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Epigenetic modulation of secondary metabolite profiles in Aspergillus calidoustus and Aspergillus westerdijkiae through histone deacetylase (HDAC) inhibition by vorinostat

Abstract

The effects of epigenetic modulation on secondary metabolite biosynthesis were investigated with five Aspergillus species cultured in the presence of either the DNA methyltransferase inhibitor 5-azacitidine or the histone deacetylase inhibitor vorinostat. With Aspergillus calidoustus and Aspergillus westerdijkiae, fermentation in the presence of vorinostat (100 μM) induced significant changes in secondary metabolite profile with examples of both induction and repression. We identified putative biosynthetic gene clusters for emericellamide in A. calidoustus and ochratoxin in A. westerdijkiae. A substantial induction in production levels was observed for two secondary metabolites: the diketopiperazine alkaloid phenylahistin in A. calidoustus and the polyketide penicillic acid in A. westerdijkiae, indicating the potential of epigenetic regulation for the activation of silent fungal biosynthetic pathways.

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References

  1. Zhang X, Hindra, Elliot MA. Unlocking the trove of metabolic treasures: activating silent biosynthetic gene clusters in bacteria and fungi. Curr Opin Microbiol. 2019;51:9–15.

    Article  CAS  Google Scholar 

  2. Pfannenstiel BT, Keller NP. On top of biosynthetic gene clusters: how epigenetic machinery influences secondary metabolism in fungi. Biotechnol Adv. 2019;37:107345.

    Article  Google Scholar 

  3. Ganesan A. Epigenetic drug discovery: a success story for cofactor interference. Philos Trans R Soc B Biol Sci. 2018;373:20170069.

    Article  Google Scholar 

  4. Shwab EK, et al. Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot Cell. 2007;6:1656–64.

    Article  CAS  Google Scholar 

  5. Fisch KM, et al. Chemical induction of silent biosynthetic pathway transcription in Aspergillus niger. J Ind Microbiol Biotechnol. 2009;36:1199–213.

    Article  CAS  Google Scholar 

  6. Zutz C, et al. Small chemical chromatin effectors alter secondary metabolite production in Aspergillus clavatus. Toxins. 2013;5:1723–41.

    Article  Google Scholar 

  7. Miao FP, Liang XR, Liu XH, Ji NY. Aspewentins A-C, norditerpenes from a cryptic pathway in an algicolous strain of Aspergillus wentii. J Nat Prod. 2014;77:429–32.

    Article  CAS  Google Scholar 

  8. Henrikson JC, Hoover AR, Joyner PM, Cichewicz RH. A chemical epigenetics approach for engineering the in situbiosynthesis of a cryptic natural product from Aspergillus niger. Org Biomol Chem. 2009;7:435–8.

    Article  CAS  Google Scholar 

  9. Li X, et al. Identification and biological evaluation of secondary metabolites from marine derived Fungi-Aspergillus sp. SCSIOW3, cultivated in the presence of epigenetic modifying agents. Molecules. 2017;22:1302.

    Article  Google Scholar 

  10. Liu W, et al. Diketopiperazine and Diphenylether derivatives from marine Algae-Derived Aspergillus versicolor OUCMDZ-2738 by epigenetic activation. Mar Drugs. 2018;17:6.

    Article  Google Scholar 

  11. Sun K, Zhu G, Hao J, Wang Y, Zhu W. Chemical-epigenetic method to enhance the chemodiversity of the marine algicolous fungus, Aspergillus terreus OUCMDZ-2739. Tetrahedron. 2018;74:83–7.

    Article  CAS  Google Scholar 

  12. Blin K, et al. antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 2019;47:W81–7.

    Article  CAS  Google Scholar 

  13. Albright JC, et al. Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation. ACS Chem Biol. 2015;10:1535–41.

    Article  CAS  Google Scholar 

  14. Pan R, Bai X, Chen J, Zhang H, Wang H. Exploring structural diversity of microbe secondary metabolites using OSMAC strategy: a literature review. Front Microbiol. 2019;10:294.

    Article  Google Scholar 

  15. Karolewiez A, Geisen R. Cloning a part of the ochratoxin A biosynthetic gene cluster of Penicillium nordicum and characterization of the ochratoxin polyketide synthase gene. Syst Appl Microbiol. 2005;28:588–95.

    Article  CAS  Google Scholar 

  16. Chiang Y-M, et al. Molecular genetic mining of the Aspergillus secondary metabolome: discovery of the emericellamide biosynthetic pathway. Chem Biol. 2008;15:527–32.

    Article  CAS  Google Scholar 

  17. Kanoh K, et al. (−)-Phenylahistin: a new mammalian cell cycle inhibitor produced by Aspergillus ustus. Bioorg Med Chem Lett. 1997;7:2847–52.

    Article  CAS  Google Scholar 

  18. Kanoh K, et al. Antitumor activity of phenylahistin in vitro and in vivo. Biosci Biotechnol Biochem. 1999;63:1130–3.

    Article  CAS  Google Scholar 

  19. Cimino P, et al. Plinabulin, an inhibitor of tubulin polymerization, targets KRAS signaling through disruption of endosomal recycling. Biomed Rep. 2019;10:218–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Houbraken J, et al. Polyphasic taxonomy of Aspergillus section Usti. Stud Mycol. 2007;59:107–28.

    Article  CAS  Google Scholar 

  21. Birkinshaw JH, Oxford AE, Raistrick H. Penicillic acid, a metabolic product of Penicillium puberulum Bainier and P. cylopium Westling. Biochem J. 1936;30:394–411.

    Article  CAS  Google Scholar 

  22. Vansteelandt M, et al. Ligerin, an antiproliferative chlorinated sesquiterpenoid from a marine-derived Penicillium strain. J Nat Prod. 2013;76:297–301.

    Article  CAS  Google Scholar 

  23. Ciegler A. Bioproduction of ochratoxin A and penicillic acid by members of the Aspergillus ochraceus group. Can J Microbiol. 1972;18:631–6.

    Article  CAS  Google Scholar 

  24. Li H, Cai Y, Lam C, Chen Y, Lan W. Metabolites of marine fungus Aspergillus sp. collected from soft coral Sarcophyton tortuosum. Chem Res Chin Univ. 2010;26:415–9.

    CAS  Google Scholar 

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Acknowledgements

This work was funded through a scholarship to MA from Imam Abdulrahman Bin Faisal University, Saudi Arabia. Aspergillus strains were provided by the US Agricultural Research Service (USDA-ARS).

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Correspondence to Mohammed Aldholmi.

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Epigenetic Modulation of Secondary Metabolite Profiles in Aspergillus calidoustus and Aspergillus westerdijkiae through Histone Deacetylase (HDAC) Inhibition by Vorinostat

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Aldholmi, M., Wilkinson, B. & Ganesan, A. Epigenetic modulation of secondary metabolite profiles in Aspergillus calidoustus and Aspergillus westerdijkiae through histone deacetylase (HDAC) inhibition by vorinostat. J Antibiot 73, 410–413 (2020). https://doi.org/10.1038/s41429-020-0286-5

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