Multiplexed live imaging deciphers nuclear force-driven chromatin dynamics and embryo development

Mechanical forces transmitted to the nucleus regulate chromatin organization and gene expression to guide cell fate transitions. However, how the forces dynamically reshape the genome in living systems remains unclear. Here, inspired by the visualization of perinuclear chromatin detachment under low tension, we develop a genetically encoded fluorescence resonance energy transfer (FRET)-based nuclear tension sensor (NuTS) that directly quantifies forces transmitted into the nucleus through LINC complex proteins SUN1/2 and their effect on chromatin reorganization. NuTS enables high spatiotemporal mapping of forces across the nuclear envelope. Combined imaging of NuTS and lamina-associated domains (LADs) reveals that force fluctuations are coupled to LADs repositioning, and that a force of approximately 6 pN on SUN2 is required to maintain perinuclear chromatin anchoring. A drop below this threshold triggers lamin A phosphorylation at Ser22, which precedes and drives perinuclear chromatin dissociation and LAD reorganization by about 10 min. LINC-complex force transmission critically regulates cell migration and is essential for embryonic notochord development in vitro and in vivo. Our study establishes a mechanochemical framework linking nuclear forces to chromatin organization and function. Here, they develop a nuclear tension sensor (NuTS) to quantify SUN2 force for perinuclear chromatin anchoring at ~6 pN. They further demonstrate that LINC-complex force transmission is critical for cell migration and zebrafish notochord development.