Engineering Material Properties of Transcription Factor Condensates to Control Gene Expression in Mammalian Cells and Mice

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 transcription factors in rather liquid condensates correlate with increased gene expression levels, whereas stiffer transcription factor condensates correlate with the opposite effect, a reduced activation of gene expression. We demonstrate the broad 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 optogenetic engineering and synthetic biology.