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

Wang, Wenjie; Drott, Milton; Greco, Claudio; Luciano-Rosario, Dianiris; Wang, Pinmei; Keller, Nancy P.

doi:10.1128/mbio.01399-21

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

Wenjie Wang, Milton Drott

, Claudio Greco

, Dianiris Luciano-Rosario, Pinmei Wang, Nancy P. Keller

mBio, Volume: 12, Issue: 4

Swansea University Author: Claudio Greco

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DOI (Published version): 10.1128/mbio.01399-21

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 metabol...

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Published in:	mBio
ISSN:	2150-7511
Published:	American Society for Microbiology 2021
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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.</abstract><type>Journal Article</type><journal>mBio</journal><volume>12</volume><journalNumber>4</journalNumber><paginationStart/><paginationEnd/><publisher>American Society for Microbiology</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2150-7511</issnElectronic><keywords>cross talk, regulatory mechanism, transcription factor, citrinin, xanthocillin, Aspergillus, Penicillium, evolutionary biology, fungi, secondary metabolism, transcription factors</keywords><publishedDay>31</publishedDay><publishedMonth>8</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-08-31</publishedDate><doi>10.1128/mbio.01399-21</doi><url/><notes/><college>COLLEGE NANME</college><department>Biosciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>SBI</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>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).</funders><projectreference/><lastEdited>2022-10-20T13:39:36.6715708</lastEdited><Created>2022-10-10T17:23:29.9767305</Created><path><level id="1">Faculty of Science and Engineering</level><level id="2">School of Biosciences, Geography and Physics - Biosciences</level></path><authors><author><firstname>Wenjie</firstname><surname>Wang</surname><order>1</order></author><author><firstname>Milton</firstname><surname>Drott</surname><orcid>0000-0001-9715-2200</orcid><order>2</order></author><author><firstname>Claudio</firstname><surname>Greco</surname><orcid>0000-0003-3067-0999</orcid><order>3</order></author><author><firstname>Dianiris</firstname><surname>Luciano-Rosario</surname><order>4</order></author><author><firstname>Pinmei</firstname><surname>Wang</surname><order>5</order></author><author><firstname>Nancy P.</firstname><surname>Keller</surname><orcid>0000-0002-4386-9473</orcid><order>6</order></author></authors><documents><document><filename>61514__25524__20e76a31f0f6487d9b9ecbe24cf6d245.pdf</filename><originalFilename>61514_VoR.pdf</originalFilename><uploaded>2022-10-20T13:38:32.4710323</uploaded><type>Output</type><contentLength>4059766</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2021 Wang et al. 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spelling	2022-10-20T13:39:36.6715708 v2 61514 2022-10-10 Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation cacac6459bd7cf4a241f63661006036f 0000-0003-3067-0999 Claudio Greco Claudio Greco true false 2022-10-10 SBI 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. Journal Article mBio 12 4 American Society for Microbiology 2150-7511 cross talk, regulatory mechanism, transcription factor, citrinin, xanthocillin, Aspergillus, Penicillium, evolutionary biology, fungi, secondary metabolism, transcription factors 31 8 2021 2021-08-31 10.1128/mbio.01399-21 COLLEGE NANME Biosciences COLLEGE CODE SBI Swansea University 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). 2022-10-20T13:39:36.6715708 2022-10-10T17:23:29.9767305 Faculty of Science and Engineering School of Biosciences, Geography and Physics - Biosciences Wenjie Wang 1 Milton Drott 0000-0001-9715-2200 2 Claudio Greco 0000-0003-3067-0999 3 Dianiris Luciano-Rosario 4 Pinmei Wang 5 Nancy P. Keller 0000-0002-4386-9473 6 61514__25524__20e76a31f0f6487d9b9ecbe24cf6d245.pdf 61514_VoR.pdf 2022-10-20T13:38:32.4710323 Output 4059766 application/pdf Version of Record true © 2021 Wang et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution 4.0 International license true eng https://creativecommons.org/licenses/by/4.0/
title	Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation
spellingShingle	Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation Claudio Greco
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
author_id_str_mv	cacac6459bd7cf4a241f63661006036f
author_id_fullname_str_mv	cacac6459bd7cf4a241f63661006036f_***_Claudio Greco
author	Claudio Greco
author2	Wenjie Wang Milton Drott Claudio Greco Dianiris Luciano-Rosario Pinmei Wang Nancy P. Keller
format	Journal article
container_title	mBio
container_volume	12
container_issue	4
publishDate	2021
institution	Swansea University
issn	2150-7511
doi_str_mv	10.1128/mbio.01399-21
publisher	American Society for Microbiology
college_str	Faculty of Science and Engineering
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hierarchy_top_title	Faculty of Science and Engineering
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department_str	School of Biosciences, Geography and Physics - Biosciences{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Biosciences, Geography and Physics - Biosciences
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description	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.
published_date	2021-08-31T04:20:23Z
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score	11.013686

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

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