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 (LMNA), 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 LMNA 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 LMNA-knockdown cells revealed a reduction in the size of Lamin B1-associated domains, with enhanced Lamin B1 binding at muscle-related genes (Myf5 and Myf6) and diminished binding at the neural gene Nes, 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 LMNA inhibition. Soft substrates (0.2 kPa) amplify the neural differentiation capacity in LMNA-knockout cells. Additionally, retinoic acid was shown to enhance the expression of neurologically related genes by suppressing LMNA 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.