title: Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation.
abstract: The microbial world offers a rich source of bioactive compounds for those able to sift through it. Technologies capable of quantitatively detecting natural products while simultaneously identifying known compounds would expedite the search for new pharmaceutical leads. Prior efforts have targeted histone deacetylases in fungi to globally activate the production of new secondary metabolites, yet no study has directly assessed its effects with minimal bias at the metabolomic level. Using untargeted metabolomics, we monitored changes in >1000 small molecules secreted from the model fungus, Aspergillus nidulans, following genetic or chemical reductions in histone deacetylase activity (HDACi). Through quantitative, differential analyses, we found that nearly equal numbers of compounds were up- and down-regulated by >100 fold. We detected products from both known and unknown biosynthetic pathways and discovered that A. nidulans is capable of producing fellutamides, proteasome inhibitors whose expression was induced by ∼100 fold or greater upon HDACi. This work adds momentum to an "omics"-driven resurgence in natural products research, where direct detection replaces bioactivity as the primary screen for new pharmacophores.
authors: †Department of Chemistry, ‡Department of Molecular Biosciences, §Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60208, United States.|∥Department of Genetics, ⊥Department of Bacteriology, #Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706, United States.
authors: Jessica C
authors: JC
authors: Albright
authors: †Department of Chemistry, ‡Department of Molecular Biosciences, §Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60208, United States.|∥Department of Genetics, ⊥Department of Bacteriology, #Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706, United States.
authors: Matthew T
authors: MT
authors: Henke
authors: †Department of Chemistry, ‡Department of Molecular Biosciences, §Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60208, United States.|∥Department of Genetics, ⊥Department of Bacteriology, #Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706, United States.
authors: Alexandra A
authors: AA
authors: Soukup
authors: †Department of Chemistry, ‡Department of Molecular Biosciences, §Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60208, United States.|∥Department of Genetics, ⊥Department of Bacteriology, #Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706, United States.
authors: Ryan A
authors: RA
authors: McClure
authors: †Department of Chemistry, ‡Department of Molecular Biosciences, §Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60208, United States.|∥Department of Genetics, ⊥Department of Bacteriology, #Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706, United States.
authors: Regan J
authors: RJ
authors: Thomson
authors: †Department of Chemistry, ‡Department of Molecular Biosciences, §Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60208, United States.|∥Department of Genetics, ⊥Department of Bacteriology, #Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706, United States.
authors: Nancy P
authors: NP
authors: Keller
authors: †Department of Chemistry, ‡Department of Molecular Biosciences, §Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60208, United States.|∥Department of Genetics, ⊥Department of Bacteriology, #Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin 53706, United States.
authors: Neil L
authors: NL
authors: Kelleher
mesh_terms: D001233:Aspergillus nidulans / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D055666:Lipopeptides / Q000096:biosynthesis / Q000302:isolation & purification; D055442:Metabolome / Q000187:drug effects* / Q000235:genetics; D055432:Metabolomics; D005810:Multigene Family; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D056572:Histone Deacetylase Inhibitors; D055666:Lipopeptides; D034741:RNA, Small Interfering; C513652:fellutamide B; D006655:Histone Deacetylases