Temporal Stretch‐Induced Nuclear Mechanosensing Coordinates Early Chromatin Accessibility and Genome Protection

Abstract Cells respond to mechanical stimuli by transmitting forces to the nucleus, activating mechanosensitive molecules that alter chromatin organization and gene expression. While force‐induced changes in cell fate are recognized, the spatiotemporal dynamics of nuclear mechanosensing remain unclear. Here, nuclear responses are investigated to temporal cyclic stretching in human dermal fibroblasts, uncovering a cascade of mechanosensitive events linking cytoskeletal remodeling, chromatin accessibility, and gene expression. Brief cyclic stretch induces rapid chromatin decondensation and nuclear softening, marked by reduced H3K9me3 levels. The stretch reinforces perinuclear actin assembly from globular actins, activated by Ca ²⁺ release from the nucleus/endoplasmic reticulum. Notably, perinuclear actin remodeling correlated with decreased H3K9me3 coordinates through emerin translocation at the nuclear envelope. Genome‐wide profiling reveals increased accessibility of loci associated with mechanotransduction and DNA damage repair. Failure to coordinate these events results in DNA damage due to impaired chromatin decondensation, demonstrating a biophysical mechanism protecting genomic integrity. These nuclear events are further evidenced in vivo using a skin tissue model, where spatial transcriptomics confirm mechanosensitive chromatin reorganization through actin‐dependent pathways in dermal fibroblasts. This study illuminates mechanisms by which temporally regulated mechanical forces elicit nuclear mechanosensing responses, linking perinuclear mechanosensitive molecules to epigenetic remodeling and downstream regulation of cell fate.