Mechanical signal-chromatin interactions: molecular networks from nuclear membrane force transmission to epigenetic regulation.

Cells transmit extracellular physical signals across the membrane into the nucleus through membrane mechanoreceptors (such as integrins, mechanically gated ion channels) and the cytoskeletal network. This process leads to redistribution of nuclear membrane tension and dynamic adjustment of chromatin conformation. This process is a core mechanism for cells to sense the microenvironment and regulate physiological activities. As a key hub for mechanotransduction, the linker of nucleoskeleton and cytoskeleton (LINC) complex cooperates with nuclear lamins through the interaction of SAD1/UNC84 domain containing protein (SUN)-Klarsicht, ANC-1 and Syne homology (KASH) domain proteins. Together, they establish a mechanical conduction pathway across the nuclear membrane, mediating the precise transmission of mechanical signals into the nucleus. This then regulates chromatin spatial arrangement and epigenetic modifications. This review systematically analyzes the transmembrane transduction mechanisms of mechanical stimuli (integrin-focal adhesion signaling axis, force-induced activation of Piezo/Transient Receptor Potential Vanilloid (TRPV) family channels, signal integration by primary cilia). It clarifies the rules for force transmission into the nucleus via the cytoskeleton-LINC complex. It reveals the regulatory effects of mechanical force on chromatin three-dimensional topological remodeling and epigenetic modifications. It focuses on organizing the molecular network of the "mechanical stimulus-structural remodeling-epigenetic regulation" cascade. This article aims to provide a theoretical framework for a deeper understanding of the role of mechanical-epigenetic coupling in tissue development and disease progression. It also offers a systematic reference for research in related fields.