. M. , and Mauck, R. L. , 2011, “ Fiber Stretch and Reorientation Modulates Mesenchymal Stem Cell Morphology and Fibrous Gene Expression on Oriented Nanofibrous Microenvironments,” Ann. Biomed. Eng., 39(11), pp. 2780–2790. [CrossRef] [PubMed]
Guilluy, C. , Osborne, L. D. , Van Landeghem, L. , Sharek, L. , Superfine, R. , Garcia-Mata, R. , and Burridge, K. , 2014, “ Isolated Nuclei Adapt to Force and Reveal a Mechanotransduction Pathway in the Nucleus,” Nat. Cell Biol., 16(4), pp. 376–381. [CrossRef] [PubMed]
Wang, N. , Tytell, J. D. , and Ingber, D. E. , 2009, “ Mechanotransduction at a Distance: Mechanically Coupling the Extracellular Matrix With the Nucleus,” Nat. Rev. Mol. Cell Biol., 10(1), pp. 75–82. [CrossRef] [PubMed]
Shivashankar, G. V. , 2011, “ Mechanosignaling to the Cell Nucleus and Gene Regulation,” Annu. Rev. Biophys., 40, pp. 361–378. [CrossRef] [PubMed]
Martins, R. P. , Finan, J. D. , Guilak, F. , and Lee, D. A. , 2012, “ Mechanical Regulation of Nuclear Structure and Function,” Annu. Rev. Biomed. Eng., 14, pp. 431–455. [CrossRef] [PubMed]
Fedorchak, G. R. , Kaminski, A. , and Lammerding, J. , 2014, “ Cellular Mechanosensing: Getting to the Nucleus of It All,” Prog. Biophys. Mol. Biol., 115(2–3), pp. 76–92. [CrossRef] [PubMed]
Osmanagic-Myers, S. , Dechat, T. , and Foisner, R. , 2015, “ Lamins at the Crossroads of Mechanosignaling,” Genes Dev., 29(3), pp. 225–237. [CrossRef] [PubMed]
Uzer, G. , Fuchs, R. K. , Rubin, J. , and Thompson, W. R. , 2016, “ Concise Review: Plasma and Nuclear Membranes Convey Mechanical Information to Regulate Mesenchymal Stem Cell Lineage,” Stem Cells, 34(6), pp. 1455–1463. [CrossRef] [PubMed]
Navarro, A. P. , Collins, M. A. , and Folker, E. S. , 2016, “ The Nucleus Is a Conserved Mechanosensation and Mechanoresponse Organelle,” Cytoskeleton, 73(2), pp. 59–67. [CrossRef] [PubMed]
Graham, D. M. , and Burridge, K. , 2016, “ Mechanotransduction and Nuclear Function,” Curr. Opin. Cell Biol., 40, pp. 98–105. [CrossRef] [PubMed]
Belaadi, N. , Aureille, J. , and Guilluy, C. , 2016, “ Under Pressure: Mechanical Stress Management in the Nucleus,” Cells, 5(2), p. 27. [CrossRef]
Gruenbaum, Y. , and Foisner, R. , 2015, “ Lamins: Nuclear Intermediate Filament Proteins With Fundamental Functions in Nuclear Mechanics and Genome Regulation,” Annu. Rev. Biochem., 84, pp. 131–164. [CrossRef] [PubMed]
Davidson, P. M. , and Lammerding, J. , 2014, “ Broken Nuclei: Lamins, Nuclear Mechanics, and Disease,” Trends Cell Biol., 24(4), pp. 247–256. [CrossRef] [PubMed]
Shimi, T. , Pfleghaar, K. , Kojima, S. , Pack, C.-G. , Solovei, I. , Goldman, A. E. , Adam, S. A. , Shumaker, D. K. , Kinjo, M. , Cremer, T. , and Goldman, R. D. , 2008, “ The A- and B-Type Nuclear Lamin Networks: Microdomains Involved in Chromatin Organization and Transcription,” Genes Dev., 22(24), pp. 3409–3421. [CrossRef] [PubMed]
Broers, J. L. V. , Peeters, E. A. G. , Kuijpers, H. J. H. , Endert, J. , Bouten, C. V. C. , Oomens, C. W. J. , Baaijens, F. P. T. , and Ramaekers, F. C. S. , 2004, “ Decreased Mechanical Stiffness in LMNA−/− Cells Is Caused by Defective Nucleo-Cytoskeletal Integrity: Implications for the Development of Laminopathies,” Hum. Mol. Genet., 13(21), pp. 2567–2580. [CrossRef] [PubMed]
Broers, J. L. V. , Ramaekers, F. C. S. , Bonne, G. , Yaou, R. B. , and Hutchison, C. J. , 2006, “ Nuclear Lamins: Laminopathies and Their Role in Premature Ageing,” Physiol. Rev., 86(3), pp. 967–1008. [CrossRef] [PubMed]
Swift, J. , Ivanovska, I. L. , Buxboim, A. , Harada, T. , Dingal, P. C. D. P. , Pinter, J. , Pajerowski, J. D. , Spinler, K. R. , Shin, J.-W. , Tewari, M. , Rehfeldt, F. , Speicher, D. W. , and Discher, D. E. , 2013, “ Nuclear Lamin-A Scales With Tissue Stiffness and Enhances Matrix-Directed Differentiation,” Science, 341(6149), p. 1240104. [CrossRef] [PubMed]
Buxboim, A. , Swift, J. , Irianto, J. , Spinler, K. R. , Dingal, P. C. D. P. , Athirasala, A. , Kao, Y.-R. C. , Cho, S. , Harada, T. , Shin, J.-W. , and Discher, D. E. , 2014, “ Matrix Elasticity Regulates Lamin-A,C Phosphorylation and Turnover With Feedback to Actomyosin,” Curr. Biol., 24(16), pp. 1909–1917. [CrossRef] [PubMed]
Ihalainen, T. O. , Aires, L. , Herzog, F. A. , Schwartlander, R. , Moeller, J. , and Vogel, V. , 2015, “ Differential Basal-to-Apical Accessibility of Lamin A/C Epitopes in the Nuclear Lamina Regulated by Changes in Cytoskeletal Tension,” Nat. Mater., 14(12), pp. 1252–1261. [CrossRef] [PubMed]
Kim, D.-H. , and Wirtz, D. , 2015, “ Cytoskeletal Tension Induces the Polarized Architecture of the Nucleus,” Biomaterials, 48, pp. 161–172. [CrossRef] [PubMed]
Machowska, M. , Piekarowicz, K. , and Rzepecki, R. , 2015, “ Regulation of Lamin Properties and Functions: Does Phosphorylation Do It All?,” Open Biol., 5(11), p. 150094. [CrossRef] [PubMed]
Lammerding, J. , Fong, L. G. , Ji, J. Y. , Reue, K. , Stewart, C. L. , Young, S. G. , and Lee, R. T. , 2006, “ Lamins A and C But Not Lamin B1 Regulate Nuclear Mechanics,” J. Biol. Chem., 281(35), pp. 25768–25780. [CrossRef] [PubMed]
Taniura, H. , Glass, C. , and Gerace, L. , 1995, “ A Chromatin Binding Site in the Tail Domain of Nuclear Lamins That Interacts With Core Histones,” J. Cell Biol., 131(1), pp. 33–44. [CrossRef] [PubMed]
Wilson, K. L. , and Foisner, R. , 2010, “ Lamin-Binding Proteins,” Cold Spring Harbor Perspect. Biol., 2(4), p. a000554. [CrossRef]
Lammerding, J. , Schulze, P. C. , Takahashi, T. , Kozlov, S. , Sullivan, T. , Kamm, R. D. , Stewart, C. L. , and Lee, R. T. , 2004, “ Lamin A/C Deficiency Causes Defective Nuclear Mechanics and Mechanotransduction,” J. Clin. Invest., 113(3), pp. 370–378. [CrossRef] [PubMed]
Cupesi, M. , Yoshioka, J. , Gannon, J. , Kudinova, A. , Stewart, C. L. , and Lammerding, J. , 2010, “ Attenuated Hypertrophic Response to Pressure Overload in a Lamin A/C Haploinsufficiency Mouse,” J. Mol. Cell. Cardiol., 48(6), pp. 1290–1297. [CrossRef] [PubMed]
Akter, R. , Rivas, D. , Geneau, G. , Drissi, H. , and Duque, G. , 2009, “ Effect of Lamin A/C Knockdown on Osteoblast Differentiation and Function,” J. Bone Miner. Res., 24(2), pp. 283–293. [CrossRef] [PubMed]
Mao, X. , Gavara, N. , and Song, G. , 2015, “ Nuclear Mechanics and Stem Cell Differentiation,” Stem Cell Rev., 11(6), pp. 804–812. [CrossRef] [PubMed]
Capell, B. C. , and Collins, F. S. , 2006, “ Human Laminopathies: Nuclei Gone Genetically Awry,” Nat. Rev. Genet., 7(12), pp. 940–952. [CrossRef] [PubMed]
Burke, B. , and Stewart, C. L. , 2006, “ The Laminopathies: The Functional Architecture of the Nucleus and Its Contribution to Disease,” Annu. Rev. Genomics Hum. Genet., 7, pp. 369–405. [CrossRef] [PubMed]
McGinty, R. K. , and Tan, S. , 2015, “ Nucleosome Structure and Function,” Chem. Rev., 115(6), pp. 2255–2273. [CrossRef] [PubMed]
Cremer, T. , and Cremer, M. , 2010, “ Chromosome Territories,” Cold Spring Harbor Perspect. Biol., 2(3), p. a003889. [CrossRef]
Woodcock, C. L. , and Ghosh, R. P. , 2010, “ Chromatin Higher-Order Structure and Dynamics,” Cold Spring Harbor Perspect. Biol., 2(5), p. a000596. [CrossRef]
Phillips-Cremins, J. E. , 2014, “ Unraveling Architecture of the Pluripotent Genome,” Curr. Opin. Cell Biol., 28, pp. 96–104. [CrossRef] [PubMed]
Parada, L. A. , McQueen, P. G. , and Misteli, T. , 2004, “ Tissue-Specific Spatial Organization of Genomes,” Genome Biol., 5, p. R44. [CrossRef] [PubMed]
Bolzer, A. , Kreth, G. , Solovei, I. , Koehler, D. , Saracoglu, K. , Fauth, C. , Müller, S. , Eils, R. , Cremer, C. , Speicher, M. R. , and Cremer, T. , 2005, “ Three-Dimensional Maps of All Chromosomes in Human Male Fibroblast Nuclei and Prometaphase Rosettes,” PLoS Biol., 3(5), p. e157. [CrossRef] [PubMed]
Hübner, M. R. , and Spector, D. L. , 2010, “ Chromatin Dynamics,” Annu. Rev. Biophys., 39, pp. 471–489. [CrossRef] [PubMed]
Guelen, L. , Pagie, L. , Brasset, E. , Meuleman, W. , Faza, M. B. , Talhout, W. , Eussen, B. H. , de Klein, A. , Wessels, L. , de Laat, W. , and van Steensel, B. , 2008, “ Domain Organization of Human Chromosomes Revealed by Mapping of Nuclear Lamina Interactions,” Nature, 453(7197), pp. 948–951. [CrossRef] [PubMed]
Peric-Hupkes, D. , Meuleman, W. , Pagie, L. , Bruggeman, S. W. M. , Solovei, I. , Brugman, W. , Gräf, S. , Flicek, P. , Kerkhoven, R. M. , van Lohuizen, M. , Reinders, M. , Wessels, L. , and van Steensel, B. , 2010, “ Molecular Maps of the Reorganization of Genome-Nuclear Lamina Interactions During Differentiation,” Mol. Cell, 38(4), pp. 603–613. [CrossRef] [PubMed]
Lund, E. , Oldenburg, A. R. , Delbarre, E. , Freberg, C. T. , Duband-Goulet, I. , Eskeland, R. , Buendia, B. , and Collas, P. , 2013, “ Lamin A/C-Promoter Interactions Specify Chromatin State-Dependent Transcription Outcomes,” Genome Res., 23(10), pp. 1580–1589. [CrossRef] [PubMed]
Demmerle, J. , Koch, A. J. , and Holaska, J. M. , 2013, “ Emerin and Histone Deacetylase 3 (HDAC3) Cooperatively Regulate Expression and Nuclear Positions of MyoD, Myf5, and Pax7 Genes During Myogenesis,” Chromosome Res., 21(8), pp. 765–779. [CrossRef] [PubMed]
Misteli, T. , 2007, “ Beyond the Sequence: Cellular Organization of Genome Function,” Cell, 128(4), pp. 787–800. [CrossRef] [PubMed]
Crisp, M. , Liu, Q. , Roux, K. , Rattner, J. B. , Shanahan, C. , Burke, B. , Stahl, P. D. , and Hodzic, D. , 2006, “ Coupling of the Nucleus and Cytoplasm: Role of the LINC Complex,” J. Cell Biol., 172(1), pp. 41–53. [CrossRef] [PubMed]
Chang, W. , Worman, H. J. , and Gundersen, G. G. , 2015, “ Accessorizing and Anchoring the LINC Complex for Multifunctionality,” J. Cell Biol., 208(1), pp. 11–22. [CrossRef] [PubMed]
Rothballer, A. , and Kutay, U. , 2013, “ The Diverse Functional LINCs of the Nuclear Envelope to the Cytoskeleton and Chromatin,” Chromosoma, 122(5), pp. 415–429. [CrossRef] [PubMed]
Borrego-Pinto, J. , Jegou, T. , Osorio, D. S. , Auradé, F. , Gorjánácz, M. , Koch, B. , Mattaj, I. W. , and Gomes, E. R. , 2012, “ Samp1 Is a Component of TAN Lines and Is Required for Nuclear Movement,” J. Cell Sci., 125(Pt. 5), pp. 1099–1105. [CrossRef] [PubMed]
Kutscheidt, S. , Zhu, R. , Antoku, S. , Luxton, G. W. G. , Stagljar, I. , Fackler, O. T. , and Gundersen, G. G. , 2014, “ FHOD1 Interaction With Nesprin-2G Mediates TAN Line Formation and Nuclear Movement,” Nat. Cell Biol., 16(7), pp. 708–715. [CrossRef] [PubMed]
Bone, C. R. , Tapley, E. C. , Gorjánácz, M. , and Starr, D. A. , 2014, “ The Caenorhabditis Elegans SUN Protein UNC-84 Interacts With Lamin to Transfer Forces From the Cytoplasm to the Nucleoskeleton During Nuclear Migration,” Mol. Biol. Cell, 25(18), pp. 2853–2865. [CrossRef] [PubMed]
Antoku, S. , Zhu, R. , Kutscheidt, S. , Fackler, O. T. , and Gundersen, G. G. , 2015, “ Reinforcing the LINC Complex Connection to Actin Filaments: The Role of FHOD1 in TAN Line Formation and Nuclear Movement,” Cell Cycle, 14(14), pp. 2200–2205. [CrossRef] [PubMed]
Kim, D.-H. , Khatau, S. B. , Feng, Y. , Walcott, S. , Sun, S. X. , Longmore, G. D. , and Wirtz, D. , 2012, “ Actin Cap Associated Focal Adhesions and Their Distinct Role in Cellular Mechanosensing,” Sci. Rep., 2, p. 555. [PubMed]
Luxton, G. W. G. , Gomes, E. R. , Folker, E. S. , Vintinner, E. , and Gundersen, G. G. , 2010, “ Linear Arrays of Nuclear Envelope Proteins Harness Retrograde Actin Flow for Nuclear Movement,” Science, 329(5994), pp. 956–959. [CrossRef] [PubMed]
Nagayama, K. , Yahiro, Y. , and Matsumoto, T. , 2011, “ Stress Fibers Stabilize the Position of Intranuclear DNA Through Mechanical Connection With the Nucleus in Vascular Smooth Muscle Cells,” FEBS Lett., 585(24), pp. 3992–3997. [CrossRef] [PubMed]
Versaevel, M. , Braquenier, J.-B. , Riaz, M. , Grevesse, T. , Lantoine, J. , and Gabriele, S. , 2014, “ Super-Resolution Microscopy Reveals LINC Complex Recruitment at Nuclear Indentation Sites,” Sci. Rep., 4, p. 7362. [CrossRef] [PubMed]
Arsenovic, P. T. , Ramachandran, I. , Bathula, K. , Zhu, R. , Narang, J. D. , Noll, N. A. , Lemmon, C. A. , Gundersen, G. G. , and Conway, D. E. , 2016, “ Nesprin-2G: A Component of the Nuclear LINC Complex, Is Subject to Myosin-Dependent Tension,” Biophys. J., 110(1), pp. 34–43. [CrossRef] [PubMed]
Nagayama, K. , Yahiro, Y. , and Matsumoto, T. , 2013, “ 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(4), pp. 473–481. [CrossRef]
Khatau, S. B. , Kusuma, S. , Hanjaya-Putra, D. , Mali, P. , Cheng, L. , Lee, J. S. H. , Gerecht, S. , and Wirtz, D. , 2012, “ The Differential Formation of the LINC-Mediated Perinuclear Actin Cap in Pluripotent and Somatic Cells,” PLoS One, 7(5), p. e36689. [CrossRef] [PubMed]
Lombardi, M. L. , Jaalouk, D. E. , Shanahan, C. M. , Burke, B. , Roux, K. J. , and Lammerding, J. , 2011, “ 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(30), pp. 26743–26753. [CrossRef] [PubMed]
Han, W. M. , Heo, S.-J. , Driscoll, T. P. , Smith, L. J. , Mauck, R. L. , and Elliott, D. M. , 2013, “ Macro- to Microscale Strain Transfer in Fibrous Tissues Is Heterogeneous and Tissue-Specific,” Biophys. J., 105(3), pp. 807–817. [CrossRef] [PubMed]
Li, Q. , Makhija, E. , Hameed, F. M. , and Shivashankar, G. V. , 2015, “ Micropillar Displacements by Cell Traction Forces Are Mechanically Correlated With Nuclear Dynamics,” Biochem. Biophys. Res. Commun., 461(2), pp. 372–377. [CrossRef] [PubMed]
Driscoll, T. P. , Cosgrove, B. D. , Heo, S.-J. , Shurden, Z. E. , and Mauck, R. L. , 2015, “ Cytoskeletal to Nuclear Strain Transfer Regulates YAP Signaling in Mesenchymal Stem Cells,” Biophys. J., 108(12), pp. 2783–2793. [CrossRef] [PubMed]
Banerjee, I. , Zhang, J. , Moore-Morris, T. , Pfeiffer, E. , Buchholz, K. S. , Liu, A. , Ouyang, K. , Stroud, M. J. , Gerace, L. , Evans, S. M. , McCulloch, A. , and Chen, J. , 2014, “ Targeted Ablation of Nesprin 1 and Nesprin 2 From Murine Myocardium Results in Cardiomyopathy, Altered Nuclear Morphology and Inhibition of the Biomechanical Gene Response,” PLoS Genet., 10(2), p. e1004114. [CrossRef] [PubMed]
Chambliss, A. B. , Khatau, S. B. , Erdenberger, N. , Robinson, D. K. , Hodzic, D. , Longmore, G. D. , and Wirtz, D. , 2013, “ The LINC-Anchored Actin Cap Connects the Extracellular Milieu to the Nucleus for Ultrafast Mechanotransduction,” Sci. Rep., 3, p. 1087. [CrossRef] [PubMed]
Lovett, D. B. , Shekhar, N. , Nickerson, J. A. , Roux, K. J. , and Lele, T. P. , 2013, “ Modulation of Nuclear Shape by Substrate Rigidity,” Cell. Mol. Bioeng., 6(2), pp. 230–238. [CrossRef] [PubMed]
Li, Y. , Lovett, D. , Zhang, Q. , Neelam, S. , Kuchibhotla, R. A. , Zhu, R. , Gundersen, G. G. , Lele, T. P. , and Dickinson, R. B. , 2015, “ Moving Cell Boundaries Drive Nuclear Shaping During Cell Spreading,” Biophys. J., 109(4), pp. 670–686. [CrossRef] [PubMed]
Mazumder, A. , and Shivashankar, G. V. , 2010, “ Emergence of a Prestressed Eukaryotic Nucleus During Cellular Differentiation and Development,” J. R. Soc. Interface R. Soc., 7(Suppl. 3), pp. S321–330. [CrossRef]
Jean, R. P. , Gray, D. S. , Spector, A. A. , and Chen, C. S. , 2004, “ Characterization of the Nuclear Deformation Caused by Changes in Endothelial Cell Shape,” ASME J. Biomech. Eng., 126(5), pp. 552–558. [CrossRef]
Anno, T. , Sakamoto, N. , and Sato, M. , 2012, “ Role of Nesprin-1 in Nuclear Deformation in Endothelial Cells Under Static and Uniaxial Stretching Conditions,” Biochem. Biophys. Res. Commun., 424(1), pp. 94–99. [CrossRef] [PubMed]
Sexton, T. , Schober, H. , Fraser, P. , and Gasser, S. M. , 2007, “ Gene Regulation Through Nuclear Organization,” Nat. Struct. Mol. Biol., 14(11), pp. 1049–1055. [CrossRef] [PubMed]
Bickmore, W. A. , and van Steensel, B. , 2013, “ Genome Architecture: Domain Organization of Interphase Chromosomes,” Cell, 152(6), pp. 1270–1284. [CrossRef] [PubMed]
Amendola, M. , and van Steensel, B. , 2014, “ Mechanisms and Dynamics of Nuclear Lamina–Genome Interactions,” Curr. Opin. Cell Biol., 28, pp. 61–68. [CrossRef] [PubMed]
Dobrzynska, A. , Gonzalo, S. , Shanahan, C. , and Askjaer, P. , 2016, “ The Nuclear Lamina in Health and Disease,” Nucleus, 7(3), pp. 233–248. [CrossRef] [PubMed]
Ragoczy, T. , Bender, M. A. , Telling, A. , Byron, R. , and Groudine, M. , 2006, “ The Locus Control Region Is Required for Association of the Murine Beta-Globin Locus With Engaged Transcription Factories During Erythroid Maturation,” Genes Dev., 20(11), pp. 1447–1457. [CrossRef] [PubMed]
Szczerbal, I. , Foster, H. A. , and Bridger, J. M. , 2009, “ The Spatial Repositioning of Adipogenesis Genes Is Correlated With Their Expression Status in a Porcine Mesenchymal Stem Cell Adipogenesis Model System,” Chromosoma, 118(5), pp. 647–663. [CrossRef] [PubMed]
Yao, J. , Fetter, R. D. , Hu, P. , Betzig, E. , and Tjian, R. , 2011, “ Subnuclear Segregation of Genes and Core Promoter Factors in Myogenesis,” Genes Dev., 25(6), pp. 569–580. [CrossRef] [PubMed]
Udagawa, K. , and Ohyama, T. , 2014, “ Positions of Pluripotency Genes and Hepatocyte-Specific Genes in the Nucleus Before and After Mouse ES Cell Differentiation,” Genet. Mol. Res., 13(1), pp. 1979–1988. [CrossRef] [PubMed]
Shachar, S. , Voss, T. C. , Pegoraro, G. , Sciascia, N. , and Misteli, T. , 2015, “ Identification of Gene Positioning Factors Using High-Throughput Imaging Mapping,” Cell, 162(4), pp. 911–923. [CrossRef] [PubMed]
Zhao, H. , Sifakis, E. G. , Sumida, N. , Millán-Ariño, L. , Scholz, B. A. , Svensson, J. P. , Chen, X. , Ronnegren, A. L. , Mallet de Lima, C. D. , Varnoosfaderani, F. S. , Shi, C. , Loseva, O. , Yammine, S. , Israelsson, M. , Rathje, L.-S. , Németi, B. , Fredlund, E. , Helleday, T. , Imreh, M. P. , and Göndör, A. , 2015, “ PARP1- and CTCF-Mediated Interactions Between Active and Repressed Chromatin at the Lamina Promote Oscillating Transcription,” Mol. Cell, 59(6), pp. 984–997. [CrossRef] [PubMed]
Harr, J. C. , Luperchio, T. R. , Wong, X. , Cohen, E. , Wheelan, S. J. , and Reddy, K. L. , 2015, “ Directed Targeting of Chromatin to the Nuclear Lamina Is Mediated by Chromatin State and A-Type Lamins,” J. Cell Biol., 208(1), pp. 33–52. [CrossRef] [PubMed]
Ottaviani, A. , Schluth-Bolard, C. , Rival-Gervier, S. , Boussouar, A. , Rondier, D. , Foerster, A. M. , Morere, J. , Bauwens, S. , Gazzo, S. , Callet-Bauchu, E. , Gilson, E. , and Magdinier, F. , 2009, “ Identification of a Perinuclear Positioning Element in Human Subtelomeres That Requires A-Type Lamins and CTCF,” EMBO J., 28(16), pp. 2428–2436. [CrossRef] [PubMed]
Cui, Y. , and Bustamante, C. , 2000, “ Pulling a Single Chromatin Fiber Reveals the Forces That Maintain Its Higher-Order Structure,” Proc. Natl. Acad. Sci. U.S.A., 97(1), pp. 127–132. [CrossRef] [PubMed]
Yao, M. , Goult, B. T. , Chen, H. , Cong, P. , Sheetz, M. P. , and Yan, J. , 2014, “ Mechanical Activation of Vinculin Binding to Talin Locks Talin in an Unfolded Conformation,” Sci. Rep., 4, p. 4610. [PubMed]
Hu, Y. , Kireev, I. , Plutz, M. , Ashourian, N. , and Belmont, A. S. , 2009, “ Large-Scale Chromatin Structure of Inducible Genes: Transcription on a Condensed, Linear Template,” J. Cell Biol., 185(1), pp. 87–100. [CrossRef] [PubMed]
Marko, J. F. , 2008, “ Micromechanical Studies of Mitotic Chromosomes,” Chromosome Res., 16(3), pp. 469–497. [CrossRef] [PubMed]
Therizols, P. , Illingworth, R. S. , Courilleau, C. , Boyle, S. , Wood, A. J. , and Bickmore, W. A. , 2014, “ Chromatin Decondensation Is Sufficient to Alter Nuclear Organization in Embryonic Stem Cells,” Science, 346(6214), pp. 1238–1242. [CrossRef] [PubMed]
Tajik, A. , Zhang, Y. , Wei, F. , Sun, J. , Jia, Q. , Zhou, W. , Singh, R. , Khanna, N. , Belmont, A. S. , and Wang, N. , 2016, “ Transcription Upregulation Via Force-Induced Direct Stretching of Chromatin,” Nat. Mater., 15(12), pp. 1287–1296. [CrossRef] [PubMed]
Verschure, P. J. , van der Kraan, I. , Manders, E. M. M. , Hoogstraten, D. , Houtsmuller, A. B. , and van Driel, R. , 2003, “ Condensed Chromatin Domains in the Mammalian Nucleus Are Accessible to Large Macromolecules,” EMBO Rep., 4(9), pp. 861–866. [CrossRef] [PubMed]
Chen, D. , Dundr, M. , Wang, C. , Leung, A. , Lamond, A. , Misteli, T. , and Huang, S. , 2005, “ Condensed Mitotic Chromatin Is Accessible to Transcription Factors and Chromatin Structural Proteins,” J. Cell Biol., 168(1), pp. 41–54. [CrossRef] [PubMed]
Bancaud, A. , Huet, S. , Daigle, N. , Mozziconacci, J. , Beaudouin, J. , and Ellenberg, J. , 2009, “ Molecular Crowding Affects Diffusion and Binding of Nuclear Proteins in Heterochromatin and Reveals the Fractal Organization of Chromatin,” EMBO J., 28(24), pp. 3785–3798. [CrossRef] [PubMed]
Becker, J. S. , Nicetto, D. , and Zaret, K. S. , 2016, “ H3K9me3-Dependent Heterochromatin: Barrier to Cell Fate Changes,” Trends Genet., 32(1), pp. 29–41. [CrossRef] [PubMed]
Mattout, A. , Biran, A. , and Meshorer, E. , 2011, “ Global Epigenetic Changes During Somatic Cell Reprogramming to iPS Cells,” J. Mol. Cell Biol., 3(6), pp. 341–350. [CrossRef] [PubMed]
Soufi, A. , Donahue, G. , and Zaret, K. S. , 2012, “ Facilitators and Impediments of the Pluripotency Reprogramming Factors' Initial Engagement With the Genome,” Cell, 151(5), pp. 994–1004. [CrossRef] [PubMed]
Towbin, B. D. , González-Aguilera, C. , Sack, R. , Gaidatzis, D. , Kalck, V. , Meister, P. , Askjaer, P. , and Gasser, S. M. , 2012, “ Step-Wise Methylation of Histone H3K9 Positions Heterochromatin at the Nuclear Periphery,” Cell, 150(5), pp. 934–947. [CrossRef] [PubMed]
Downing, T. L. , Soto, J. , Morez, C. , Houssin, T. , Fritz, A. , Yuan, F. , Chu, J. , Patel, S. , Schaffer, D. V. , and Li, S. , 2013, “ Biophysical Regulation of Epigenetic State and Cell Reprogramming,” Nat. Mater., 12(12), pp. 1154–1162. [CrossRef] [PubMed]
Caiazzo, M. , Okawa, Y. , Ranga, A. , Piersigilli, A. , Tabata, Y. , and Lutolf, M. P. , 2016, “ Defined Three-Dimensional Microenvironments Boost Induction of Pluripotency,” Nat. Mater., 15(3), pp. 344–352. [CrossRef] [PubMed]
Akhtar, A. , and Gasser, S. M. , 2007, “ The Nuclear Envelope and Transcriptional Control,” Nat. Rev. Genet., 8(7), pp. 507–517. [CrossRef] [PubMed]
Mekhail, K. , and Moazed, D. , 2010, “ The Nuclear Envelope in Genome Organization, Expression and Stability,” Nat. Rev. Mol. Cell Biol., 11(5), pp. 317–328. [CrossRef] [PubMed]
Towbin, B. D. , Meister, P. , and Gasser, S. M. , 2009, “ The Nuclear Envelope: A Scaffold for Silencing?,” Curr. Opin. Genet. Dev., 19(2), pp. 180–186. [CrossRef] [PubMed]
Jost, K. L. , Haase, S. , Smeets, D. , Schrode, N. , Schmiedel, J. M. , Bertulat, B. , Herzel, H. , Cremer, M. , and Cardoso, M. C. , 2011, “ 3D-Image Analysis Platform Monitoring Relocation of Pluripotency Genes During Reprogramming,” Nucleic Acids Res., 39(17), pp. e113–e113. [CrossRef] [PubMed]
Zink, D. , Amaral, M. D. , Englmann, A. , Lang, S. , Clarke, L. A. , Rudolph, C. , Alt, F. , Luther, K. , Braz, C. , Sadoni, N. , Rosenecker, J. , and Schindelhauer, D. , 2004, “ Transcription-Dependent Spatial Arrangements of CFTR and Adjacent Genes in Human Cell Nuclei,” J. Cell Biol., 166(6), pp. 815–825. [CrossRef] [PubMed]
Brown, K. E. , Baxter, J. , Graf, D. , Merkenschlager, M. , and Fisher, A. G. , 1999, “ Dynamic Repositioning of Genes in the Nucleus of Lymphocytes Preparing for Cell Division,” Mol. Cell, 3(2), pp. 207–217. [CrossRef] [PubMed]
Reddy, K. L. , Zullo, J. M. , Bertolino, E. , and Singh, H. , 2008, “ Transcriptional Repression Mediated by Repositioning of Genes to the Nuclear Lamina,” Nature, 452(7184), pp. 243–247. [CrossRef] [PubMed]
Kumaran, R. I. , and Spector, D. L. , 2008, “ A Genetic Locus Targeted to the Nuclear Periphery in Living Cells Maintains Its Transcriptional Competence,” J. Cell Biol., 180(1), pp. 51–65. [CrossRef] [PubMed]
Finlan, L. E. , Sproul, D. , Thomson, I. , Boyle, S. , Kerr, E. , Perry, P. , Ylstra, B. , Chubb, J. R. , and Bickmore, W. A. , 2008, “ Recruitment to the Nuclear Periphery Can Alter Expression of Genes in Human Cells,” PLoS Genet, 4(3), p. e1000039. [CrossRef] [PubMed]
Gartenberg, M. R. , Neumann, F. R. , Laroche, T. , Blaszczyk, M. , and Gasser, S. M. , 2004, “ Sir-Mediated Repression Can Occur Independently of Chromosomal and Subnuclear Contexts,” Cell, 119(7), pp. 955–967. [CrossRef] [PubMed]
Schübeler, D. , Francastel, C. , Cimbora, D. M. , Reik, A. , Martin, D. I. , and Groudine, M. , 2000, “ Nuclear Localization and Histone Acetylation: A Pathway for Chromatin Opening and Transcriptional Activation of the Human Beta-Globin Locus,” Genes Dev., 14(8), pp. 940–950. [PubMed]
Chuang, C.-H. , Carpenter, A. E. , Fuchsova, B. , Johnson, T. , de Lanerolle, P. , and Belmont, A. S. , 2006, “ Long-Range Directional Movement of an Interphase Chromosome Site,” Curr. Biol., 16(8), pp. 825–831. [CrossRef] [PubMed]
Dundr, M. , Ospina, J. K. , Sung, M.-H. , John, S. , Upender, M. , Ried, T. , Hager, G. L. , and Matera, A. G. , 2007, “ Actin-Dependent Intranuclear Repositioning of an Active Gene Locus in vivo,” J. Cell Biol., 179(6), pp. 1095–1103. [CrossRef] [PubMed]
Levi, V. , Ruan, Q. , Plutz, M. , Belmont, A. S. , and Gratton, E. , 2005, “ Chromatin Dynamics in Interphase Cells Revealed by Tracking in a Two-Photon Excitation Microscope,” Biophys. J., 89(6), pp. 4275–4285. [CrossRef] [PubMed]
Mehta, I. S. , Amira, M. , Harvey, A. J. , and Bridger, J. M. , 2010, “ Rapid Chromosome Territory Relocation by Nuclear Motor Activity in Response to Serum Removal in Primary Human Fibroblasts,” Genome Biol., 11, p. R5. [CrossRef] [PubMed]
Kind, J. , Pagie, L. , Ortabozkoyun, H. , Boyle, S. , de Vries, S. S. , Janssen, H. , Amendola, M. , Nolen, L. D. , Bickmore, W. A. , and van Steensel, B. , 2013, “ Single-Cell Dynamics of Genome-Nuclear Lamina Interactions,” Cell, 153(1), pp. 178–192. [CrossRef] [PubMed]
Padeken, J. , and Heun, P. , 2014, “ Nucleolus and Nuclear Periphery: Velcro for Heterochromatin,” Curr. Opin. Cell Biol., 28, pp. 54–60. [CrossRef] [PubMed]
Van Koningsbruggen, S. , Gierlinski, M. , Schofield, P. , Martin, D. , Barton, G. J. , Ariyurek, Y. , den Dunnen, J. T. , and Lamond, A. I. , 2010, “ High-Resolution Whole-Genome Sequencing Reveals That Specific Chromatin Domains From Most Human Chromosomes Associate With Nucleoli,” Mol. Biol. Cell, 21(21), pp. 3735–3748. [CrossRef] [PubMed]
Németh, A. , Conesa, A. , Santoyo-Lopez, J. , Medina, I. , Montaner, D. , Péterfia, B. , Solovei, I. , Cremer, T. , Dopazo, J. , and Längst, G. , 2010, “ Initial Genomics of the Human Nucleolus,” PLoS Genet., 6(3), p. e1000889. [CrossRef] [PubMed]
Zhang, Q. , Bethmann, C. , Worth, N. F. , Davies, J. D. , Wasner, C. , Feuer, A. , Ragnauth, C. D. , Yi, Q. , Mellad, J. A. , Warren, D. T. , Wheeler, M. A. , Ellis, J. A. , Skepper, J. N. , Vorgerd, M. , Schlotter-Weigel, B. , Weissberg, P. L. , Roberts, R. G. , Wehnert, M. , and Shanahan, C. M. , 2007, “ 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(23), pp. 2816–2833. [CrossRef] [PubMed]
Makhija, E. , Jokhun, D. S. , and Shivashankar, G. V. , 2016, “ Nuclear Deformability and Telomere Dynamics Are Regulated by Cell Geometric Constraints,” Proc. Natl. Acad. Sci. U.S.A., 113(1), pp. E32–40. [CrossRef] [PubMed]
Lammerding, J. , Hsiao, J. , Schulze, P. C. , Kozlov, S. , Stewart, C. L. , and Lee, R. T. , 2005, “ Abnormal Nuclear Shape and Impaired Mechanotransduction in Emerin-Deficient Cells,” J. Cell Biol., 170(5), pp. 781–791. [CrossRef] [PubMed]
Zwerger, M. , Jaalouk, D. E. , Lombardi, M. L. , Isermann, P. , Mauermann, M. , Dialynas, G. , Herrmann, H. , Wallrath, L. L. , and Lammerding, J. , 2013, “ Myopathic Lamin Mutations Impair Nuclear Stability in Cells and Tissue and Disrupt Nucleo-Cytoskeletal Coupling,” Hum. Mol. Genet., 22(12), pp. 2335–2349. [CrossRef] [PubMed]
Denais, C. M. , Gilbert, R. M. , Isermann, P. , McGregor, A. L. , te Lindert, M. , Weigelin, B. , Davidson, P. M. , Friedl, P. , Wolf, K. , and Lammerding, J. , 2016, “ Nuclear Envelope Rupture and Repair During Cancer Cell Migration,” Science, 352(6283), pp. 353–358. [CrossRef] [PubMed]
Raab, M. , Gentili, M. , de Belly, H. , Thiam, H. R. , Vargas, P. , Jimenez, A. J. , Lautenschlaeger, F. , Voituriez, R. , Lennon-Duménil, A. M. , Manel, N. , and Piel, M. , 2016, “ ESCRT III Repairs Nuclear Envelope Ruptures During Cell Migration to Limit DNA Damage and Cell Death,” Science, 352(6283), pp. 359–362. [CrossRef] [PubMed]
Bell, E. S. , and Lammerding, J. , 2016, “ Causes and Consequences of Nuclear Envelope Alterations in Tumour Progression,” Eur. J. Cell Biol., 95(11), pp. 449–464. [CrossRef] [PubMed]
Irianto, J. , Pfeifer, C. R. , Ivanovska, I. L. , Swift, J. , and Discher, D. E. , 2016, “ Nuclear Lamins in Cancer,” Cell. Mol. Bioeng., 9(2), pp. 258–267. [CrossRef] [PubMed]
Swift, J. , and Discher, D. E. , 2014, “ The Nuclear Lamina Is Mechano-Responsive to ECM Elasticity in Mature Tissue,” J. Cell Sci., 127(14), pp. 3005–3015. [CrossRef] [PubMed]
Knight, M. M. , Lee, D. A. , and Bader, D. L. , 1998, “ The Influence of Elaborated Pericellular Matrix on the Deformation of Isolated Articular Chondrocytes Cultured in Agarose,” Biochim. Biophys. Acta, 1405(1–3), pp. 67–77. [CrossRef] [PubMed]
Choi, J. B. , Youn, I. , Cao, L. , Leddy, H. A. , Gilchrist, C. L. , Setton, L. A. , and Guilak, F. , 2007, “ Zonal Changes in the Three-Dimensional Morphology of the Chondron Under Compression: The Relationship Among Cellular, Pericellular, and Extracellular Deformation in Articular Cartilage,” J. Biomech., 40(12), pp. 2596–2603. [CrossRef] [PubMed]
Dahl, K. N. , Scaffidi, P. , Islam, M. F. , Yodh, A. G. , Wilson, K. L. , and Misteli, T. , 2006, “ Distinct Structural and Mechanical Properties of the Nuclear Lamina in Hutchinson-Gilford Progeria Syndrome,” Proc. Natl. Acad. Sci. U.S.A., 103(27), pp. 10271–10276. [CrossRef] [PubMed]
Scaffidi, P. , and Misteli, T. , 2008, “ Lamin A-Dependent Misregulation of Adult Stem Cells Associated With Accelerated Ageing,” Nat. Cell Biol., 10(4), pp. 452–459. [CrossRef] [PubMed]
Verstraeten, V. L. R. M. , Ji, J. Y. , Cummings, K. S. , Lee, R. T. , and Lammerding, J. , 2008, “ Increased Mechanosensitivity and Nuclear Stiffness in Hutchinson-Gilford Progeria Cells: Effects of Farnesyltransferase Inhibitors,” Aging Cell, 7(3), pp. 383–393. [CrossRef] [PubMed]
Mounkes, L. C. , Kozlov, S. , Hernandez, L. , Sullivan, T. , and Stewart, C. L. , 2003, “ A Progeroid Syndrome in Mice Is Caused by Defects in A-Type Lamins,” Nature, 423(6937), pp. 298–301. [CrossRef] [PubMed]
Hale, C. M. , Shrestha, A. L. , Khatau, S. B. , Stewart-Hutchinson, P. J. , Hernandez, L. , Stewart, C. L. , Hodzic, D. , and Wirtz, D. , 2008, “ Dysfunctional Connections Between the Nucleus and the Actin and Microtubule Networks in Laminopathic Models,” Biophys. J., 95(11), pp. 5462–5475. [CrossRef] [PubMed]
Mehta, I. S. , Eskiw, C. H. , Arican, H. D. , Kill, I. R. , and Bridger, J. M. , 2011, “ Farnesyltransferase Inhibitor Treatment Restores Chromosome Territory Positions and Active Chromosome Dynamics in Hutchinson-Gilford Progeria Syndrome Cells,” Genome Biol., 12(8), p. R74. [CrossRef] [PubMed]
Shumaker, D. K. , Dechat, T. , Kohlmaier, A. , Adam, S. A. , Bozovsky, M. R. , Erdos, M. R. , Eriksson, M. , Goldman, A. E. , Khuon, S. , Collins, F. S. , Jenuwein, T. , and Goldman, R. D. , 2006, “ Mutant Nuclear Lamin A Leads to Progressive Alterations of Epigenetic Control in Premature Aging,” Proc. Natl. Acad. Sci. U.S.A., 103(23), pp. 8703–8708. [CrossRef] [PubMed]
Mattout, A. , Pike, B. L. , Towbin, B. D. , Bank, E. M. , Gonzalez-Sandoval, A. , Stadler, M. B. , Meister, P. , Gruenbaum, Y. , and Gasser, S. M. , 2011, “ An EDMD Mutation in C. Elegans Lamin Blocks Muscle-Specific Gene Relocation and Compromises Muscle Integrity,” Curr. Biol., 21(19), pp. 1603–1614. [CrossRef] [PubMed]
Simon, D. N. , Zastrow, M. S. , and Wilson, K. L. , 2010, “ Direct Actin Binding to A- and B-Type Lamin Tails and Actin Filament Bundling by the Lamin A Tail,” Nucleus, 1(3), pp. 264–272. [CrossRef] [PubMed]
Worman, H. J. , and Schirmer, E. C. , 2015, “ Nuclear Membrane Diversity: Underlying Tissue-Specific Pathologies in Disease?,” Curr. Opin. Cell Biol., 34, pp. 101–112. [CrossRef] [PubMed]
Heessen, S. , and Fornerod, M. , 2007, “ The Inner Nuclear Envelope as a Transcription Factor Resting Place,” EMBO Rep., 8(10), pp. 914–919. [CrossRef] [PubMed]
Gesson, K. , Rescheneder, P. , Skoruppa, M. P. , von Haeseler, A. , Dechat, T. , and Foisner, R. , 2016, “ A-Type Lamins Bind Both Hetero- and Euchromatin, the Latter Being Regulated by Lamina-Associated Polypeptide 2 Alpha,” Genome Res., 26(4), pp. 462–473. [CrossRef] [PubMed]
Solovei, I. , Wang, A. S. , Thanisch, K. , Schmidt, C. S. , Krebs, S. , Zwerger, M. , Cohen, T. V. , Devys, D. , Foisner, R. , Peichl, L. , Herrmann, H. , Blum, H. , Engelkamp, D. , Stewart, C. L. , Leonhardt, H. , and Joffe, B. , 2013, “ LBR and Lamin A/C Sequentially Tether Peripheral Heterochromatin and Inversely Regulate Differentiation,” Cell, 152(3), pp. 584–598. [CrossRef] [PubMed]
Mislow, J. M. K. , Holaska, J. M. , Kim, M. S. , Lee, K. K. , Segura-Totten, M. , Wilson, K. L. , and McNally, E. M. , 2002, “ Nesprin-1α Self-Associates and Binds Directly to Emerin and Lamin A in vitro,” FEBS Lett., 525(1–3), pp. 135–140. [CrossRef] [PubMed]
Zhang, Q. , Ragnauth, C. D. , Skepper, J. N. , Worth, N. F. , Warren, D. T. , Roberts, R. G. , Weissberg, P. L. , Ellis, J. A. , and Shanahan, C. M. , 2005, “ Nesprin-2 Is a Multi-Isomeric Protein That Binds Lamin and Emerin at the Nuclear Envelope and Forms a Subcellular Network in Skeletal Muscle,” J. Cell Sci., 118(Pt. 4), pp. 673–687. [CrossRef] [PubMed]
Neumann, S. , Schneider, M. , Daugherty, R. L. , Gottardi, C. J. , Eming, S. A. , Beijer, A. , Noegel, A. A. , and Karakesisoglou, I. , 2010, “ Nesprin-2 Interacts With {Alpha}-Catenin and Regulates Wnt Signaling at the Nuclear Envelope,” J. Biol. Chem., 285(45), pp. 34932–34938. [CrossRef] [PubMed]
Markiewicz, E. , Tilgner, K. , Barker, N. , van de Wetering, M. , Clevers, H. , Dorobek, M. , Hausmanowa-Petrusewicz, I. , Ramaekers, F. C. S. , Broers, J. L. V. , Blankesteijn, W. M. , Salpingidou, G. , Wilson, R. G. , Ellis, J. A. , and Hutchison, C. J. , 2006, “ The Inner Nuclear Membrane Protein Emerin Regulates Beta-Catenin Activity by Restricting Its Accumulation in the Nucleus,” EMBO J., 25(14), pp. 3275–3285. [CrossRef] [PubMed]
Chang, W. , Folker, E. S. , Worman, H. J. , and Gundersen, G. G. , 2013, “ Emerin Organizes Actin Flow for Nuclear Movement and Centrosome Orientation in Migrating Fibroblasts,” Mol. Biol. Cell, 24(24), pp. 3869–3880. [CrossRef] [PubMed]
Holaska, J. M. , Kowalski, A. K. , and Wilson, K. L. , 2004, “ Emerin Caps the Pointed End of Actin Filaments: Evidence for an Actin Cortical Network at the Nuclear Inner Membrane,” PLoS Biol., 2(9), p. e231. [CrossRef] [PubMed]
Mehta, I. S. , Elcock, L. S. , Amira, M. , Kill, I. R. , and Bridger, J. M. , 2008, “ Nuclear Motors and Nuclear Structures Containing A-Type Lamins and Emerin: Is There a Functional Link?,” Biochem. Soc. Trans., 36(Pt. 6), pp. 1384–1388. [CrossRef] [PubMed]
Eberharter, A. , and Becker, P. B. , 2002, “ Histone Acetylation: A Switch Between Repressive and Permissive Chromatin. Second in Review Series on Chromatin Dynamics,” EMBO Rep., 3(3), pp. 224–229. [CrossRef] [PubMed]
Milon, B. C. , Cheng, H. , Tselebrovsky, M. V. , Lavrov, S. A. , Nenasheva, V. V. , Mikhaleva, E. A. , Shevelyov, Y. Y. , and Nurminsky, D. I. , 2012, “ Role of Histone Deacetylases in Gene Regulation at Nuclear Lamina,” PLoS One, 7(11), p. e49692. [CrossRef] [PubMed]
Zullo, J. M. , Demarco, I. A. , Piqué-Regi, R. , Gaffney, D. J. , Epstein, C. B. , Spooner, C. J. , Luperchio, T. R. , Bernstein, B. E. , Pritchard, J. K. , Reddy, K. L. , and Singh, H. , 2012, “ DNA Sequence-Dependent Compartmentalization and Silencing of Chromatin at the Nuclear Lamina,” Cell, 149(7), pp. 1474–1487. [CrossRef] [PubMed]
Jain, N. , Iyer, K. V. , Kumar, A. , and Shivashankar, G. V. , 2013, “ Cell Geometric Constraints Induce Modular Gene-Expression Patterns Via Redistribution of HDAC3 Regulated by Actomyosin Contractility,” Proc. Natl. Acad. Sci., 110(28), pp. 11349–11354. [CrossRef]
Li, Y. , Chu, J. S. , Kurpinski, K. , Li, X. , Bautista, D. M. , Yang, L. , Sung, K.-L. P. , and Li, S. , 2011, “ Biophysical Regulation of Histone Acetylation in Mesenchymal Stem Cells,” Biophys. J., 100(8), pp. 1902–1909. [CrossRef] [PubMed]
Demmerle, J. , Koch, A. J. , and Holaska, J. M. , 2012, “ The Nuclear Envelope Protein Emerin Binds Directly to Histone Deacetylase 3 (HDAC3) and Activates HDAC3 Activity,” J. Biol. Chem., 287(26), pp. 22080–22088. [CrossRef] [PubMed]
Lu, W. , Schneider, M. , Neumann, S. , Jaeger, V.-M. , Taranum, S. , Munck, M. , Cartwright, S. , Richardson, C. , Carthew, J. , Noh, K. , Goldberg, M. , Noegel, A. A. , and Karakesisoglou, I. , 2012, “ Nesprin Interchain Associations Control Nuclear Size,” Cell. Mol. Life Sci., 69(20), pp. 3493–3509. [CrossRef] [PubMed]
Taranum, S. , Sur, I. , Müller, R. , Lu, W. , Rashmi, R. N. , Munck, M. , Neumann, S. , Karakesisoglou, I. , and Noegel, A. A. , 2012, “ Cytoskeletal Interactions at the Nuclear Envelope Mediated by Nesprins, Cytoskeletal Interactions at the Nuclear Envelope Mediated by Nesprins,” Int. J. Cell Biol., 2012, p. e736524. [CrossRef]
Ketema, M. , Wilhelmsen, K. , Kuikman, I. , Janssen, H. , Hodzic, D. , and Sonnenberg, A. , 2007, “ Requirements for the Localization of Nesprin-3 at the Nuclear Envelope and Its Interaction With Plectin,” J. Cell Sci., 120(Pt. 19), pp. 3384–3394. [CrossRef] [PubMed]
Muchir, A. , van Engelen, B. G. , Lammens, M. , Mislow, J. M. , McNally, E. , Schwartz, K. , and Bonne, G. , 2003, “ Nuclear Envelope Alterations in Fibroblasts From LGMD1B Patients Carrying Nonsense Y259X Heterozygous or Homozygous Mutation in Lamin A/C Gene,” Exp. Cell Res., 291(2), pp. 352–362. [CrossRef] [PubMed]
Libotte, T. , Zaim, H. , Abraham, S. , Padmakumar, V. C. , Schneider, M. , Lu, W. , Munck, M. , Hutchison, C. , Wehnert, M. , Fahrenkrog, B. , Sauder, U. , Aebi, U. , Noegel, A. A. , and Karakesisoglou, I. , 2005, “ Lamin A/C-Dependent Localization of Nesprin-2: A Giant Scaffolder at the Nuclear Envelope,” Mol. Biol. Cell, 16(7), pp. 3411–3424. [CrossRef] [PubMed]
Folker, E. S. , Ostlund, C. , Luxton, G. W. G. , Worman, H. J. , and Gundersen, G. G. , 2011, “ Lamin A Variants That Cause Striated Muscle Disease Are Defective in Anchoring Transmembrane Actin-Associated Nuclear Lines for Nuclear Movement,” Proc. Natl. Acad. Sci. U.S.A., 108(1), pp. 131–136. [CrossRef] [PubMed]
Enyedi, B. , and Niethammer, P. , 2016, “ A Case for the Nuclear Membrane as a Mechanotransducer,” Cell. Mol. Bioeng., 9(2), pp. 247–251. [CrossRef] [PubMed]
Wallrath, L. L. , Bohnekamp, J. , and Magin, T. M. , 2016, “ Cross Talk Between the Cytoplasm and Nucleus During Development and Disease,” Curr. Opin. Genet. Dev., 37, pp. 129–136. [CrossRef] [PubMed]
McKee, C. T. , Raghunathan, V. K. , Nealey, P. F. , Russell, P. , and Murphy, C. J. , 2011, “ Topographic Modulation of the Orientation and Shape of Cell Nuclei and Their Influence on the Measured Elastic Modulus of Epithelial Cells,” Biophys. J., 101(9), pp. 2139–2146. [CrossRef] [PubMed]
Pajerowski, J. D. , Dahl, K. N. , Zhong, F. L. , Sammak, P. J. , and Discher, D. E. , 2007, “ Physical Plasticity of the Nucleus in Stem Cell Differentiation,” Proc. Natl. Acad. Sci. U.S.A., 104(40), pp. 15619–15624. [CrossRef] [PubMed]
Stewart-Hutchinson, P. J. , Hale, C. M. , Wirtz, D. , and Hodzic, D. , 2008, “ Structural Requirements for the Assembly of LINC Complexes and Their Function in Cellular Mechanical Stiffness,” Exp. Cell Res., 314(8), pp. 1892–1905. [CrossRef] [PubMed]
Münter, S. , Enninga, J. , Vazquez-Martinez, R. , Delbarre, E. , David-Watine, B. , Nehrbass, U. , and Shorte, S. L. , 2006, “ Actin Polymerisation at the Cytoplasmic Face of Eukaryotic Nuclei,” BMC Cell Biol., 7(23), p. 23. [CrossRef] [PubMed]
González-Granado, J. M. , Silvestre-Roig, C. , Rocha-Perugini, V. , Trigueros-Motos, L. , Cibrián, D. , Morlino, G. , Blanco-Berrocal, M. , Osorio, F. G. , Freije, J. M. P. , López-Otín, C. , Sánchez-Madrid, F. , and Andrés, V. , 2014, “ Nuclear Envelope Lamin-A Couples Actin Dynamics With Immunological Synapse Architecture and T Cell Activation,” Sci. Signalling, 7(322), p. ra37. [CrossRef]
Morgan, J. T. , Pfeiffer, E. R. , Thirkill, T. L. , Kumar, P. , Peng, G. , Fridolfsson, H. N. , Douglas, G. C. , Starr, D. A. , and Barakat, A. I. , 2011, “ Nesprin-3 Regulates Endothelial Cell Morphology, Perinuclear Cytoskeletal Architecture, and Flow-Induced Polarization,” Mol. Biol. Cell, 22(22), pp. 4324–4334. [CrossRef] [PubMed]
Chancellor, T. J. , Lee, J. , Thodeti, C. K. , and Lele, T. , 2010, “ Actomyosin Tension Exerted on the Nucleus Through Nesprin-1 Connections Influences Endothelial Cell Adhesion, Migration, and Cyclic Strain-Induced Reorientation,” Biophys. J., 99(1), pp. 115–123. [CrossRef] [PubMed]
Ho, C. Y. , Jaalouk, D. E. , Vartiainen, M. K. , and Lammerding, J. , 2013, “ Lamin A/C and Emerin Regulate MKL1-SRF Activity by Modulating Actin Dynamics,” Nature, 497(7450), pp. 507–511. [CrossRef] [PubMed]
Bertrand, A. T. , Ziaei, S. , Ehret, C. , Duchemin, H. , Mamchaoui, K. , Bigot, A. , Mayer, M. , Quijano-Roy, S. , Desguerre, I. , Lainé, J. , Ben Yaou, R. , Bonne, G. , and Coirault, C. , 2014, “ Cellular Microenvironments Reveal Defective Mechanosensing Responses and Elevated YAP Signaling in LMNA-Mutated Muscle Precursors,” J. Cell Sci., 127(Pt. 13), pp. 2873–2884. [CrossRef] [PubMed]
Foster, C. R. , Robson, J. L. , Simon, W. J. , Twigg, J. , Cruikshank, D. , Wilson, R. G. , and Hutchison, C. J. , 2011, “ The Role of Lamin A in Cytoskeleton Organization in Colorectal Cancer Cells: A Proteomic Investigation,” Nucleus, 2(5), pp. 434–443. [CrossRef] [PubMed]
Chen, B. , Gilbert, L. A. , Cimini, B. A. , Schnitzbauer, J. , Zhang, W. , Li, G.-W. , Park, J. , Blackburn, E. H. , Weissman, J. S. , Qi, L. S. , and Huang, B. , 2013, “ Dynamic Imaging of Genomic Loci in Living Human Cells by an Optimized CRISPR/Cas System,” Cell, 155(7), pp. 1479–1491. [CrossRef] [PubMed]
Godin, A. G. , Lounis, B. , and Cognet, L. , 2014, “ Super-Resolution Microscopy Approaches for Live Cell Imaging,” Biophys. J., 107(8), pp. 1777–1784. [CrossRef] [PubMed]
Spagnol, S. T. , and Dahl, K. N. , 2016, “ Spatially Resolved Quantification of Chromatin Condensation Through Differential Local Rheology in Cell Nuclei Fluorescence Lifetime Imaging,” PLoS One, 11(1), p. e0146244. [CrossRef] [PubMed]
Fedorchak, G. , and Lammerding, J. , 2016, “ Cell Microharpooning to Study Nucleo-Cytoskeletal Coupling,” Methods Mol. Biol., 1411, pp. 241–254. [PubMed]
Rodriguez, M. L. , McGarry, P. J. , and Sniadecki, N. J. , 2013, “ Review on Cell Mechanics: Experimental and Modeling Approaches,” ASME Appl. Mech. Rev., 65(6), p. 060801. [CrossRef]
Mak, M. , Kim, T. , Zaman, M. H. , and Kamm, R. D. , 2015, “ Multiscale Mechanobiology: Computational Models for Integrating Molecules to Multicellular Systems,” Integr. Biol. Quant. Biosci. Nano Macro, 7(10), pp. 1093–1108.
Nava, M. M. , Raimondi, M. T. , and Pietrabissa, R. , 2014, “ Bio-Chemo-Mechanical Models for Nuclear Deformation in Adherent Eukaryotic Cells,” Biomech. Model. Mechanobiol., 13(5), pp. 929–943. [CrossRef] [PubMed]
Shemesh, T. , Geiger, B. , Bershadsky, A. D. , and Kozlov, M. M. , 2005, “ Focal Adhesions as Mechanosensors: A Physical Mechanism,” Proc. Natl. Acad. Sci. U.S.A., 102(35), pp. 12383–12388. [CrossRef] [PubMed]
Chan, C. E. , and Odde, D. J. , 2008, “ Traction Dynamics of Filopodia on Compliant Substrates,” Science, 322(5908), pp. 1687–1691. [CrossRef] [PubMed]
Hytönen, V. P. , and Vogel, V. , 2008, “ How Force Might Activate Talin's Vinculin Binding Sites: SMD Reveals a Structural Mechanism,” PLoS Comput. Biol., 4(2), p. e24. [CrossRef] [PubMed]
Paszek, M. J. , Boettiger, D. , Weaver, V. M. , and Hammer, D. A. , 2009, “ Integrin Clustering Is Driven by Mechanical Resistance From the Glycocalyx and the Substrate,” PLoS Comput. Biol., 5(12), p. e1000604. [CrossRef] [PubMed]
Elosegui-Artola, A. , Oria, R. , Chen, Y. , Kosmalska, A. , Pérez-González, C. , Castro, N. , Zhu, C. , Trepat, X. , and Roca-Cusachs, P. , 2016, “ Mechanical Regulation of a Molecular Clutch Defines Force Transmission and Transduction in Response to Matrix Rigidity,” Nat. Cell Biol., 18(5), pp. 540–548. [CrossRef] [PubMed]
Cao, X. , Lin, Y. , Driscoll, T. P. , Franco-Barraza, J. , Cukierman, E. , Mauck, R. L. , and Shenoy, V. B. , 2015, “ A Chemomechanical Model of Matrix and Nuclear Rigidity Regulation of Focal Adhesion Size,” Biophys. J., 109(9), pp. 1807–1817. [CrossRef] [PubMed]
Maraldi, M. , and Garikipati, K. , 2015, “ The Mechanochemistry of Cytoskeletal Force Generation,” Biomech. Model. Mechanobiol., 14(1), pp. 59–72. [CrossRef] [PubMed]
Ronan, W. , Deshpande, V. S. , McMeeking, R. M. , and McGarry, J. P. , 2013, “ Cellular Contractility and Substrate Elasticity: A Numerical Investigation of the Actin Cytoskeleton and Cell Adhesion,” Biomech. Model. Mechanobiol., 13(2), pp. 417–435. [CrossRef] [PubMed]
Jamali, Y. , Jamali, T. , and Mofrad, M. R. K. , 2013, “ An Agent Based Model of Integrin Clustering: Exploring the Role of Ligand Clustering, Integrin Homo-Oligomerization, Integrin–Ligand Affinity, Membrane Crowdedness and Ligand Mobility,” J. Comput. Phys., 244, pp. 264–278. [CrossRef]
Zemel, A. , Rehfeldt, F. , Brown, A. E. X. , Discher, D. E. , and Safran, S. A. , 2010, “ Optimal Matrix Rigidity for Stress Fiber Polarization in Stem Cells,” Nat. Phys., 6(6), pp. 468–473. [CrossRef] [PubMed]
Gouget, C. L. M. , Hwang, Y. , and Barakat, A. I. , 2016, “ Model of Cellular Mechanotransduction Via Actin Stress Fibers,” Biomech. Model. Mechanobiol., 15(2), pp. 331–344. [CrossRef] [PubMed]
Kang, J. , Puskar, K. M. , Ehrlicher, A. J. , LeDuc, P. R. , and Schwartz, R. S. , 2015, “ Structurally Governed Cell Mechanotransduction Through Multiscale Modeling,” Sci. Rep., 5, p. 8622. [CrossRef] [PubMed]
De Santis, G. , Lennon, A. B. , Boschetti, F. , Verhegghe, B. , Verdonck, P. , and Prendergast, P. J. , 2011, “ How Can Cells Sense the Elasticity of a Substrate? An Analysis Using a Cell Tensegrity Model,” Eur. Cell. Mater., 22, pp. 202–213. [CrossRef] [PubMed]
Kim, T. , Hwang, W. , Lee, H. , and Kamm, R. D. , 2009, “ Computational Analysis of Viscoelastic Properties of Crosslinked Actin Networks,” PLoS Comput. Biol., 5(7), p. e1000439. [CrossRef] [PubMed]
Huisman, E. M. , van Dillen, T. , Onck, P. R. , and Van der Giessen, E. , 2007, “ Three-Dimensional Cross-Linked F-Actin Networks: Relation Between Network Architecture and Mechanical Behavior,” Phys. Rev. Lett., 99(20), p. 208103. [CrossRef] [PubMed]
Wang, S. , and Wolynes, P. G. , 2012, “ Active Contractility in Actomyosin Networks,” Proc. Natl. Acad. Sci., 109(17), pp. 6446–6451. [CrossRef]
Alvarado, J. , Sheinman, M. , Sharma, A. , MacKintosh, F. C. , and Koenderink, G. H. , 2013, “ Molecular Motors Robustly Drive Active Gels to a Critically Connected State,” Nat. Phys., 9(9), pp. 591–597. [CrossRef]
Åström, J. A. , Kumar, P. B. S. , Vattulainen, I. , and Karttunen, M. , 2008, “ Strain Hardening, Avalanches, and Strain Softening in Dense Cross-Linked Actin Networks,” Phys. Rev. E, 77(5), p. 051913. [CrossRef]
Zeng, Y. , Yip, A. K. , Teo, S.-K. , and Chiam, K.-H. , 2012, “ A Three-Dimensional Random Network Model of the Cytoskeleton and Its Role in Mechanotransduction and Nucleus Deformation,” Biomech. Model. Mechanobiol., 11(1–2), pp. 49–59. [CrossRef] [PubMed]
Zemel, A. , 2015, “ Active Mechanical Coupling Between the Nucleus, Cytoskeleton and the Extracellular Matrix, and the Implications for Perinuclear Actomyosin Organization,” Soft Matter, 11(12), pp. 2353–2363. [CrossRef] [PubMed]
Caille, N. , Thoumine, O. , Tardy, Y. , and Meister, J.-J. , 2002, “ Contribution of the Nucleus to the Mechanical Properties of Endothelial Cells,” J. Biomech., 35(2), pp. 177–187. [CrossRef] [PubMed]
Ferko, M. C. , Bhatnagar, A. , Garcia, M. B. , and Butler, P. J. , 2007, “ Finite-Element Stress Analysis of a Multicomponent Model of Sheared and Focally Adhered Endothelial Cells,” Ann. Biomed. Eng., 35(2), pp. 208–223. [CrossRef] [PubMed]
Slomka, N. , and Gefen, A. , 2010, “ Confocal Microscopy-Based Three-Dimensional Cell-Specific Modeling for Large Deformation Analyses in Cellular Mechanics,” J. Biomech., 43(9), pp. 1806–1816. [CrossRef] [PubMed]
Jean, R. P. , Chen, C. S. , and Spector, A. A. , 2005, “ Finite-Element Analysis of the Adhesion-Cytoskeleton-Nucleus Mechanotransduction Pathway During Endothelial Cell Rounding: Axisymmetric Model,” ASME J. Biomech. Eng., 127(4), pp. 594–600. [CrossRef]
Dahl, K. N. , Kahn, S. M. , Wilson, K. L. , and Discher, D. E. , 2004, “ The Nuclear Envelope Lamina Network Has Elasticity and a Compressibility Limit Suggestive of a Molecular Shock Absorber,” J. Cell Sci., 117(Pt. 20), pp. 4779–4786. [CrossRef] [PubMed]
Tessier, F. , Boal, D. H. , and Discher, D. E. , 2003, “ Networks With Fourfold Connectivity in Two Dimensions,” Phys. Rev. E, 67(1), p. 011903. [CrossRef]
Funkhouser, C. M. , Sknepnek, R. , Shimi, T. , Goldman, A. E. , Goldman, R. D. , and Olvera de la Cruz, M. , 2013, “ Mechanical Model of Blebbing in Nuclear Lamin Meshworks,” Proc. Natl. Acad. Sci. U.S.A., 110(9), pp. 3248–3253. [CrossRef] [PubMed]
Arya, G. , and Schlick, T. , 2006, “ Role of Histone Tails in Chromatin Folding Revealed by a Mesoscopic Oligonucleosome Model,” Proc. Natl. Acad. Sci., 103(44), pp. 16236–16241. [CrossRef]
Cocco, S. , Marko, J. F. , Monasson, R. , Sarkar, A. , and Yan, J. , 2003, “ Force-Extension Behavior of Folding Polymers,” Eur. Phys. J. E Soft Matter, 10(3), pp. 249–263. [CrossRef] [PubMed]
Barbieri, M. , Chotalia, M. , Fraser, J. , Lavitas, L.-M. , Dostie, J. , Pombo, A. , and Nicodemi, M. , 2012, “ Complexity of Chromatin Folding Is Captured by the Strings and Binders Switch Model,” Proc. Natl. Acad. Sci. U.S.A., 109(40), pp. 16173–16178. [CrossRef] [PubMed]
Marenduzzo, D. , Micheletti, C. , and Cook, P. R. , 2006, “ Entropy-Driven Genome Organization,” Biophys. J., 90(10), pp. 3712–3721. [CrossRef] [PubMed]
Carrero, G. , Hendzel, M. J. , and de Vries, G. , 2006, “ Modelling the Compartmentalization of Splicing Factors,” J. Theor. Biol., 239(3), pp. 298–312. [CrossRef] [PubMed]
Stricker, J. , Sabass, B. , Schwarz, U. S. , and Gardel, M. L. , 2010, “ Optimization of Traction Force Microscopy for Micron-Sized Focal Adhesions,” J. Phys. Condens. Matter Inst. Phys. J., 22(19), p. 194104. [CrossRef]
Lessey, E. C. , Guilluy, C. , and Burridge, K. , 2012, “ From Mechanical Force to RhoA Activation,” Biochemistry, 51(38), pp. 7420–7432. [CrossRef] [PubMed]
Borau, C. , Kamm, R. D. , and García-Aznar, J. M. , 2014, “ A Time-Dependent Phenomenological Model for Cell Mechano-Sensing,” Biomech. Model. Mechanobiol., 13(2), pp. 451–462. [CrossRef] [PubMed]
Étienne, J. , Fouchard, J. , Mitrossilis, D. , Bufi, N. , Durand-Smet, P. , and Asnacios, A. , 2015, “ Cells as Liquid Motors: Mechanosensitivity Emerges From Collective Dynamics of Actomyosin Cortex,” Proc. Natl. Acad. Sci., 112(9), pp. 2740–2745. [CrossRef]
Moreo, P. , García-Aznar, J. M. , and Doblaré, M. , 2008, “ Modeling Mechanosensing and Its Effect on the Migration and Proliferation of Adherent Cells,” Acta Biomater., 4(3), pp. 613–621. [CrossRef] [PubMed]
McGarry, J. P. , Fu, J. , Yang, M. T. , Chen, C. S. , McMeeking, R. M. , Evans, A. G. , and Deshpande, V. S. , 2009, “ Simulation of the Contractile Response of Cells on an Array of Micro-Posts,” Philos. Trans. R. Soc. London Math. Phys. Eng. Sci., 367(1902), pp. 3477–3497. [CrossRef]
Marcq, P. , Yoshinaga, N. , and Prost, J. , 2011, “ Rigidity Sensing Explained by Active Matter Theory,” Biophys. J., 101(6), pp. L33–L35. [CrossRef] [PubMed]
Parameswaran, H. , Lutchen, K. R. , and Suki, B. , 2014, “ A Computational Model of the Response of Adherent Cells to Stretch and Changes in Substrate Stiffness,” J. Appl. Physiol., 116(7), pp. 825–834. [CrossRef] [PubMed]
Vernerey, F. J. , and Farsad, M. , 2011, “ A Constrained Mixture Approach to Mechano-Sensing and Force Generation in Contractile Cells,” J. Mech. Behav. Biomed. Mater., 4(8), pp. 1683–1699. [CrossRef] [PubMed]
Milan, J. L. , Wendling-Mansuy, S. , Jean, M. , and Chabrand, P. , 2007, “ Divided Medium-Based Model for Analyzing the Dynamic Reorganization of the Cytoskeleton During Cell Deformation,” Biomech. Model. Mechanobiol., 6(6), pp. 373–390. [CrossRef] [PubMed]
Milan, J.-L. , Lavenus, S. , Pilet, P. , Louarn, G. , Wendling, S. , Heymann, D. , Layrolle, P. , and Chabrand, P. , 2013, “ Computational Model Combined With in vitro Experiments to Analyse Mechanotransduction During Mesenchymal Stem Cell Adhesion,” Eur. Cell. Mater., 25, pp. 97–113. [CrossRef] [PubMed]
Milan, J.-L. , Manifacier, I. , Beussman, K. M. , Han, S. J. , Sniadecki, N. J. , About, I. , and Chabrand, P. , 2016, “ In Silico CDM Model Sheds Light on Force Transmission in Cell From Focal Adhesions to Nucleus,” J. Biomech., 49(13), pp. 2625–2634. [CrossRef] [PubMed]
King, M. C. , and Lusk, C. P. , 2016, “ A Model for Coordinating Nuclear Mechanics and Membrane Remodeling to Support Nuclear Integrity,” Curr. Opin. Cell Biol., 41, pp. 9–17. [CrossRef] [PubMed]
Saunders, C. A. , and Luxton, G. W. G. , 2016, “ LINCing Defective Nuclear-Cytoskeletal Coupling and DYT1 Dystonia,” Cell. Mol. Bioeng., 9(2), pp. 207–216. [CrossRef] [PubMed]
Baker, B. M. , and Chen, C. S. , 2012, “ Deconstructing the Third Dimension: How 3D Culture Microenvironments Alter Cellular Cues,” J. Cell Sci., 125(Pt. 13), pp. 3015–3024. [CrossRef] [PubMed]
Grinnell, F. , Ho, C.-H. , Tamariz, E. , Lee, D. J. , and Skuta, G. , 2003, “ Dendritic Fibroblasts in Three-Dimensional Collagen Matrices,” Mol. Biol. Cell, 14(2), pp. 384–395. [CrossRef] [PubMed]
Hakkinen, K. M. , Harunaga, J. S. , Doyle, A. D. , and Yamada, K. M. , 2011, “ Direct Comparisons of the Morphology, Migration, Cell Adhesions, and Actin Cytoskeleton of Fibroblasts in Four Different Three-Dimensional Extracellular Matrices,” Tissue Eng. Part A, 17(5–6), pp. 713–724. [CrossRef] [PubMed]
Jorgens, D. M. , Inman, J. L. , Wojcik, M. , Robertson, C. , Palsdottir, H. , Tsai, W.-T. , Huang, H. , Bruni-Cardoso, A. , López, C. S. , Bissell, M. J. , Xu, K. , and Auer, M. , 2016, “ Deep Nuclear Invaginations Linked to Cytoskeletal Filaments: Integrated Bioimaging of Epithelial Cells in 3D Culture,” J. Cell Sci. (in press).
Deguchi, S. , Maeda, K. , Ohashi, T. , and Sato, M. , 2005, “ Flow-Induced Hardening of Endothelial Nucleus as an Intracellular Stress-Bearing Organelle,” J. Biomech., 38(9), pp. 1751–1759. [CrossRef] [PubMed]
Harada, T. , Swift, J. , Irianto, J. , Shin, J.-W. , Spinler, K. R. , Athirasala, A. , Diegmiller, R. , Dingal, P. C. D. P. , Ivanovska, I. L. , and Discher, D. E. , 2014, “ Nuclear Lamin Stiffness Is a Barrier to 3D Migration, But Softness Can Limit Survival,” J. Cell Biol., 204(5), pp. 669–682. [CrossRef] [PubMed]
Balestrini, J. L. , Chaudhry, S. , Sarrazy, V. , Koehler, A. , and Hinz, B. , 2012, “ The Mechanical Memory of Lung Myofibroblasts,” Integr. Biol. Quant. Biosci. Nano Macro, 4(4), pp. 410–421.
Yang, C. , Tibbitt, M. W. , Basta, L. , and Anseth, K. S. , 2014, “ Mechanical Memory and Dosing Influence Stem Cell Fate,” Nat. Mater., 13(6), pp. 645–652. [CrossRef] [PubMed]
Heo, S.-J. , Thorpe, S. D. , Driscoll, T. P. , Duncan, R. L. , Lee, D. A. , and Mauck, R. L. , 2015, “ Biophysical Regulation of Chromatin Architecture Instills a Mechanical Memory in Mesenchymal Stem Cells,” Sci. Rep., 5, p. 16895. [CrossRef] [PubMed]
Heo, S. J. , Driscoll, T. P. , Thorpe, S. D. , Nerurkar, N. L. , Baker, B. M. , Yang, M. T. , Chen, C. S. , Lee, D. A. , and Mauck, R. L. , 2016, “ Differentiation Alters Stem Cell Nuclear Architecture, Mechanics, and Mechano-sensitivity,” eLife, 5, p. e18207. [CrossRef] [PubMed]
Cao, X. , Moeendarbary, E. , Isermann, P. , Davidson, P. M. , Wang, X. , Chen, M. B. , Burkart, A. K. , Lammerding, J. , Kamm, R. D. , and Shenoy, V. B. , 2016, “ A Chemomechanical Model for Nuclear Morphology and Stresses during Cell Transendothelial Migration,” Biophys. J., 111(7), pp. 1541–1552. [CrossRef]

Figures

Grahic Jump Location
Fig. 1

Primary sites of cellular mechanotransduction. Cells attach to the extracellular matrix via integrins and other associated proteins that form focal adhesions. Forces (F) generated by extracellular strain or active cell contraction are produced at the focal adhesions and transmitted through the cell cytoskeleton primarily by actin stress fibers (shown in red) and intermediate filaments (shown in green). Tension within the cytoskeleton transmits forces to the nucleus, which initiates nuclear remodeling and potential mechanotransduction mechanisms. Additionally, stretch of the plasma membrane and cytoskeletal tension may open stretch-activated ion channels. The resulting influx of ions alters the electrochemical potential of the cell and mediates downstream signaling. Color figures are available online.

Grahic Jump Location
Fig. 2

Extracellular forces deform the nucleus. (a)–(c) Force applied to endothelial cells by displacing an RGD-coated bead bound to integrins on the cell surface produces nuclear deformation and displacement of intranuclear nucleoli. (d) Extracellular loading also displaces fluorescently labeled YFP-coilin and CFP-SMN proteins, which are markers for Cajal bodies within the nucleus. Inset: Bright-field image of HeLa cell with RGD-coated bead in black and nucleus outlined with dotted line. Scale bar: 10 μm. (e) Prior to loading, the CFP signal is quenched by fluorescence resonance energy transfer (FRET) due to the association between coilin and SMN. With applied stress, the coilin and SMN proteins separate, resulting in an increase in CFP fluorescence. Adapted with permission from Refs. [34] and [37]. Refer to electronic document for color images.

Grahic Jump Location
Fig. 3

Schematic illustrating the structure of the nuclear envelope. Adjacent to the inner nuclear membrane is the nuclear lamina, which is a meshwork of intermediate filaments that are the primary structural support for the nucleus. Heterochromatic lamina-associated domains (LADs) bind to the lamina and other proteins associated with the nuclear envelope (e.g., emerin). Linker of the nucleoskeleton and cytoskeleton (LINC) complexes are composed of nesprins and SUN proteins as well as other associated molecules (e.g., emerin, FHOD1, and Samp1) and connect the nuclear lamina with the cytoplasmic cytoskeleton. Color figures are available online.

Grahic Jump Location
Fig. 4

Compressive loading of the apical nuclear surface. (a) Apical actin stress fibers (green) form deep indentations within the nucleus, which deform the nuclear lamina (red) and intranuclear chromatin (blue). Scale bar: 3 μm. (b) and (c) Cross-sectional images of nucleus showing actin stress fibers within nuclear indentations and substantial local nuclear deformations. Scale bars: 1.5 μm. Adapted with permission from Ref. [92]. Color figures are available online.

Grahic Jump Location
Fig. 5

Relocation of gene loci within the nucleus during stem cell differentiation. (a) In stem cells, pluripotent and housekeeping genes are actively transcribed within the nuclear interior while lineage-specific genes are silenced at the nuclear periphery. (b) With lineage commitment, lineage-specific genes are detached from the nuclear lamina and relocated to the nuclear interior. In contrast, pluripotent genes are silenced and attach to the nuclear lamina. (c) Additionally, some lineage-specific genes remain inactive despite being displaced from the nuclear envelope and are transcribed only after terminal differentiation. Adapted with permission from Ref. [78]. Color figures are available online.

Grahic Jump Location
Fig. 6

A stiff nuclear lamina prevents large deformations of the nucleus. (a) Kymographs of the nuclear envelope demonstrate that elongated cells on rectangular micropatterned islands (gray lines) have significantly smaller local perturbations of the nuclear surface compared to round cells on circular islands (red lines). These differences in the stability of the nuclear envelope are due to remodeling of the nuclear lamina, since (b) knockout of lamin A/C in elongated cells produces larger fluctuations in the nuclear surface, whereas (c) overexpression of lamin A/C in round cells has the opposite effect. Adapted with permission from Ref. [154]. Color figures are available online.

Grahic Jump Location
Fig. 7

Proteins associated with the nuclear lamina. In addition to the components of the LINC complex, numerous lamina-associated polypeptides (LAPs) bind to the nuclear lamina and serve various functions. Emerin, LAP2β, and MAN1 help connect heterochromatic LADs to the nuclear lamina via their interaction with BAF. In addition, HDAC3 and LBR directly bind chromatin. These proteins, as well as the nuclear lamina itself, also bind various transcription factors (TFs) involved in important signaling pathways (e.g., c-Fos, SREB1, β-catenin, and Smads). CTCF helps position chromatin at the nuclear envelope and also flanks regions of histone modifications associated with gene silencing (i.e., H3K9me3 and H3K27me3). Soluble lamin A/C dimers associate with actively transcribed euchromatin within the nuclear interior via LAP2α. Lamin A/C and emerin are also likely involved in the actomyosin machinery potentially responsible for relocating gene loci to the nuclear interior upon activation. Color figures are available online.

Grahic Jump Location
Fig. 8

Changes in biophysical stimuli dynamically modulate nuclear and cytoskeletal structure. (Left) Force applied to the nucleus promotes assembly of the lamina and nuclear stiffening. This in turn increases the forces at focal adhesions generated by actomyosin contractility, which leads to further growth of focal adhesions and stress fibers. Increased actin polymerization and nuclear loading induce import of transcription factors (e.g., MKL1 and YAP), which drive further structural remodeling in the cytoplasm via upregulation of several cytoskeletal proteins (e.g., myosin-IIA). (Right) Loss of nuclear loading causes disassembly and degradation of lamin A/C. This softens the nucleus and disrupts existing LINC complexes, causing reductions in stress fiber and focal adhesion size as well as cytoskeletal tension. Increased levels of G-actin and loss of nuclear loading lead to sequestration of MKL1 and YAP within the cytoplasm and downregulation of cytoskeletal proteins.

Grahic Jump Location
Fig. 9

Simple calculation of forces required to locally deform nuclear lamina and decondense chromatin. (a) Application of local force (F) via micropipette aspiration of isolated nuclei displaces the nuclear lamina a distance L, while the intranuclear chromatin is excluded from the pipette lumen. This provides an estimate of the network elastic modulus of the nuclear lamina. (b) Force applied to the nuclear envelope is transmitted to the nuclear lamina and attached chromatin fiber, which act in parallel and have stiffnesses Knl and Kchr, respectively. (c) Micropipette aspiration of live adherent fibroblasts produces substantial local deformation of the nucleus, which is more than sufficient to decondense chromatin and potentially initiate gene transcription. Adapted with permission from Refs. [33] and [239].

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