Dynamic Mechanotransductive Self-Reinforcement of Transcription Factors Induces Memory of Gene Expression

Cells adjust to their environment through mechanotransduction, which describes changes in chemical pathways and cell structure to mechanical cues. Recent experiments have shown that transcription factors which regulate gene expression, such as YAP, RUNX2, and miR-21, can exhibit memory of the cell’s environment over time scales of days to weeks. If cultured on an initially stiff (soft) substrate for enough time (priming phase), the cell maintains altered transcriptional activity after the substrate is switched (cooling phase) to soft (stiff) compared to controls. We develop a dynamic self-reinforcement model, posed as a series of Waddington landscapes, to explain mechanical memory during cooling which depends on the priming time and the priming stiffness. Memory naturally emerges beyond the threshold of a critical priming stiffness and a critical level of self-reinforcement. This matches experimental data for osteogenic transcription factors, and we identify biological positive feedback relationships which correlate with the model. The model only assumes mechanosensitive gene expression and both slow and fast dynamics in the cell. Predicting non-linear, hysteretic cell dynamics can be used advantageously to design drug programs which maximize the effect-to-dose ratio.