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Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation
mBio, Volume: 12, Issue: 4
Swansea University Author: Claudio Greco
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The fungal kingdom has provided advances in our ability to identify biosynthetic gene clusters (BGCs) and to examine how gene composition of BGCs evolves across species and genera. However, little is known about the evolution of specific BGC regulators that mediate how BGCs produce secondary metabol...
American Society for Microbiology
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The fungal kingdom has provided advances in our ability to identify biosynthetic gene clusters (BGCs) and to examine how gene composition of BGCs evolves across species and genera. However, little is known about the evolution of specific BGC regulators that mediate how BGCs produce secondary metabolites (SMs). A bioinformatics search for conservation of the Aspergillus fumigatus xanthocillin BGC revealed an evolutionary trail of xan-like BGCs across Eurotiales species. Although the critical regulatory and enzymatic genes were conserved in Penicillium expansum, overexpression (OE) of the conserved xan BGC transcription factor (TF) gene, PexanC, failed to activate the putative xan BGC transcription or xanthocillin production in P. expansum, in contrast to the role of AfXanC in A. fumigatus. Surprisingly, OE::PexanC was instead found to promote citrinin synthesis in P. expansum via trans induction of the cit pathway-specific TF, ctnA, as determined by cit BGC expression and chemical profiling of ctnA deletion and OE::PexanC single and double mutants. OE::AfxanC results in significant increases of xan gene expression and metabolite synthesis in A. fumigatus but had no effect on either xanthocillin or citrinin production in P. expansum. Bioinformatics and promoter mutation analysis led to the identification of an AfXanC binding site, 5′-AGTCAGCA-3′, in promoter regions of the A. fumigatus xan BGC genes. This motif was not in the ctnA promoter, suggesting a different binding site of PeXanC. A compilation of a bioinformatics examination of XanC orthologs and the presence/absence of the 5′-AGTCAGCA-3′ binding motif in xan BGCs in multiple Aspergillus and Penicillium spp. supports an evolutionary divergence of XanC regulatory targets that we speculate reflects an exaptation event in the Eurotiales.
cross talk, regulatory mechanism, transcription factor, citrinin, xanthocillin, Aspergillus, Penicillium, evolutionary biology, fungi, secondary metabolism, transcription factors
Faculty of Science and Engineering
This project was supported in part by National Institutes of Health grant 2R01GM112739-05A1 to N.P.K., by the China Scholarship Council (CSC) (W.W.), and by postdoctoral fellowship award 2019-67012-29662 to M.D. from the U.S. Department of Agriculture National Institute of Food and Agriculture (USDA NIFA).