Abstract
Living cells and tissues experience various complex modes of forces that are important in physiology and disease. However, how different force modes impact gene expression is elusive. Here we apply local forces of different modes via a magnetic bead bound to the integrins on a cell and quantified cell stiffness, chromatin deformation, and DHFR (dihydrofolate reductase) gene transcription. In-plane stresses result in lower cell stiffness than out-of-plane stresses that lead to bead rolling along the cell long axis (i.e., alignment of actin stress fibers) or at different angles (90° or 45°). However, chromatin stretching and ensuing DHFR gene upregulation by the in-plane mode are similar to those induced by the 45° stress mode. Disrupting stress fibers abolishes differences in cell stiffness, chromatin stretching, and DHFR gene upregulation under different force modes and inhibiting myosin II decreases cell stiffness, chromatin deformation, and gene upregulation. Theoretical modeling using discrete anisotropic stress fibers recapitulates experimental results and reveals underlying mechanisms of force-mode dependence. Our findings suggest that forces impact biological responses of living cells such as gene transcription via previously underappreciated means.
Highlights
Living cells and tissues experience various complex modes of forces that are important in physiology and disease
While it is well known that shear stresses at the cell apical surface produce different signals and cellular effects than do stretching forces at the base or sides of endothelial cells, as vessel diameter changes during dilation or constriction[9,10], the underlying mechanisms of how gene transcription is altered by various force modes remain unclear
We computed stretching of the chromatin domain containing the DHFR gene by quantifying the tensile strains and the shear strains of the chromatin[21] and found that the in-plane stress mode resulted in the strains that were higher than the 0° mode and lower than the 90° mode (Fig. 2g, h)
Summary
Living cells and tissues experience various complex modes of forces that are important in physiology and disease. We apply local forces of different modes via a magnetic bead bound to the integrins on a cell and quantified cell stiffness, chromatin deformation, and DHFR (dihydrofolate reductase) gene transcription. While it is well known that shear stresses at the cell apical surface produce different signals and cellular effects than do stretching forces at the base or sides of endothelial cells, as vessel diameter changes during dilation or constriction[9,10], the underlying mechanisms of how gene transcription is altered by various force modes remain unclear. Experimental results in living cells and theoretical modeling analyses using discrete anisotropic elements reveal that stress fiber anisotropy determines force-mode dependent cell stiffness and chromatin stretching and regulates gene upregulation
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