Epigenetic Remodeling Stores Mechanical Memory and Stabilizes Gene Regulation

Cells are constantly exposed to physical forces during development, regeneration, and disease, yet how they retain a memory of past mechanical experiences and translate transient inputs into lasting molecular and phenotypic states remains unclear. Here we show that mechanical priming imprints persistent epigenetic and gene-regulatory programs in human mesenchymal stem cells. Cells cultured on physiologically soft or stiff substrates for defined durations retained substrate-dependent morphology and cytoskeletal organization even after removal from the priming environment, establishing a phenotypic signature of mechanical memory. This persistence was accompanied by progressive changes in histone modifications: active marks captured through global acetylation and H3k27ac, while the repressive mark H3K9me3 evolved from transient shifts after short priming to semi-stable patterns with prolonged priming. Super-resolution imaging revealed correlated remodeling of nanoscale chromatin domains and lamina-associated regions, indicating that nuclear architecture encodes the duration of mechanical exposure. Perturbation experiments showed that mechanotransduction pathways are required for memory formation, whereas epigenetic inhibition erases established memory, underscoring complementary roles for cytoskeletal force transmission and chromatin regulation. Transcriptomic profiling further demonstrated reinforcement of gene regulatory networks, with cell–matrix signaling and epigenetic read/write programs becoming progressively stabilized under longer priming. To unify these findings, we developed a mesoscale mechanotransduction–chromatin model that describes a self-reinforcing axis linking mechanical inputs to chromatin remodeling and transcriptional stability. Together, these results establish the epigenome and chromatin architecture as central repositories of mechanical memory and reveal a general principle by which cells record their mechanical history, with broad implications for development, diseases such as cancer and fibrosis, and regenerative medicine.