Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage

Summary

Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a calcium-dependent nuclear softening driven by loss of H3K9me3-marked heterochromatin. The resulting changes in chromatin rheology and architecture are required to insulate genetic material from mechanical force. Failure to mount this nuclear mechanoresponse results in DNA damage. Persistent, high-amplitude stretch induces supracellular alignment of tissue to redistribute mechanical energy before it reaches the nucleus. This tissue-scale mechanoadaptation functions through a separate pathway mediated by cell-cell contacts and allows cells/tissues to switch off nuclear mechanotransduction to restore initial chromatin state. Our work identifies an unconventional role of chromatin in altering its own mechanical state to maintain genome integrity in response to deformation.

Graphical Abstract

Highlights

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  Stretch triggers amplitude-dependent supracellular and nuclear mechanoresponses

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  H3K9me3 heterochromatin mediates nuclear stiffness and membrane tension

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  Nuclear deformation-triggered Ca ²⁺ alters chromatin rheology to prevent DNA damage

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  Supracellular alignment redistributes stress to restore chromatin state

Abstract

When tissues are stretched, cells respond via two distinct mechanosensory mechanisms to protect the genome from damage and maintain tissue homeostasis. First, rapid heterochromatin-mediated mechanosensing, independent of known cellular mechanosensors, drives calcium-dependent nuclear softening. If the mechanical stress persists, a second, tissue-level reorganization occurs, mediated by cell-cell contacts to redistribute mechanical energy to prevent force transmission to the nucleus.