Effect of heterochromatin segregation and peripheral tethering on the rigidity of the cell nucleus.

The eukaryotic cell nucleus is a mechanically sensitive organelle that transmits external forces to chromosomes, influencing genome organization and function. While chromatin—particularly transcriptionally inactive heterochromatin—resists deformation, its liquid-like behavior complicates the understanding of nuclear elasticity. To investigate how heterochromatin contributes to nuclear mechanics, we developed a polymer physics model of the nucleus validated by micromechanical measurements, chromosome conformation capture data, and scaling analyses. Our simulations and analyses reveal that peripheral tethering of heterochromatin to the nuclear lamina is essential for transmitting mechanical forces to chromatin and generating an elastic response. Increased heterochromatin levels enhance nuclear stiffness by populating the chromatin–lamina linkages. Additionally, crosslinking the heterochromatin segments near the nuclear periphery (to emulate various structural proteins) further stiffens the nucleus, but only when peripheral tethering is present. In contrast, affinity interactions associated with chromatin segregation do not contribute to the nuclear rigidity. Overall, when the nucleus is deformed by external forces, gel-like peripheral heterochromatin bears mechanical stress, whereas the more fluid-like euchromatin remains relatively unperturbed. These findings suggest that the chromatin organization and lamina attachment of heterochromatin are key determinants of nuclear mechanics and mechanosensing.