Decreasing Lamin A Triggers Cell Fate Transitions through Heterochromatin-Nuclear Periphery Detethering

The interplay between nuclear architecture and extracellular matrix stiffness orchestrates cell fate decisions, yet the molecular mechanisms remain poorly defined. Here, we investigate the role of Lamin A (<i>LMNA</i>), a nuclear structural protein whose expression correlates with tissue stiffness, in regulating cellular differentiation and fate decision. Using myoblasts and fibroblasts as models, it was observed that cells with low <i>LMNA</i> expression showed that higher cell deformation elevated expression of neurological genes and exhibited potential for differentiation into a neural-like fate. CUT&Tag sequencing of <i>LMNA</i>-knockdown cells revealed a reduction in the size of Lamin B1-associated domains, with enhanced Lamin B1 binding at muscle-related genes (<i>Myf5</i> and <i>Myf6</i>) and diminished binding at the neural gene <i>Nes</i>, suggesting that changes in gene expression are associated with alterations in chromatin structure. Further analysis identified the dissolution of H3K9me2/3-labeled heterochromatin regions and their redistribution in the nucleoplasm following <i>LMNA</i> inhibition. Soft substrates (0.2 kPa) amplify the neural differentiation capacity in <i>LMNA</i>-knockout cells. Additionally, retinoic acid was shown to enhance the expression of neurologically related genes by suppressing <i>LMNA</i> expression. These findings reveal a novel substrate stiffness-induced mechanism by which Lamin A regulates cell fate transitions and provide a new approach for neural cell generation.