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Quantitative Characterization of Gene Regulatory Circuits Associated With Fungal Secondary Metabolism to Discover Novel Natural Products

Summary

Scientists developed a special technology using tiny channels and fluorescent markers to understand how fungi control their genes that produce valuable compounds. By precisely measuring how different genes turn on and off in individual fungal cells, they can now predict and control when and how much of useful medicines and other bioactive molecules are made. They successfully used this knowledge to create new pathways that produce novel compounds, including new types of dendrobine molecules never seen before.

Background

Filamentous fungi are valuable cell factories for producing secondary metabolites and bioactive compounds, but controlling their gene expression and biosynthetic pathways remains challenging. Microbial gene regulatory circuits (GRCs) are vital for regulating gene expression and synthesizing bioactive compounds, yet precise quantification at the single-cell level in multicellular organisms is difficult.

Objective

To develop an advanced microfluidic platform combined with mathematical modeling to precisely characterize fungal gene regulatory circuits at the single-cell level and enable control of secondary metabolite production and discovery of novel natural products.

Results

Quantitative characterization revealed distinct expression patterns and timing for 30 regulatory combinations. Using optimized GRC elements, researchers successfully controlled beauvericin and mycophenolic acid production, activated silent biosynthetic gene clusters, and discovered novel dendrobine compounds from an engineered Epicoccum dendrobii pathway.

Conclusion

The microfluidic platform enables precise quantification of fungal gene regulatory circuits and supports rational design of synthetic biology systems. Quantified GRCs can effectively control secondary metabolite production timing and intensity, and facilitate activation of silent gene clusters for discovery of novel natural products.
  • Published in:Advanced Science,
  • Study Type:Experimental Research,
  • Source: PMID: 39467708, DOI: 10.1002/advs.202407195
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