An LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

ABSTRACT Biosynthesis of many ecologically important secondary metabolites (SMs) in filamentous fungi is controlled by several global transcriptional regulators, like the chromatin modifier LaeA, and tied to both development and vegetative growth. In Aspergillus molds, asexual development is regulat...

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Autores principales:	Abigail L. Lind, Fang Yun Lim, Alexandra A. Soukup, Nancy P. Keller, Antonis Rokas
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	biosynthetic gene cluster conidia hyphal growth hypoxia mycelial growth specialized metabolism Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c3becbac9eef416aa30704f486e1ae60
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spelling	oai:doaj.org-article:c3becbac9eef416aa30704f486e1ae602021-11-15T15:22:14ZAn LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>10.1128/mSphere.00050-182379-5042https://doaj.org/article/c3becbac9eef416aa30704f486e1ae602018-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00050-18https://doaj.org/toc/2379-5042ABSTRACT Biosynthesis of many ecologically important secondary metabolites (SMs) in filamentous fungi is controlled by several global transcriptional regulators, like the chromatin modifier LaeA, and tied to both development and vegetative growth. In Aspergillus molds, asexual development is regulated by the BrlA > AbaA > WetA transcriptional cascade. To elucidate BrlA pathway involvement in SM regulation, we examined the transcriptional and metabolic profiles of ΔbrlA, ΔabaA, and ΔwetA mutant and wild-type strains of the human pathogen Aspergillus fumigatus. We find that BrlA, in addition to regulating production of developmental SMs, regulates vegetative SMs and the SrbA-regulated hypoxia stress response in a concordant fashion to LaeA. We further show that the transcriptional and metabolic equivalence of the ΔbrlA and ΔlaeA mutations is mediated by an LaeA requirement preventing heterochromatic marks in the brlA promoter. These results provide a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen. IMPORTANCE Filamentous fungi produce a spectacular variety of small molecules, commonly known as secondary or specialized metabolites (SMs), which are critical to their ecologies and lifestyles (e.g., penicillin, cyclosporine, and aflatoxin). Elucidation of the regulatory network that governs SM production is a major question of both fundamental and applied research relevance. To shed light on the relationship between regulation of development and regulation of secondary metabolism in filamentous fungi, we performed global transcriptomic and metabolomic analyses on mutant and wild-type strains of the human pathogen Aspergillus fumigatus under conditions previously shown to induce the production of both vegetative growth-specific and asexual development-specific SMs. We find that the gene brlA, previously known as a master regulator of asexual development, is also a master regulator of secondary metabolism and other cellular processes. We further show that brlA regulation of SM is mediated by laeA, one of the master regulators of SM, providing a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen.Abigail L. LindFang Yun LimAlexandra A. SoukupNancy P. KellerAntonis RokasAmerican Society for Microbiologyarticlebiosynthetic gene clusterconidiahyphal growthhypoxiamycelial growthspecialized metabolismMicrobiologyQR1-502ENmSphere, Vol 3, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	biosynthetic gene cluster conidia hyphal growth hypoxia mycelial growth specialized metabolism Microbiology QR1-502
spellingShingle	biosynthetic gene cluster conidia hyphal growth hypoxia mycelial growth specialized metabolism Microbiology QR1-502 Abigail L. Lind Fang Yun Lim Alexandra A. Soukup Nancy P. Keller Antonis Rokas An LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
description	ABSTRACT Biosynthesis of many ecologically important secondary metabolites (SMs) in filamentous fungi is controlled by several global transcriptional regulators, like the chromatin modifier LaeA, and tied to both development and vegetative growth. In Aspergillus molds, asexual development is regulated by the BrlA > AbaA > WetA transcriptional cascade. To elucidate BrlA pathway involvement in SM regulation, we examined the transcriptional and metabolic profiles of ΔbrlA, ΔabaA, and ΔwetA mutant and wild-type strains of the human pathogen Aspergillus fumigatus. We find that BrlA, in addition to regulating production of developmental SMs, regulates vegetative SMs and the SrbA-regulated hypoxia stress response in a concordant fashion to LaeA. We further show that the transcriptional and metabolic equivalence of the ΔbrlA and ΔlaeA mutations is mediated by an LaeA requirement preventing heterochromatic marks in the brlA promoter. These results provide a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen. IMPORTANCE Filamentous fungi produce a spectacular variety of small molecules, commonly known as secondary or specialized metabolites (SMs), which are critical to their ecologies and lifestyles (e.g., penicillin, cyclosporine, and aflatoxin). Elucidation of the regulatory network that governs SM production is a major question of both fundamental and applied research relevance. To shed light on the relationship between regulation of development and regulation of secondary metabolism in filamentous fungi, we performed global transcriptomic and metabolomic analyses on mutant and wild-type strains of the human pathogen Aspergillus fumigatus under conditions previously shown to induce the production of both vegetative growth-specific and asexual development-specific SMs. We find that the gene brlA, previously known as a master regulator of asexual development, is also a master regulator of secondary metabolism and other cellular processes. We further show that brlA regulation of SM is mediated by laeA, one of the master regulators of SM, providing a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen.
format	article
author	Abigail L. Lind Fang Yun Lim Alexandra A. Soukup Nancy P. Keller Antonis Rokas
author_facet	Abigail L. Lind Fang Yun Lim Alexandra A. Soukup Nancy P. Keller Antonis Rokas
author_sort	Abigail L. Lind
title	An LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_short	An LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full	An LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_fullStr	An LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full_unstemmed	An LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_sort	laea- and brla-dependent cellular network governs tissue-specific secondary metabolism in the human pathogen <named-content content-type="genus-species">aspergillus fumigatus</named-content>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/c3becbac9eef416aa30704f486e1ae60
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An LaeA- and BrlA-Dependent Cellular Network Governs Tissue-Specific Secondary Metabolism in the Human Pathogen <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

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