Mechano-osmotic signals control chromatin state and fate transitions in pluripotent stem cells [scMultiome]

Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although the signaling circuits and gene regulatory networks regulating pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological transitions and mechanical deformations that occur during state transitions remains a fundamental open question. Here, we discover that stem cell fate transitions are gated by two critical signals - nuclear envelope fluctuations and osmotic stress - that emanate from growth factor signaling-controlled changes in nuclear volume and nucleoplasm viscosity/density to subsequently trigger changes in nuclear architecture and transcription. We observe that fate transitions in the early human embryo and in an in vitro pluripotency exit model are guided by rapid changes in nuclear volume and nuclear envelope mechanics. These changes alter nuclear mechanosensitivity and trigger changes in nucleoplasmic viscosity and nuclear condensates that together prime chromatin for a cell fate transition. However, while this mechanical priming accelerates fate transitions, sustained biochemical signals are required for robust induction of differentiation. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signaling and chromatin state to control cell fate transition dynamics.