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Identification and Mechanism of Action of the Global Secondary Metabolism Regulator SaraC in Stereum hirsutum

Summary

This research discovered a protein called SaraC that can activate silent genes in fungi to produce new natural compounds. By manipulating DNA methylation, SaraC acts as a master switch to turn on multiple metabolic pathways that are normally inactive. This discovery has important implications for drug discovery and biotechnology. Impacts on everyday life: • Could lead to discovery of new medicines from fungi • Provides new tools for producing valuable natural compounds • Advances understanding of how genes are regulated • May enable more efficient production of beneficial fungal products • Could help develop improved methods for controlling fungal metabolism

Background

DNA methylation is an important factor in regulating gene expression. The researchers found a hypothetical bifunctional transcription regulator/O6Meguanine-DNA methyltransferase (named SaraC) in Stereum hirsutum FP-91666 that is widely present in both bacteria and fungi. While its function in bacteria is mainly for DNA repair, its role in fungi was previously unknown.

Objective

The study aimed to confirm SaraC’s function in DNA binding and demethylation, and investigate its role as a global regulator of secondary metabolism in fungi through overexpression experiments and analysis of genome-wide effects on methylation, transcription, and metabolite production.

Results

The results confirmed that SaraC has DNA binding and demethylation functions. Overall methylation levels were significantly downregulated in the transformants, while various genes related to secondary metabolism were upregulated. Metabolomic analyses showed the SaraC overexpression transformant SA6 produced more hybrid polyketides, including 2 novel compounds that were isolated and identified. The findings demonstrated that SaraC can effectively stimulate expression of secondary metabolism-related genes.

Conclusion

The study identified SaraC as a global secondary metabolism regulator in fungi that can activate silent gene clusters through DNA demethylation. This represents a powerful new tool for discovering novel metabolites, as SaraC is conserved across fungal species. The findings expand understanding of SaraC-like proteins beyond their known DNA repair functions to include regulation of secondary metabolism.
  • Published in:Microbiology Spectrum,
  • Study Type:Laboratory Research,
  • Source: 10.1128/spectrum.02624-22
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