Biotechnology Letters

, Volume 41, Issue 12, pp 1439–1449 | Cite as

Epigenetic modification enhances ergot alkaloid production of Claviceps purpurea

  • Jing-Jing Chen
  • Meng-Yao Han
  • Ting Gong
  • Yun-Ming Qiao
  • Jin-Ling Yang
  • Ping ZhuEmail author
Original Research Paper



To enhance ergot alkaloid production of Claviceps purpurea Cp-1 strain by epigenetic modification approach.


The chemical epigenetic modifiers were screened to promote ergot alkaloid production of the Cp-1 strain. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) was found to significantly enhance the alkaloid productivity of the strain. Particularly, the titers of total ergot alkaloids were gradually increased with the increase of SAHA concentration in the fermentation medium, and the highest production of ergot alkaloids could be achieved at the concentration of 500 μM SAHA. Specially, the titers of ergometrine and total ergot alkaloids were as high as 95.4 mg/L and 179.7 mg/L, respectively, which were twice of those of the control. Furthermore, the mRNA expression levels of the most functional genes in the ergot alkaloid synthesis (EAS) gene cluster were up-regulated under SAHA treatment. It was proposed that SAHA might increase histone acetylation in the EAS gene cluster region in the chromosome, which would loosen the chromosome structure, and subsequently up-regulate the mRNA expression levels of genes involved in the biosynthesis of ergot alkaloids, thereby resulting in the markedly increase in the production of ergot alkaloids.


The ergot alkaloid production by the C. purpurea Cp-1 strain can be effectively increased by the application of histone deacetylase inhibitor. Our work provides a reference for using the chemical epigenetic modifiers to improve SM production in other fungi.


Ergot alkaloid Claviceps purpurea Biosynthetic pathway Epigenetic Gene expression 



This work was supported by the National Natural Science Foundation of China (Grant no 81603002), CAMS Innovation Fund for Medical Sciences (Grant Nos. CIFMS-2016-I2M-2-002 and CIFMS-2017-I2M-4-004), and the Drug Innovation Major Project (Grant No. 2018ZX09711001-006).

Supporting information

Supplementary Figure 1—The mycelium wet weight of Cp-1 strain in fermentation medium supplemented with different HDACi and HATi for 14 days.

Supplementary Figure 2—The mycelium wet weight of Cp-1 strain in fermentation medium supplemented with different concentrations of SAHA for 14 days.

Supplementary Figure 3—The mycelium wet weight of Cp-1 strain in fermentation medium supplemented with different concentrations of sodium valproate for 14 days.

Supplementary Figure 4—Volcano plot for all DEGs, which plotted FDR against FC. Each point represents a gene, the green dot and red dot represent significantly up-regulated and down-regulated genes, respectively. The black dot represents a gene that does not show significant difference.

Supplementary Figure 5—Functional annotation of DEGs based on cluster of orthologous groups of proteins (COG) categorization.

Supplementary Figure 6—Functional annotation of DEGs based on gene ontology (GO) categorization. GO analysis was performed for three main categories (cellular component, molecular function and biological process).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10529_2019_2750_MOESM1_ESM.docx (785 kb)
Electronic supplementary material 1 (DOCX 785 kb)


  1. Albright JC, Henke MT, Soukup AA, McClure RA, Thomson RJ, Keller NP, Kelleher NL (2015) Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation. ACS Chem Biol 10:1535–1541CrossRefGoogle Scholar
  2. Asilonu E, Bucke C, Keshavarz T (2000) Enhancement of chrysogenin production in cultures of Penicillium chrysogenum by uronic acid oligosaccharides. Biotechnol Lett 22:931–936CrossRefGoogle Scholar
  3. Bai J, Dou MM, Yan D, Liu BQ, Wan WJ, Tang Y, Hu YC (2018) Epigenetic modification in histone deacetylase deletion strain of Calcarisporium arbuscula leads to diverse diterpenoids. Acta Pharm Sin B 8:687–697CrossRefGoogle Scholar
  4. Bok JW, Chiang YM, Szewczyk E, Reyes-Dominguez Y, Davidson AD, Sanchez JF, Lo HC, Watanabe K, Strauss J, Oakley BR (2009) Chromatin-level regulation of biosynthetic gene clusters. Nat Chem Biol 5:462CrossRefGoogle Scholar
  5. Chen J-J, Han M-Y, Gong T, Yang J-L, Zhu P (2017) Recent progress in ergot alkaloid research. RSC Adv 7:27384–27396CrossRefGoogle Scholar
  6. Chung YM, El-Shazly M, Chuang DW, Hwang TL, Asai T, Oshima Y, Ashour ML, Wu YC, Chang FR (2013) Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, induces the production of anti-inflammatory cyclodepsipeptides from Beauveria felina. J Nat Prod 76:1260–1266CrossRefGoogle Scholar
  7. de Groot AN, van Dongen PW, Vree TB, Hekster YA, van Roosmalen J (1998) Ergot alkaloids. Drugs 56:523–535CrossRefGoogle Scholar
  8. Fan A, Mi W, Liu Z, Zeng G, Zhang P, Hu Y, Fang W, Yin WB (2017) Deletion of a histone acetyltransferase leads to the pleiotropic activation of natural products in Metarhizium robertsii. Org Lett 19:1686–1689CrossRefGoogle Scholar
  9. Flieger M, Wurst M, Shelby R (1997) Ergot alkaloids-sources, structures and analytical methods. Folia Microbiol 42:3–30CrossRefGoogle Scholar
  10. Florea S, Panaccione DG, Schardl CL (2017) Ergot alkaloids of the family Clavicipitaceae. Phytopathology 107:504–518CrossRefGoogle Scholar
  11. Haarmann T, Machado C, Lübbe Y, Correia T, Schardl CL, Panaccione DG, Tudzynski P (2005) The ergot alkaloid gene cluster in Claviceps purpurea: extension of the cluster sequence and intra species evolution. Phytochemistry 66:1312–1320CrossRefGoogle Scholar
  12. Han Y-S, van der Heijden R, Verpoorte R (2002) Improved anthraquinone accumulation in cell cultures of Cinchona 'Robusta' by feeding of biosynthetic precursors and inhibitors. Biotechnol Lett 24:705–710CrossRefGoogle Scholar
  13. Henrikson JC, Hoover AR, Joyner PM, Cichewicz RH (2009) A chemical epigenetics approach for engineering the in situ biosynthesis of a cryptic natural product from Aspergillus niger. Org Biomol Chem 7:435–438CrossRefGoogle Scholar
  14. Hoffmeister D, Keller NP (2007) Natural products of filamentous fungi: enzymes, genes, and their regulation. Nat Prod Rep 24:393–416CrossRefGoogle Scholar
  15. Hulvová H, Galuszka P, Frébortová J, Frébort I (2013) Parasitic fungus Claviceps as a source for biotechnological production of ergot alkaloids. Biotechnol Adv 31:79–89CrossRefGoogle Scholar
  16. Khaldi N, Seifuddin FT, Turner G, Haft D, Nierman WC, Wolfe KH, Fedorova ND (2010) SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet Biol 47:736–741CrossRefGoogle Scholar
  17. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705CrossRefGoogle Scholar
  18. Kuo MH, Allis CD (1998) Roles of histone acetyltransferases and deacetylases in gene regulation. BioEssays 20:615–626CrossRefGoogle Scholar
  19. Lorenz N, Wilson EV, Machado C, Schardl CL, Tudzynski P (2007) Comparison of ergot alkaloid biosynthesis gene clusters in Claviceps species indicates loss of late pathway steps in evolution of C. fusiformis. Appl Environ Microb 73:7185–7191CrossRefGoogle Scholar
  20. Lorenz N, Haarmann T, Pažoutová S, Jung M, Tudzynski P (2009) The ergot alkaloid gene cluster: functional analyses and evolutionary aspects. Phytochemistry 70:1822–1832CrossRefGoogle Scholar
  21. Lyu HN, Liu HW, Keller NP, Yin WB (2019) Harnessing diverse transcriptional regulators for natural product discovery in fungi. Nat Prod Rep. CrossRefPubMedGoogle Scholar
  22. Macheleidt J, Mattern DJ, Fischer J, Netzker T, Weber J, Schroeckh V, Valiante V, Brakhage AA (2016) Regulation and role of fungal secondary metabolites. Annu Rev Genet 50:371–392CrossRefGoogle Scholar
  23. Millard CS, Chao Y-P, Liao JC, Donnelly MI (1996) Enhanced production of succinic acid by overexpression of phosphoenolpyruvate carboxylase in Escherichia coli. Appl Environ Microb 62:1808–1810Google Scholar
  24. Ortel I, Keller U (2009) Combinatorial assembly of simple and complex D-lysergic acid alkaloid peptide classes in the ergot fungus Claviceps purpurea. J Biol Chem 284:6650–6660CrossRefGoogle Scholar
  25. Pfannenstiel BT, Keller NP (2019) On top of biosynthetic gene clusters: how epigenetic machinery influences secondary metabolism in fungi. Biotechnol Adv 37:107345CrossRefGoogle Scholar
  26. Schardl CL, Young CA, Hesse U, Amyotte SG, Andreeva K, Calie PJ, Fleetwood DJ, Haws DC, Moore N, Oeser B (2013) Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the Clavicipitaceae reveals dynamics of alkaloid loci. PLoS Genet 9:e1003323CrossRefGoogle Scholar
  27. Shwab EK, Bok JW, Tribus M, Galehr J, Graessle S, Keller NP (2007) Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot Cell 6:1656–1664CrossRefGoogle Scholar
  28. Strauss J, Reyes-Dominguez Y (2011) Regulation of secondary metabolism by chromatin structure and epigenetic codes. Fungal Genet Biol 48:62–69CrossRefGoogle Scholar
  29. Tudzynski P, Hölter K, Correia T, Arntz C, Grammel N, Keller U (1999) Evidence for an ergot alkaloid gene cluster in Claviceps purpurea. Mol Genet Genomics 261:133–141CrossRefGoogle Scholar
  30. Tudzynski P, Correia T, Keller U (2001) Biotechnology and genetics of ergot alkaloids. Appl Microbiol Biot 57:593–605CrossRefGoogle Scholar
  31. Vendrell M, Angulo E, Casadó V, Lluis C, Franco R, Albericio F, Royo M (2007) Novel ergopeptides as dual ligands for adenosine and dopamine receptors. J Med Chem 50:3062–3069CrossRefGoogle Scholar
  32. Wallwey C, Li S-M (2011) Ergot alkaloids: structure diversity, biosynthetic gene clusters and functional proof of biosynthetic genes. Nat Prod Rep 28:496–510CrossRefGoogle Scholar
  33. Williams RB, Henrikson JC, Hoover AR, Lee AE, Cichewicz RH (2008) Epigenetic remodeling of the fungal secondary metabolome. Org Biomol Chem 6:1895–1897CrossRefGoogle Scholar
  34. Wu GW, Zhou HC, Zhang P, Wang XN, Li W, Zhang WW, Liu XZ, Liu HW, Keller NP, An ZQ, Yin WB (2016) Polyketide production of pestaloficiols and macrodiolide ficiolides revealed by manipulations of epigenetic regulators in an endophytic fungus. Org Lett 18:1832–1835CrossRefGoogle Scholar
  35. Xu FS, Wang YL, Zheng M, Xi X, Cao H, Cui X, Guo H, Han C (2018) Yield enhancement strategies of rare pharmaceutical metabolites from endophytes. Biotechnol Lett 40:797–807CrossRefGoogle Scholar
  36. Zutz C, Gacek A, Sulyok M, Wagner M, Strauss J, Rychli K (2013) Small chemical chromatin effectors alter secondary metabolite production in Aspergillus clavatus. Toxins 5:1723–1741CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Jing-Jing Chen
    • 1
  • Meng-Yao Han
    • 1
  • Ting Gong
    • 1
  • Yun-Ming Qiao
    • 1
  • Jin-Ling Yang
    • 1
  • Ping Zhu
    • 1
    Email author
  1. 1.State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biosynthesis of Natural Products, CAMS Key Laboratory of Enzyme and Biocatalysis of Natural DrugsInstitute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina

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