Chromatin condensates tune nuclear mechanosensing and preserve nuclear integrity to prevent cGAS activation.

Cells and tissue integrity are constantly challenged by the necessity to adapt and respond to mechanical loads. Among cellular components, the nucleus possesses mechano-sensing and mechanotransduction capabilities, yet the molecular mechanisms involved remain poorly defined. Here we investigate whether the mechanical properties of chromatin and its organization into condensates contribute to nuclear adaptation to external forces, while preserving its integrity. By interrogating the effects of MLL4 loss-of-function in Kabuki Syndrome, we find that the balancing of transcriptional and Polycomb condensates tunes nuclear responsiveness to external mechanical forces. MLL4 assembles into mechanosensitive condensates through its prion-like domain, and this response is regulated by the chromatin context. Furthermore, the mechano-sensing activity of MLL4 condensates is instrumental to withstand the physical challenges nuclei experience during cell confinement and migration by preserving their integrity. In Kabuki Syndrome, persistent nuclear envelope rupture triggers cGAS-STING activation, leading to programmed cell death. Together, these findings identify chromatin condensates as active regulators of nuclear mechanosensing and establish a mechanistic link between defective chromatin organization and cGAS-STING activation in Kabuki syndrome.