Fischer, A. A. M.; Kong, D.; Grimm, M. M.; Grether, J.; Groth, J.; Fliegauf, M.; Grimbacher, B.; Ye, H.; Weber, W.

Phase separation of biomolecules into condensates is a key mechanism in the spatiotemporal organization of biochemical processes in cells. However, the impact of the material properties of biomolecular condensates on important processes, such as the control of gene expression, remains largely elusive. Here, we systematically tune the material properties of optogenetically induced transcription factor condensates and probe their impact on the activation of target promoters. We demonstrate that rather liquid condensates correlate with increased gene expression levels, whereas a gradual transition to more stiff condensates converts otherwise activating transcription factors into dominant negative inhibitors. We demonstrate the general nature of these findings in mammalian cells and mice, as well as by using different synthetic and natural transcription factors. We observe these effects for both transgenic and cell-endogenous promoters. Our findings provide a novel materials-based layer in the control of gene expression, which opens novel opportunities in (opto-)genetic engineering and synthetic biology.