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305 The Rockefeller University Press $30.00 J. Cell Biol. Vol. 216 No. 2 305–315 https://doi.org/10.1083/jcb.201610042 Introduction Tissue physical properties depend on the cells that make the tissue and also seem to be affected by tissue use. For example, muscle, cartilage, and bone, when suitably exercised, generate or resist mechanical forces that can be many times the weights of these tissues. It is therefore understandable that these tissues and their cells require some stiffness or rigidity to maintain their form under high stress. Brain and marrow, in contrast, are protected from external stress by bone, and so perhaps one reason they are soft is that they simply do not need to be stiff to resist stress. It is now reasonably well established that cells have the ability to sense and respond to mechanical forces of varying magnitude, direction, and frequency (Discher et al., 2005; Ingber, 2006). Furthermore, because the largest organelle of a cell is its nucleus, it is also plausible that the nucleus has a similar ability to mechanosense the tissue microenvironment. Forces and resistance external to nuclei are increasingly understood to affect processes ranging from protein conformation and assembly to localization of transcription factors, chromosome organization, and nuclear envelope dilation to rupture—all of which might affect gene expression (Fig. 1). Tissue stiffness is molecularly determined by the most abundant proteins in vertebrates, the highly helical fibrillar collagens of the ECM. Cells interact physically with the ECM as the cytoskeleton exerts stress on the ECM via adhesions, and this stress is sufficient to alter the morphologies of cells (Marganski et al., 2003; Discher et al., 2005) and their nuclei (Dahl et al., 2008; Khatau et al., 2009; Versaevel et al., 2012; Kim et al., 2014a, 2015). With soft ECM, most normal cell types down-regulate their actin–myosin contractile machinery and exert much less tension than with stiff ECM. Importantly, cytoskeleton-induced stresses on matrix outside of the cell put an equal-but-opposite cytoskeletal stress on the nucleus inside (Chancellor et al., 2010; Lovett et al., 2013; Swift et al., 2013; Alam et al., 2015); it is as if the nucleus is just a spheroidal inclusion of ECM anchored within the cell by factors and assemblies that are functionally analogous to focal adhesions (which are well known to be mechanosensitive). Indeed, much like the plasma membrane and cortex at the cell–ECM boundary, the nuclear envelope is a dynamic, force-sensitive interface between the cytoplasm and the chromatin. The nuclear envelope’s main structural “cortex” is the lamina, composed of the helix-rich fibrillar lamin proteins (Goldman et al., 2002) that assemble just below the inner nuclear membrane (INM; Gruenbaum et al., 2005). Lamins are A-type (lamins A and C from the LMNA gene) or B-type (lamins B1 and B2) and tether the nucleus to the cytoskeleton via the linker of nucleoskeleton and cytoskeleton complex (Crisp et al., 2006), referred to as LINC proteins. The nuclear envelope harbors many other proteins (Schirmer et al., 2003; Korfali et al., 2012), and some, such as those of the LEM (LAP2, emerin, and MAN1) family, specifically associate with the lamins. Heterochromatin at the nuclear periphery (Paddy et al., 1990; Solovei et al., 2013) and a wide range of transcription factors (Lloyd et al., 2002; Margalit et al., 2005; Rodríguez et al., 2010; Wilson and Foisner, 2010) also interact with the lamina. The nuclear envelope and its lamina are thus well positioned to serve as a multiplexing interface that can mechanotransduce in its regulation of the cell’s genome. Recent approaches that range from methods for probing nuclear mechanics to mass spectrometry (MS)–based characterization of protein folding have expanded our understanding of nuclear mechanosensing. We start the review by discussing the insights these new technological advances have provided, in particular in the assessment of the direct physical effects that external force has on nuclear protein conformation and phosphorylation states. This is followed by summaries of stress-induced changes in localization of transcription factors, The nucleus is linked mechanically to the extracellular matrix via multiple polymers that transmit forces to the nuclear envelope and into the nuclear interior. Here, we review some of the emerging mechanisms of nuclear mechanosensing, which range from changes in protein conformation and transcription factor localization to chromosome reorganization and membrane dilation up to rupture. Nuclear mechanosensing encompasses biophysically complex pathways that often converge on the main structural proteins of the nucleus, the lamins. We also perform meta-analyses of public transcriptomics and proteomics data, which indicate that some of the mechanosensing pathways relaying signals from the collagen matrix to the nucleus apply to a broad range of species, tissues, and diseases. Mechanosensing by the nucleus: From pathways to scaling relationships