title: Discovery of McrA, a master regulator of Aspergillus secondary metabolism.
abstract: Fungal secondary metabolites (SMs) are extremely important in medicine and agriculture, but regulation of their biosynthesis is incompletely understood. We have developed a genetic screen in Aspergillus nidulans for negative regulators of fungal SM gene clusters and we have used this screen to isolate mutations that upregulate transcription of the non-ribosomal peptide synthetase gene required for nidulanin A biosynthesis. Several of these mutations are allelic and we have identified the mutant gene by genome sequencing. The gene, which we designate mcrA, is conserved but uncharacterized, and it encodes a putative transcription factor. Metabolite profiles of mcrA deletant, mcrA overexpressing, and parental strains reveal that mcrA regulates at least ten SM gene clusters. Deletion of mcrA stimulates SM production even in strains carrying a deletion of the SM regulator laeA, and deletion of mcrA homologs in Aspergillus terreus and Penicillum canescens alters the secondary metabolite profile of these organisms. Deleting mcrA in a genetic dereplication strain has allowed us to discover two novel compounds as well as an antibiotic not known to be produced by A. nidulans. Deletion of mcrA upregulates transcription of hundreds of genes including many that are involved in secondary metabolism, while downregulating a smaller number of genes.
authors: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, Kansas, 66045, USA.
authors: C Elizabeth
authors: CE
authors: Oakley
authors: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, Kansas, 66045, USA.
authors: Manmeet
authors: M
authors: Ahuja
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California, 90089, USA.
authors: Wei-Wen
authors: WW
authors: Sun
authors: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, Kansas, 66045, USA.
authors: Ruth
authors: R
authors: Entwistle
authors: Division of OMICS analysis, Nagoya University Graduate School of Medicine, 65 Tsurumai, Nagoya, Aichi, 466-8550, Japan.
authors: Tomohiro
authors: T
authors: Akashi
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California, 90089, USA.
authors: Junko
authors: J
authors: Yaegashi
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California, 90089, USA.
authors: Chun-Jun
authors: CJ
authors: Guo
authors: Genome Sequencing and Analysis Program, Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA.
authors: Gustavo C
authors: GC
authors: Cerqueira
authors: Genome Sequencing and Analysis Program, Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA.
authors: Jennifer
authors: J
authors: Russo Wortman
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California, 90089, USA.|Department of Chemistry, Dornsife Colleges of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California, 90089, USA.
authors: Clay C C
authors: CC
authors: Wang
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California, 90089, USA.|Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City, Taiwan, 71710, Republic of China.
authors: Yi-Ming
authors: YM
authors: Chiang
authors: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, Kansas, 66045, USA.
authors: Berl R
authors: BR
authors: Oakley
mesh_terms: D001233:Aspergillus nidulans / Q000235:genetics* / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D005810:Multigene Family; D009154:Mutation; D010453:Peptide Synthases / Q000235:genetics* / Q000378:metabolism*; D064210:Secondary Metabolism; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D005656:Fungal Proteins; D014157:Transcription Factors; D010453:Peptide Synthases