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Awakening of Fungal Secondary Metabolite Gene Clusters

  • Juliane Fischer
  • Volker Schroeckh
  • Axel A. BrakhageEmail author
Part of the Fungal Biology book series (FUNGBIO)

Abstract

Sequencing of fungal genomes and systematic genome mining concerning so far undiscovered secondary metabolite (SM) gene clusters have uncovered the great potential of fungal species for SM biosynthesis. Until now, only for relatively few clusters the corresponding metabolites are known. Even less is known about the regulation of their production. However, the latter is crucial to explore the full biosynthesis potential of fungal strains. It can be expected that this knowledge will lead to the discovery of novel drugs. Here, we discuss some of the strategies allowing for the activation of unknown silent SM gene clusters. For example, the application of cultivation conditions simulating the natural environment of fungi led to the discovery of new natural products. Especially co-cultivation of distinct bacterial and fungal partners often caused the modulation of gene expression and the formation of novel molecules. Interestingly, even the addition of bacterial molecules such as lipopolysaccharide was apparently sufficient to trigger a response of the fungal partner. Another successful approach is to delete, overexpress or inhibit histone-modifying enzymes/genes. In line, approaches targeting histone acetyltransferases led to some new and interesting products. Although these methods allow for activation of silent gene clusters without rationale prediction, they will not help to systematically activate distinct SM clusters in fungal genomes. This problem can be overcome by novel technologies of synthetic biology. One example is the expression of fungal SM gene clusters as polycistronic mRNA that encodes all required pathway-specific genes separated by 2A peptide sequences.

Keywords

Secondary metabolite gene cluster Synthetic microbiology Natural products Aspergillus nidulans Microbial communication Co-cultivation Histone modifications Chromatin Acetyltransferases Genetic engineering 

References

  1. Albright JC, Henke MT, Soukup AA, McClure RA, Thomson RJ, Keller NP, Kelleher NL. Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation. ACS Chem Biol. 2015;10(6):1535–41.CrossRefGoogle Scholar
  2. Amaike S, Keller NP. Distinct roles for VeA and LaeA in development and pathogenesis of Aspergillus flavus. Eukaryot Cell. 2009;8:1051–60.CrossRefGoogle Scholar
  3. Andersen MR, Nielsen JB, Klitgaard A, Petersen LM, Zachariasen M, Hansen TJ, Blicher LH, Gotfredsen CH, Larsen TO, Nielsen KF, Mortensen UH. Accurate prediction of secondary metabolite gene clusters in filamentous fungi. Proc Natl Acad Sci U S A. 2013;110:E99–107.CrossRefGoogle Scholar
  4. Bajaj I, Veiga T, van Dissel D, Pronk J, Daran J-M. Functional characterization of a Penicillium chrysogenum mutanase gene induced upon co-cultivation with Bacillus subtilis. BMC Microbiol. 2014;14:114.CrossRefGoogle Scholar
  5. Baker SP, Grant PA. The SAGA continues: expanding the cellular role of a transcriptional co-activator complex. Oncogene. 2007;26:5329–40.CrossRefGoogle Scholar
  6. Bayram O, Krappmann S, Ni M, Bok JW, Helmstaedt K, Valerius O, Braus-Stromeyer S, Kwon NJ, Keller NP, Yu JH, Braus GH. VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science. 2008;320:1504–6.CrossRefGoogle Scholar
  7. Bell BG, Schellevis F, Stobberingh E, Goossens H, Pringle M. A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect Dis. 2014;14:13.CrossRefGoogle Scholar
  8. Berger H, Basheer A, Bock S, Reyes-Dominguez Y, Dalik T, Altmann F, Strauss J. Dissecting individual steps of nitrogen transcription factor cooperation in the Aspergillus nidulans nitrate cluster. Mol Microbiol. 2008;69:1385–98.CrossRefGoogle Scholar
  9. Bergmann S, Schumann J, Scherlach K, Lange C, Brakhage AA, Hertweck C. Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nat Chem Biol. 2007;3:213–7.CrossRefGoogle Scholar
  10. Bergmann S, Funk AN, Scherlach K, Schroeckh V, Shelest E, Horn U, Hertweck C, Brakhage AA. Activation of a silent fungal polyketide biosynthesis pathway through regulatory cross talk with a cryptic nonribosomal peptide synthetase gene cluster. Appl Environ Microbiol. 2010;76:8143–9.CrossRefGoogle Scholar
  11. Bertrand S, Schumpp O, Bohni N, Monod M, Gindro K, Wolfender J-L. De novo production of metabolites by fungal Co-culture of trichophyton rubrum and bionectria ochroleuca. J Nat Prod. 2013;76:1157–65.CrossRefGoogle Scholar
  12. Biran A, Meshorer E. Concise review: chromatin and genome organization in reprogramming. Stem Cells. 2012;30:1793–9.CrossRefGoogle Scholar
  13. Bok JW, Keller NP. LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot Cell. 2004;3:527–35.CrossRefGoogle Scholar
  14. Bok JW, Balajee SA, Marr KA, Andes D, Nielsen KF, Frisvad JC, Keller NP. LaeA, a regulator of morphogenetic fungal virulence factors. Eukaryot Cell. 2005;4:1574–82.CrossRefGoogle Scholar
  15. Bok JW, Chiang Y-M, Szewczyk E, Reyes-Dominguez Y, Davidson AD, Sanchez JF, Lo H-C, Watanabe K, Strauss J, Oakley BR, Wang CCC, Keller NP. Chromatin-level regulation of biosynthetic gene clusters. Nat Chem Biol. 2009;5:462–4.CrossRefGoogle Scholar
  16. Brakhage AA. Regulation of fungal secondary metabolism. Nat Rev Microbiol. 2013;11:21–32.CrossRefGoogle Scholar
  17. Brakhage AA, Schroeckh V. Fungal secondary metabolites—strategies to activate silent gene clusters. Fungal Genet Biol. 2011;48:15–22.CrossRefGoogle Scholar
  18. Brakhage AA, Schuemann J, Bergmann S, Scherlach K, Schroeckh V, Hertweck C. Activation of fungal silent gene clusters: a new avenue to drug discovery. Prog Drug Res. 2008;66(1):3–12.Google Scholar
  19. Braus GH, Irniger S, Bayram O. Fungal development and the COP9 signalosome. Curr Opin Microbiol. 2010;13:672–6.CrossRefGoogle Scholar
  20. Bromann K, Toivari M, Viljanen K, Vuoristo A, Ruohonen L, Nakari-Setala T. Identification and characterization of a novel diterpene gene cluster in Aspergillus nidulans. PLoS One. 2012;7, e35450.CrossRefGoogle Scholar
  21. Brown DW, Yu JH, Kelkar HS, Fernandes M, Nesbitt TC, Keller NP, Adams TH, Leonard TJ. Twenty-five coregulated transcripts define a sterigmatocystin gene cluster in Aspergillus nidulans. Proc Natl Acad Sci U S A. 1996;93:1418–22.CrossRefGoogle Scholar
  22. Butchko RA, Brown DW, Busman M, Tudzynski B, Wiemann P. Lae1 regulates expression of multiple secondary metabolite gene clusters in Fusarium verticillioides. Fungal Genet Biol. 2012;49:602–12.CrossRefGoogle Scholar
  23. Caddick MX, Arst Jr HN. Deletion of the 389 N-terminal residues of the transcriptional activator AREA does not result in nitrogen metabolite derepression in Aspergillus nidulans. J Bacteriol. 1998;180:5762–4.Google Scholar
  24. Carrozza MJ, Utley RT, Workman JL, Cote J. The diverse functions of histone acetyltransferase complexes. Trends Genet. 2003;19:321–9.CrossRefGoogle Scholar
  25. Chang PK, Ehrlich KC. Genome-wide analysis of the Zn(II)(2)Cys(6) zinc cluster-encoding gene family in Aspergillus flavus. Appl Microbiol Biotechnol. 2013;97:4289–300.CrossRefGoogle Scholar
  26. Chiang YM, Szewczyk E, Davidson AD, Keller N, Oakley BR, Wang CC. A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus nidulans. J Am Chem Soc. 2009;131:2965–70.CrossRefGoogle Scholar
  27. Chung YM, El-Shazly M, Chuang DW, Hwang TL, Asai T, Oshima Y, Ashour ML, Wu YC, Chang FR. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, induces the production of anti-inflammatory cyclodepsipeptides from Beauveria felina. J Nat Prod. 2013;76:1260–6.CrossRefGoogle Scholar
  28. Craney A, Ahmed S, Nodwell J. Towards a new science of secondary metabolism. J Antibiot (Tokyo). 2013;66:387–400.CrossRefGoogle Scholar
  29. Crawford JM, Townsend CA. New insights into the formation of fungal aromatic polyketides. Nat Rev Microbiol. 2010;8:879–89.CrossRefGoogle Scholar
  30. Cueto M, Jensen PR, Kauffman C, Fenical W, Lobkovsky E, Clardy J. Pestalone, a New antibiotic produced by a marine fungus in response to bacterial challenge. J Nat Prod. 2001;64:1444–6.CrossRefGoogle Scholar
  31. Degenkolb T, Heinze S, Schlegel B, Strobel G, Gräfe U. Formation of New Lipoaminopeptides, Acremostatins A, B, and C, by Co-cultivation of Acremonium sp. Tbp-5 and Mycogone rosea DSM 12973. Biosci Biotechnol Biochem. 2002;66:883–6.CrossRefGoogle Scholar
  32. Espeso EA, Penalva MA. Three binding sites for the Aspergillus nidulans PacC zinc-finger transcription factor are necessary and sufficient for regulation by ambient pH of the isopenicillin N synthase gene promoter. J Biol Chem. 1996;271:28825–30.CrossRefGoogle Scholar
  33. Flaherty JE, Payne GA. Overexpression of aflR leads to upregulation of pathway gene transcription and increased aflatoxin production in Aspergillus flavus. Appl Environ Microbiol. 1997;63:3995–4000.Google Scholar
  34. Gacek A, Strauss J. The chromatin code of fungal secondary metabolite gene clusters. Appl Microbiol Biotechnol. 2012a;95:1389–404.CrossRefGoogle Scholar
  35. Gacek A, Strauss J. The chromatin code of fungal secondary metabolite gene clusters. Appl Microbiol Biotechnol. 2012b;95:1389–404.CrossRefGoogle Scholar
  36. Gacek-Matthews A, Noble LM, Gruber C, Berger H, Sulyok M, Marcos AT, Strauss J, Andrianopoulos A. KdmA, a histone H3 demethylase with bipartite function, differentially regulates primary and secondary metabolism in Aspergillus nidulans. Mol Microbiol. 2015;96(4):839–60.CrossRefGoogle Scholar
  37. Giese H, Sondergaard TE, Sorensen JL. The AreA transcription factor in Fusarium graminearum regulates the use of some nonpreferred nitrogen sources and secondary metabolite production. Fungal Biol. 2013;117:814–21.CrossRefGoogle Scholar
  38. Govind CK, Zhang F, Qiu H, Hofmeyer K, Hinnebusch AG. Gcn5 promotes acetylation, eviction, and methylation of nucleosomes in transcribed coding regions. Mol Cell. 2007;25:31–42.CrossRefGoogle Scholar
  39. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997;389:349–52.CrossRefGoogle Scholar
  40. Gsaller F, Hortschansky P, Beattie SR, Klammer V, Tuppatsch K, Lechner BE, Rietzschel N, Werner ER, Vogan AA, Chung D, Mühlenhoff U, Kato M, Cramer RA, Brakhage AA, Haas H. The Janus transcription factor HapX controls fungal adaptation to both iron starvation and iron excess. EMBO J. 2014;33:2261–76.CrossRefGoogle Scholar
  41. Hertweck C. The biosynthetic logic of polyketide diversity. Angew Chem Int Ed Engl. 2009a;48:4688–716.CrossRefGoogle Scholar
  42. Hertweck C. Hidden biosynthetic treasures brought to light. Nat Chem Biol. 2009b;5:450–2.CrossRefGoogle Scholar
  43. Hoff B, Schmitt EK, Kuck U. CPCR1, but not its interacting transcription factor AcFKH1, controls fungal arthrospore formation in Acremonium chrysogenum. Mol Microbiol. 2005;56:1220–33.CrossRefGoogle Scholar
  44. Hortschansky P, Eisendle M, Al-Abdallah Q, Schmidt AD, Bergmann S, Thön M, Kniemeyer O, Abt B, Seeber B, Werner ER, Kato M, Brakhage AA, Haas H. Interaction of HapX with the CCAAT-binding complex—a novel mechanism of gene regulation by iron. EMBO J. 2007;26:3157–68.CrossRefGoogle Scholar
  45. Inglis DO, Binkley J, Skrzypek MS, Arnaud MB, Cerqueira GC, Shah P, Wymore F, Wortman JR, Sherlock G. Comprehensive annotation of secondary metabolite biosynthetic genes and gene clusters of Aspergillus nidulans, A. fumigatus, A. niger and A. oryzae. BMC Microbiol. 2013;13:91.CrossRefGoogle Scholar
  46. Jabra-Rizk M. Pathogenesis of polymicrobial biofilms. Open Mycol J. 2011;5:39–43.CrossRefGoogle Scholar
  47. Kale SP, Milde L, Trapp MK, Frisvad JC, Keller NP, Bok JW. Requirement of LaeA for secondary metabolism and sclerotial production in Aspergillus flavus. Fungal Genet Biol. 2008;45:1422–9.CrossRefGoogle Scholar
  48. Kamerewerd J, Zadra I, Kurnsteiner H, Kuck U. PcchiB1, encoding a class V chitinase, is affected by PcVelA and PcLaeA, and is responsible for cell wall integrity in Penicillium chrysogenum. Microbiology. 2011;157:3036–48.CrossRefGoogle Scholar
  49. Karimi-Aghcheh R, Bok JW, Phatale PA, Smith KM, Baker SE, Lichius A, Omann M, Zeilinger S, Seiboth B, Rhee C, Keller NP, Freitag M, Kubicek CP. Functional analyses of Trichoderma reesei LAE1 reveal conserved and contrasting roles of this regulator. G3 (Bethesda). 2013;3:369–78.CrossRefGoogle Scholar
  50. Kennedy J, Turner G. delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine synthetase is a rate limiting enzyme for penicillin production in Aspergillus nidulans. Mol Gen Genet. 1996;253:189–97.CrossRefGoogle Scholar
  51. Khaldi N, Seifuddin FT, Turner G, Haft D, Nierman WC, Wolfe KH, Fedorova ND. SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet Biol. 2010;47:736–41.CrossRefGoogle Scholar
  52. Knuf C, Nielsen J. Aspergilli: systems biology and industrial applications. Biotechnol J. 2012;7:1147–55.CrossRefGoogle Scholar
  53. König CC, Scherlach K, Schroeckh V, Horn F, Nietzsche S, Brakhage AA, Hertweck C. Bacterium induces cryptic meroterpenoid pathway in the pathogenic fungus Aspergillus fumigatus. ChemBioChem. 2013;14:938–42.CrossRefGoogle Scholar
  54. Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H, Greko C, So AD, Bigdeli M, Tomson G, Woodhouse W, Ombaka E, Peralta AQ, Qamar FN, Mir F, Kariuki S, Bhutta ZA, Coates A, Bergstrom R, Wright GD, Brown ED, Cars O. Antibiotic resistance-the need for global solutions. Lancet Infect Dis. 2013;13:1057–98.CrossRefGoogle Scholar
  55. Lee I, Oh JH, Shwab EK, Dagenais TR, Andes D, Keller NP. HdaA, a class 2 histone deacetylase of Aspergillus fumigatus, affects germination and secondary metabolite production. Fungal Genet Biol. 2009;46:782–90.CrossRefGoogle Scholar
  56. Li C, Wang J, Luo C, Ding W, Cox DG. A new cyclopeptide with antifungal activity from the co-culture broth of two marine mangrove fungi. Nat Prod Res. 2014;28:616–21.CrossRefGoogle Scholar
  57. Lopez-Berges MS, Hera C, Sulyok M, Schafer K, Capilla J, Guarro J, Di Pietro A. The velvet complex governs mycotoxin production and virulence of Fusarium oxysporum on plant and mammalian hosts. Mol Microbiol. 2013;87:49–65.CrossRefGoogle Scholar
  58. Maiya S, Grundmann A, Li SM, Turner G. The fumitremorgin gene cluster of Aspergillus fumigatus: identification of a gene encoding brevianamide F synthetase. Chembiochem. 2006;7:1062–9.CrossRefGoogle Scholar
  59. Medema MH, Blin K, Cimermancic P, de Jager V, Zakrzewski P, Fischbach MA, Weber T, Takano E, Breitling R. antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res. 2011;39:W339–46.CrossRefGoogle Scholar
  60. Michielse CB, Pfannmuller A, Macios M, Rengers P, Dzikowska A, Tudzynski B. The interplay between the GATA transcription factors AreA, the global nitrogen regulator and AreB in Fusarium fujikuroi. Mol Microbiol. 2014;91:472–93.CrossRefGoogle Scholar
  61. Mihlan M, Homann V, Liu TW, Tudzynski B. AREA directly mediates nitrogen regulation of gibberellin biosynthesis in Gibberella fujikuroi, but its activity is not affected by NMR. Mol Microbiol. 2003;47:975–91.CrossRefGoogle Scholar
  62. Moree WJ, Phelan VV, Wu C-H, Bandeira N, Cornett DS, Duggan BM, Dorrestein PC. Interkingdom metabolic transformations captured by microbial imaging mass spectrometry. Proc Natl Acad Sci. 2012;109:13811–6.CrossRefGoogle Scholar
  63. Mueller JE, Canze M, Bryk M. The requirements for COMPASS and Paf1 in transcriptional silencing and methylation of histone H3 in Saccharomyces cerevisiae. Genetics. 2006;173:557–67.CrossRefGoogle Scholar
  64. Nathan C, Cars O. Antibiotic resistance—problems, progress, and prospects. N Engl J Med. 2014;371:1761–3.CrossRefGoogle Scholar
  65. Netzker T, Fischer J, Weber J, Mattern DJ, Konig CC, Valiante V, Schroeckh V, Brakhage AA. Microbial communication leading to the activation of silent fungal secondary metabolite gene clusters. Front Microbiol. 2015;6:299.CrossRefGoogle Scholar
  66. Niehaus EM, Janevska S, von Bargen KW, Sieber CM, Harrer H, Humpf HU, Tudzynski B. Apicidin F: characterization and genetic manipulation of a new secondary metabolite gene cluster in the rice pathogen Fusarium fujikuroi. PLoS One. 2014;9, e103336.CrossRefGoogle Scholar
  67. Nützmann HW, Reyes-Dominguez Y, Scherlach K, Schroeckh V, Horn F, Gacek A, Schümann J, Hertweck C, Strauss J, Brakhage AA. Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation. Proc Natl Acad Sci. 2011;108:14282–7.CrossRefGoogle Scholar
  68. Nützmann HW, Fischer J, Scherlach K, Hertweck C, Brakhage AA. Distinct amino acids of histone H3 control secondary metabolism in Aspergillus nidulans. Appl Environ Microbiol. 2013;79:6102–9.CrossRefGoogle Scholar
  69. Oh D-C, Jensen PR, Kauffman CA, Fenical W. Libertellenones A-D: induction of cytotoxic diterpenoid biosynthesis by marine microbial competition. Bioorg Med Chem. 2005;13:5267–73.CrossRefGoogle Scholar
  70. Oh D-C, Kauffman CA, Jensen PR, Fenical W. Induced production of emericellamides A and B from the marine-derived fungus emericella sp. in competing co-culture. J Nat Prod. 2007;70:515–20.Google Scholar
  71. Palmer JM, Bok JW, Lee S, Dagenais TR, Andes DR, Kontoyiannis DP, Keller NP. Loss of CclA, required for histone 3 lysine 4 methylation, decreases growth but increases secondary metabolite production in Aspergillus fumigatus. PeerJ. 2013;1, e4.CrossRefGoogle Scholar
  72. Park HB, Kwon HC, Lee C-H, Yang HO. Glionitrin A, an antibiotic-antitumor metabolite derived from competitive interaction between abandoned mine microbes. J Nat Prod. 2009;72:248–52.CrossRefGoogle Scholar
  73. Patananan AN, Palmer JM, Garvey GS, Keller NP, Clarke SG. A novel automethylation reaction in the Aspergillus nidulans LaeA protein generates S-methylmethionine. J Biol Chem. 2013;288:14032–45.CrossRefGoogle Scholar
  74. Patterson GML, Bolis CM. Fungal cellwall polysaccharides elicit an antifungal secondary metabolite (phytoalexin) in the cyanobacterium scytonema ocelutum. J Phycol. 1997;33:54–60.Google Scholar
  75. Perrin RM, Fedorova ND, Bok JW, Cramer RA, Wortman JR, Kim HS, Nierman WC, Keller NP. Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog. 2007;3, e50.CrossRefGoogle Scholar
  76. Priebe S, Linde J, Albrecht D, Guthke R, Brakhage AA. FungiFun: a web-based application for functional categorization of fungal genes and proteins. Fungal Genet Biol. 2011;48:353–8.CrossRefGoogle Scholar
  77. Rahman H, Austin B, Mitchell WJ, Morris PC, Jamieson DJ, Adams DR, Spragg AM, Schweizer M. Novel anti-infective compounds from marine bacteria. Mar Drugs. 2010;8:498–518.CrossRefGoogle Scholar
  78. Rateb ME, Hallyburton I, Houssen WE, Bull AT, Goodfellow M, Santhanam R, Jaspars M, Ebel R. Induction of diverse secondary metabolites in Aspergillus fumigatus by microbial co-culture. RSC Advances. 2013;3:14444–50.CrossRefGoogle Scholar
  79. Reyes-Dominguez Y, Bok JW, Berger H, Shwab EK, Basheer A, Gallmetzer A, Scazzocchio C, Keller N, Strauss J. Heterochromatic marks are associated with the repression of secondary metabolism clusters in Aspergillus nidulans. Mol Microbiol. 2010;76:1376–86.CrossRefGoogle Scholar
  80. Richter L, Wanka F, Boecker S, Storm D, Kurt T, Vural Ö, Süßmuth R, Meyer V. Engineering of Aspergillus niger for the production of secondary metabolites. Fungal Biol Biotechnol. 2014;1:4.CrossRefGoogle Scholar
  81. Roze LV, Arthur AE, Hong SY, Chanda A, Linz JE. The initiation and pattern of spread of histone H4 acetylation parallel the order of transcriptional activation of genes in the aflatoxin cluster. Mol Microbiol. 2007;66:713–26.CrossRefGoogle Scholar
  82. Roze LV, Koptina AV, Laivenieks M, Beaudry RM, Jones DA, Kanarsky AV, Linz JE. Willow volatiles influence growth, development, and secondary metabolism in Aspergillus parasiticus. Appl Microbiol Biotechnol. 2011;92:359–70.CrossRefGoogle Scholar
  83. Sanchez JF, Somoza AD, Keller NP, Wang CCC. Advances in Aspergillus secondary metabolite research in the post-genomic era. Nat Prod Rep. 2012;29:351–71.CrossRefGoogle Scholar
  84. Sarikaya Bayram O, Bayram O, Valerius O, Park HS, Irniger S, Gerke J, Ni M, Han KH, Yu JH, Braus GH. LaeA control of velvet family regulatory proteins for light-dependent development and fungal cell-type specificity. PLoS Genet. 2010;6, e1001226.CrossRefGoogle Scholar
  85. Sarikaya-Bayram O, Palmer JM, Keller N, Braus GH, Bayram O. One Juliet and four Romeos: VeA and its methyltransferases. Front Microbiol. 2015;6:1.CrossRefGoogle Scholar
  86. Scherlach K, Nützmann HW, Schroeckh V, Dahse HM, Brakhage AA, Hertweck C. Cytotoxic pheofungins from an engineered fungus impaired in posttranslational protein modification. Angew Chem Int Ed Engl. 2001;50:9843–7.CrossRefGoogle Scholar
  87. Schmitt EK, Hoff B, Kuck U. Regulation of cephalosporin biosynthesis. Adv Biochem Eng Biotechnol. 2004;88:1–43.Google Scholar
  88. Schrettl M, Carberry S, Kavanagh K, Haas H, Jones GW, O'Brien J, Nolan A, Stephens J, Fenelon O, Doyle S. Self-protection against gliotoxin—a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLoS Pathog. 2010;6, e1000952.CrossRefGoogle Scholar
  89. Schroeckh V, Scherlach K, Nützmann H-W, Shelest E, Schmidt-Heck W, Schuemann J, Martin K, Hertweck C, Brakhage AA. Intimate bacterial–fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc Natl Acad Sci U S A. 2009a;106:14558–63.CrossRefGoogle Scholar
  90. Schroeckh V, Scherlach K, Nutzmann HW, Shelest E, Schmidt-Heck W, Schuemann J, Martin K, Hertweck C, Brakhage AA. Intimate bacterial-fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc Natl Acad Sci U S A. 2009b;106:14558–63.CrossRefGoogle Scholar
  91. Shaaban MI, Bok JW, Lauer C, Keller NP. Suppressor mutagenesis identifies a velvet complex remediator of Aspergillus nidulans secondary metabolism. Eukaryot Cell. 2010;9:1816–24.CrossRefGoogle Scholar
  92. Shilatifard A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem. 2006;75:243–69.CrossRefGoogle Scholar
  93. Shimizu K, Hicks JK, Huang TP, Keller NP. Pka, Ras and RGS protein interactions regulate activity of AflR, a Zn(II)2Cys6 transcription factor in Aspergillus nidulans. Genetics. 2003;165:1095–104.Google Scholar
  94. Shwab EK, Bok JW, Tribus M, Galehr J, Graessle S, Keller NP. Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot Cell. 2007;6:1656–64.CrossRefGoogle Scholar
  95. Smith DJ, Burnham MK, Bull JH, Hodgson JE, Ward JM, Browne P, Brown J, Barton B, Earl AJ, Turner G. Beta-lactam antibiotic biosynthetic genes have been conserved in clusters in prokaryotes and eukaryotes. EMBO J. 1990;9:741–7.Google Scholar
  96. Soukup AA, Chiang YM, Bok JW, Reyes-Dominguez Y, Oakley BR, Wang CC, Strauss J, Keller NP. Overexpression of the Aspergillus nidulans histone 4 acetyltransferase EsaA increases activation of secondary metabolite production. Mol Microbiol. 2012;86:314–30.CrossRefGoogle Scholar
  97. Stocker-Worgotter E. Metabolic diversity of lichen-forming ascomycetous fungi: culturing, polyketide and shikimatemetabolite production, and PKS genes. Nat Prod Rep. 2008;25:188–200.CrossRefGoogle Scholar
  98. Svahn KS, Göransson U, Chryssanthou E, Olsen B, Sjölin J, Strömstedt AA. Induction of gliotoxin secretion in Aspergillus fumigatus by bacteria-associated molecules. PLoS One. 2014;9, e93685.CrossRefGoogle Scholar
  99. Then Bergh K, Brakhage AA. Regulation of the Aspergillus nidulans Penicillin biosynthesis gene acvA (pcbAB) by amino acids: implication for involvement of transcription factor PACC. Appl Environ Microbiol. 1998;64:843–9.Google Scholar
  100. Thön M, Al Abdallah Q, Hortschansky P, Scharf DH, Eisendle M, Haas H, Brakhage AA. The CCAAT-binding complex coordinates the oxidative stress response in eukaryotes. Nucleic Acids Res. 2010;38:1098–113.CrossRefGoogle Scholar
  101. Tilburn J, Sarkar S, Widdick DA, Espeso EA, Orejas M, Mungroo J, Peñalva MA, Arst Jr HN. The Aspergillus PacC zinc finger transcription factor mediates regulation of both acid- and alkaline-expressed genes by ambient pH. EMBO J. 1995;14:779–90.Google Scholar
  102. Tribus M, Galehr J, Trojer P, Brosch G, Loidl P, Marx F, Haas H, Graessle S. HdaA, a major class 2 histone deacetylase of Aspergillus nidulans, affects growth under conditions of oxidative stress. Eukaryot Cell. 2005;4:1736–45.CrossRefGoogle Scholar
  103. Tudzynski B. Nitrogen regulation of fungal secondary metabolism in fungi. Front Microbiol. 2014;5:656.CrossRefGoogle Scholar
  104. Unkles SE, Valiante V, Mattern DJ, Brakhage AA. Synthetic biology tools for bioprospecting of natural products in eukaryotes. Chem Biol. 2014;21:502–8.CrossRefGoogle Scholar
  105. Watanabe T, Izaki K, Takahashi H. New polyenic antibiotics active against gram-positive and - negative bacteria. I. Isolation and purification of antibiotics produced by Gluconobacter sp. W-315. J Antibiot (Tokyo). 1982;35:1141–7.Google Scholar
  106. Wiemann P, Tudzynski B. The nitrogen regulation network and its impact on secondary metabolism and pathogenicity. Norwich: Caister Academic Press; 2013. p. 111–42.Google Scholar
  107. Wu D, Oide S, Zhang N, Choi MY, Turgeon BG. ChLae1 and ChVel1 regulate T-toxin production, virulence, oxidative stress response, and development of the maize pathogen Cochliobolus heterostrophus. PLoS Pathog. 2012;8, e1002542.CrossRefGoogle Scholar
  108. Yin W, Keller NP. Transcriptional regulatory elements in fungal secondary metabolism. J Microbiol. 2011;49:329–39.CrossRefGoogle Scholar
  109. Yin WB, Amaike S, Wohlbach DJ, Gasch AP, Chiang YM, Wang CC, Bok JW, Rohlfs M, Keller NP. An Aspergillus nidulans bZIP response pathway hardwired for defensive secondary metabolism operates through aflR. Mol Microbiol. 2012;83:1024–34.CrossRefGoogle Scholar
  110. Zuck KM, Shipley S, Newman DJ. Induced production of N-formyl alkaloids from aspergillus fumigatus by co-culture with streptomyces peucetius. J Nat Prod. 2011;74:1653–7.Google Scholar
  111. Zhu F, Chen G, Chen X, Huang M, Wan X. Aspergicin, a new antibacterial alkaloid produced by mixed fermentation of two marine-derived mangrove epiphytic fungi. Chem Nat Compd. 2011;47:767–9.CrossRefGoogle Scholar
  112. Zutz C, Gacek A, Sulyok M, Wagner M, Strauss J, Rychli K. Small chemical chromatin effectors alter secondary metabolite production in Aspergillus clavatus. Toxins (Basel). 2013;5:1723–41.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Juliane Fischer
    • 1
    • 2
  • Volker Schroeckh
    • 1
  • Axel A. Brakhage
    • 1
    • 2
    Email author
  1. 1.Department of Molecular and Applied MicrobiologyLeibniz Institute for Natural Product Research and Infection Biology (HKI)JenaGermany
  2. 2.Institute of MicrobiologyFriedrich Schiller UniversityJenaGermany

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