Mechano-Epigenetics: Decoding the Nuclear Response to Mechanical Cues

How do cells translate extracellular matrix (ECM) stiffness into stable gene expression programs? Combining hydrogel-based culturing, super-resolution microscopy and functional genomics, we investigated how mechanical cues remodel the Nuclear Lamina (NL) and 3D genome organisation. Our findings show that ECM stiffness profoundly alters NL composition, modulates long-range chromatin interactions and induces changes in chromatin motion. These structural shifts impact the expression of a defined set of genes characterised by apparent bivalent chromatin marks (H3K4me3 and H3K27me3). Our results indicate that these adaptive gene expression programs are governed by the Polycomb Repressive Complex 2 (PRC2). Furthermore, we have mapped the regulatory landscape of this response, defining specific enhancers that are directly modulated by mechanical stress. Notably, we identified a high enrichment of G-quadruplex (G4) DNA structures at these mechano-sensitive regulatory elements, positioning G4s as a potential apparatus for sensing nuclear mechanical signals and orchestrating the epigenetic landscape.