Abstract
Physical forces arising in the extra-cellular environment have a profound impact on cell fate and gene regulation; however the underlying biophysical mechanisms that control this sensitivity remain elusive. It is hypothesized that gene expression may be influenced by the physical deformation of the nucleus in response to force. Here, using 3T3s as a model, we demonstrate that extra-cellular forces cause cell nuclei to rapidly deform (<1 s) preferentially along their shorter nuclear axis, in an anisotropic manner. Nuclear anisotropy is shown to be regulated by the cytoskeleton within intact cells, with actin and microtubules resistant to orthonormal strains. Importantly, nuclear anisotropy is intrinsic, and observed in isolated nuclei. The sensitivity of this behaviour is influenced by chromatin organization and lamin-A expression. An anisotropic response to force was also highly conserved amongst an array of examined nuclei from differentiated and undifferentiated cell types. Although the functional purpose of this conserved material property remains elusive, it may provide a mechanism through which mechanical cues in the microenvironment are rapidly transmitted to the genome.
Highlights
Mechanical forces transmitted through the cell directly affect nuclear shape and function, have been implicated in altered gene expression[1,2], and affect numerous processes at the cellular level[3,4]
Whole-cell compression with a custom-built indenter revealed strain anisotropy in mouse embryonic fibroblast (MEF) nuclei, an observation that diminished in lamin A/C deficient cells[22]
By measuring nuclear strains and defining a quantitative measure of anisotropy, we demonstrate that nuclear anisotropy is prominent in NIH 3T3 fibroblasts, and highly conserved in a variety of cell types
Summary
Mechanical forces transmitted through the cell directly affect nuclear shape and function, have been implicated in altered gene expression[1,2], and affect numerous processes at the cellular level[3,4]. How nuclei respond to physical cues depends on their inherent material properties, which alone direct diverse biological functions Mechanosensitive proteins, such as lamins, are known to control and regulate these properties by physically coupling the inner nucleus with the cell’s cytoskeleton, focal adhesions and integrins[3,5]. Whole-cell compression with a custom-built indenter revealed strain anisotropy in mouse embryonic fibroblast (MEF) nuclei, an observation that diminished in lamin A/C deficient cells[22] These studies demonstrated that nuclear prestress governs nuclear shape, while cytoskeletal organization governs nuclear deformation in response to mechanical stress[5,11,15]. It seems likely that the cytoskeleton plays a role in directing anisotropy of nuclear deformations since it acts as a direct link to external force Nuclear components such as lamins or chromatin organization may inherently influence nuclear behaviour. Nuclear anisotropy may provide a direct mechanism through which extra-cellular forces are controllably transmitted to the genome, the nucleus itself may act as a mechanosensor in the cell, as recently proposed[4]
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