Dynamic regulation of metabolic pathways is widely regarded as an effective strategy for improving microbial cell factory performance. In recent years, optogenetics has emerged as an attractive approach in synthetic biology and metabolic engineering because of its high spatiotemporal precision, reversibility, and elimination of costly chemical inducers. However, under industrial high-cell-density fermentation conditions, light penetration becomes severely limited, preventing a large fraction of cells from receiving sufficient illumination. This “light-shading effect” has become a major bottleneck restricting the industrial implementation of optogenetic technologies.
Recently, the research team led by Professor Jifeng Yuan at Xiamen University published a research article entitled “Engineered optogenetic circuits in yeast with self-sustained outputs” in Advanced Science. The team developed a novel optogenetic quorum-sensing system in yeast capable of “recording” transient light stimulation, thereby enabling dynamic regulation from short-term light exposure to long-lasting population-level gene expression.
Based on the team’s previous work on rewiring the yeast galactose regulon with distinct expression profiles through GPCR(G-protein coupled receptor) signaling cascades in Saccharomyces cerevisiae (Cell Reports Methods, 2023, 3, 100647), the researchers proposed an integrated “optogenetics and quorum sensing” design strategy and developed an optogenetic quorum-sensing system (OptoQS) based on the yeast GPCR signaling pathway. In this study, To validate the performance of OptoQS, the research team engineered the yeast GPCR signaling pathway and optimized α-factor copy number together with GPA1 expression, achieving a gene expression dynamic range of up to approximately 73-fold. Furthermore, the introduction of a feedforward autoinduction loop substantially enhanced population-level signal propagation and enabled sustained pathway activation after light removal. Flow cytometry and mathematical modeling further demonstrated that the engineered circuit could maintain stable activation states and continuously accumulate α-factor following transient light stimulation, highlighting its capability to “record” physical stimuli. To demonstrate practical applicability, the researchers applied OptoQS to the biosynthesis of 3-hydroxypropionate (3HP) in yeast. After only short-term blue-light exposure, the engineered strains maintained long-term metabolic activation and achieved 0.76 g/L 3HP in shake-tube cultures and 4.97 g/L in fed-batch bioreactor fermentation, demonstrating the robustness and scalability of the system under industrially relevant conditions.
The research team believes that this study establishes a new framework for optogenetic engineering by integrating quorum-sensing-mediated signal propagation with light-controlled gene regulation. Compared with conventional optogenetic strategies that rely on continuous illumination, OptoQS significantly reduces light input requirements and potential phototoxicity while improving population-level expression consistency. The design principles demonstrated in this work may be further extended to high-density industrial fermentation, solid-state fermentation, advanced synthetic gene circuits, and even mammalian cell engineering, providing a promising route toward next-generation low-energy and intelligent biomanufacturing systems.
Professor Jifeng Yuan of Xiamen University is the corresponding author of the study. The study's co-first authors are Cong Fan (postdoctoral researcher) and Haofeng Chen (PhD student) from Xiamen University. This research was supported by the National Key Research and Development Program (2024YFC3407000), the National Natural Science Foundation of China (32270087), and the Basic Research Operating Funds for Central Universities (20720240120).
Link to the thesis: https://doi.org/10.1002/advs.75865
