Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation

ABSTRACT 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 secondar...

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Autores principales:	Wenjie Wang, Milton Drott, Claudio Greco, Dianiris Luciano-Rosario, Pinmei Wang, Nancy P. Keller
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	cross talk regulatory mechanism transcription factor citrinin xanthocillin Aspergillus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c4ffbd3f49af4055be62c1d1b63b9aec
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spelling	oai:doaj.org-article:c4ffbd3f49af4055be62c1d1b63b9aec2021-11-10T18:37:51ZTranscription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation10.1128/mBio.01399-212150-7511https://doaj.org/article/c4ffbd3f49af4055be62c1d1b63b9aec2021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01399-21https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE Fungal secondary metabolites (SMs) are an important source of pharmaceuticals on one hand and toxins on the other. Efforts to identify the biosynthetic gene clusters (BGCs) that synthesize SMs have yielded significant insights into how variation in the genes that compose BGCs may impact subsequent metabolite production within and between species. However, the role of regulatory genes in BGC activation is less well understood. Our finding that the bZIP transcription factor XanC, located in the xanthocillin BGC of both Aspergillus fumigatus and Penicillium expansum, has functionally diverged to regulate different BGCs in these two species emphasizes that the diversification of BGC regulatory elements may sometimes occur through exaptation, which is the co-option of a gene that evolved for one function to a novel function. Furthermore, this work suggests that the loss/gain of transcription factor binding site targets may be an important mediator in the evolution of secondary-metabolism regulatory elements.Wenjie WangMilton DrottClaudio GrecoDianiris Luciano-RosarioPinmei WangNancy P. KellerAmerican Society for Microbiologyarticlecross talkregulatory mechanismtranscription factorcitrininxanthocillinAspergillusMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cross talk regulatory mechanism transcription factor citrinin xanthocillin Aspergillus Microbiology QR1-502
spellingShingle	cross talk regulatory mechanism transcription factor citrinin xanthocillin Aspergillus Microbiology QR1-502 Wenjie Wang Milton Drott Claudio Greco Dianiris Luciano-Rosario Pinmei Wang Nancy P. Keller Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation
description	ABSTRACT 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. IMPORTANCE Fungal secondary metabolites (SMs) are an important source of pharmaceuticals on one hand and toxins on the other. Efforts to identify the biosynthetic gene clusters (BGCs) that synthesize SMs have yielded significant insights into how variation in the genes that compose BGCs may impact subsequent metabolite production within and between species. However, the role of regulatory genes in BGC activation is less well understood. Our finding that the bZIP transcription factor XanC, located in the xanthocillin BGC of both Aspergillus fumigatus and Penicillium expansum, has functionally diverged to regulate different BGCs in these two species emphasizes that the diversification of BGC regulatory elements may sometimes occur through exaptation, which is the co-option of a gene that evolved for one function to a novel function. Furthermore, this work suggests that the loss/gain of transcription factor binding site targets may be an important mediator in the evolution of secondary-metabolism regulatory elements.
format	article
author	Wenjie Wang Milton Drott Claudio Greco Dianiris Luciano-Rosario Pinmei Wang Nancy P. Keller
author_facet	Wenjie Wang Milton Drott Claudio Greco Dianiris Luciano-Rosario Pinmei Wang Nancy P. Keller
author_sort	Wenjie Wang
title	Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation
title_short	Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation
title_full	Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation
title_fullStr	Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation
title_full_unstemmed	Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation
title_sort	transcription factor repurposing offers insights into evolution of biosynthetic gene cluster regulation
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/c4ffbd3f49af4055be62c1d1b63b9aec
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Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation

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