Epigenetics of Fungal Secondary Metabolism Related Genes

  • Ming-Yueh Wu
  • Jae-Hyuk YuEmail author
Part of the Fungal Biology book series (FUNGBIO)


Fungal secondary metabolites play multiple biological roles in development, virulence, defense, adaptation, and stress response. Many of these low-molecular-mass compounds are of intense interest to humankind due to their economic applications (antibiotics and drugs) and/or adverse effects (mycotoxins). Many filamentous fungal secondary metabolites are synthesized by enzymes and related regulator(s) are encoded by clustered genes. Expression of these clusters are governed by various transcription factors and signaling elements. Recent studies have further revealed that fungal secondary metabolite genes are subject to epigenetic regulation. This chapter presents a concise summary of the epigenetic modifications and remodeling of the genes associated with fungal secondary metabolism, focusing on the genetic elements involved in epigenetic regulation, including HepA, (LaeA), complex proteins associated with Set1 (COMPASS) complex, histone deacetylases (HDACs), Spt-Ada-Gcn5-acetyltransferase (SAGA/ADA) complex, and small ubiquitin-like modifier (SUMO). Finally, the current applications of these epigenetic regulators are discussed.


Epigenetics Fungi Secondary metabolism Gene Cluster Regulation Chromatin Histone Methylation Acetylation Sumoylation 



We thank Dr. Ellin Doyle for critically reviewing the manuscript. This work was supported by USDA Hatch (WIS01665) and the Intelligent Synthetic Biology Center of Global Frontier Project (2011-0031955) funded by the Ministry of Education, Science and Technology grants to JHY.


  1. 1.
    Brakhage AA, Schroeckh V (2011) Fungal secondary metabolites—strategies to activate silent gene clusters. Fungal Genet Biol 48(1):15–22PubMedGoogle Scholar
  2. 2.
    Brakhage AA, Schuemann J, Bergmann S, Scherlach K, Schroeckh V, Hertweck C (2008) Activation of fungal silent gene clusters: a new avenue to drug discovery. Natural compounds as drugs. Springer, Basel p. 1–12Google Scholar
  3. 3.
    Howard RJ, Valent B (1996) Breaking and entering: host penetration by the fungal rice blast pathogen Magnaporthe grisea. Annu Rev Microbiol 50(1):491–512PubMedGoogle Scholar
  4. 4.
    Kimura N, Tsuge T (1993) Gene cluster involved in melanin biosynthesis of the filamentous fungus Alternaria alternata. J Bacteriol 175(14):4427–4435PubMedCentralPubMedGoogle Scholar
  5. 5.
    Tsai H-F, Chang YC, Washburn RG, Wheeler MH, Kwon-Chung KJ (1998) The developmentally regulated alb1 gene of Aspergillus fumigatus: Its role in modulation of conidial morphology and virulence. J Bacteriol 180(12):3031–3038PubMedCentralPubMedGoogle Scholar
  6. 6.
    Leonard KJ (1977) Virulence, temperature optima, and competitive abilities of isolines of races T and O of Bipolaris maydis. Phytopathology 67(11):1273–1279Google Scholar
  7. 7.
    Klittich CJR, Bronson CR (1986) Reduced fitness associated with tox1 of Cochliobolus heterostrophus. Phytopathology 76(12):1294–1298Google Scholar
  8. 8.
    Yim G, Wang HH (2007) Antibiotics as signalling molecules. Philos Trans R Soc B Biol Sci 362(1483):1195–1200Google Scholar
  9. 9.
    Yu J-H, Keller N (2005) Regulation of secondary metabolism in filamentous fungi. Annu Rev Phytopathol 43:437–458PubMedGoogle Scholar
  10. 10.
    Calvo AM, Wilson RA, Bok JW, Keller NP (2002 Sep) Relationship between secondary metabolism and fungal development. Microbiol Mol Biol Rev 66(3):447–459PubMedCentralPubMedGoogle Scholar
  11. 11.
    Fox EM, Howlett BJ (2008) Secondary metabolism: regulation and role in fungal biology. Curr Opin Microbiol 11(6):481–487PubMedGoogle Scholar
  12. 12.
    Ma L-J, Van Der Does HC, Borkovich KA, Coleman JJ, Daboussi M-J, Di Pietro A et al (2010) Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium. Nature 464(7287):367–373PubMedCentralPubMedGoogle Scholar
  13. 13.
    Palmer JM, Keller NP (2010) Secondary metabolism in fungi: does chromosomal location matter? Curr Opin Microbiol 13(4):431–436PubMedCentralPubMedGoogle Scholar
  14. 14.
    Fedorova ND, Khaldi N, Joardar VS, Maiti R, Amedeo P, Anderson MJ et al (2008) Genomic islands in the pathogenic filamentous fungus Aspergillus fumigatus. PLoS Genet 4(4):e1000046PubMedCentralPubMedGoogle Scholar
  15. 15.
    Bouhired S, Weber M, Kempf-Sontag A, Keller NP, Hoffmeister D (2007) Accurate prediction of the Aspergillus nidulans terrequinone gene cluster boundaries using the transcriptional regulator LaeA. Fungal Genet Biol 44(11):1134–1145PubMedGoogle Scholar
  16. 16.
    Bok JW, Hoffmeister D, Maggio-Hall LA, Murillo R, Glasner JD, Keller NP (2006) Genomic mining for Aspergillus natural products. Chem Biol 13(1):31–37PubMedGoogle Scholar
  17. 17.
    Freitag M, Selker EU (2005) Controlling DNA methylation: many roads to one modification. Curr Opin Genet Dev 15(2):191–199PubMedGoogle Scholar
  18. 18.
    Selker EU, Jensen BC, Richardson GA (1987) A portable signal causing faithful DNA methylation de novo in Neurospora crassa. Science 238(4823):48–53PubMedGoogle Scholar
  19. 19.
    Singer MJ, Marcotte BA, Selker EU (1995) DNA methylation associated with repeat-induced point mutation in Neurospora crassa. Mol Cell Biol 15(10):5586–5597PubMedCentralPubMedGoogle Scholar
  20. 20.
    Miao VPW, Freitag M, Selker EU (2000) Short tpa-rich segments of the ζ-η region induce DNA methylation in Neurospora crassa. J Mol Biol 300(2):249–273PubMedGoogle Scholar
  21. 21.
    Tamaru H, Selker EU (2003) Synthesis of signals for de novo DNA methylation in Neurospora crassa. Mol Cell Biol 23(7):2379–2394PubMedCentralPubMedGoogle Scholar
  22. 22.
    Rossignol JL, Faugeron G (1995) Mip: An epigenetic gene silencing process in Ascobolus immersus. Gene silencing in higher plants and related phenomena in other eukaryotes: Springer, Verlag p. 179–191Google Scholar
  23. 23.
    Barry C, Faugeron G, Rossignol J-L (1993) Methylation induced premeiotically in Ascobolus: coextension with DNA repeat lengths and effect on transcript elongation. Proc Natl Acad Sci 90(10):4557–4561PubMedCentralPubMedGoogle Scholar
  24. 24.
    Rhounim L, Rossignol J-L, Faugeron G (1992) Epimutation of repeated genes in Ascobolus immersus. EMBO J 11(12):4451PubMedCentralPubMedGoogle Scholar
  25. 25.
    Faugeron G, Rhounim L, Rossignol J-L (1990) How does the cell count the number of ectopic copies of a gene in the premeiotic inactivation process acting in Ascoborus immersus? Genetics 124(3):585–591PubMedCentralPubMedGoogle Scholar
  26. 26.
    Jorgensen RA, Que Q, Stam M (1999) Do unintended antisense transcripts contribute to sense cosuppression in plants? Trends Genet 15(1):11–12PubMedGoogle Scholar
  27. 27.
    Catalanotto C, Azzalin G, Macino G, Cogoni C (2000) Transcription: gene silencing in worms and fungi. Nature 404(6775):245–245PubMedGoogle Scholar
  28. 28.
    Romano N, Macino G Quelling: transient inactivation of gene expression in Neurospora crassa by transformation with homologous sequences. Mol Microbiol 6(22):3343–3353Google Scholar
  29. 29.
    Chen B, Choi GH, Nuss DL (1994) Attenuation of fungal virulence by synthetic infectious hypovirus transcripts. Science 264(5166):1762–1764PubMedGoogle Scholar
  30. 30.
    Choi GH, Nuss DL (1992) Hypovirulence of chestnut blight fungus conferred by an infectious viral cDNA. Science 257(5071):800–803PubMedGoogle Scholar
  31. 31.
    Nuss DL (2011) Mycoviruses, RNA silencing, and viral RNA recombination. Adv Virus Res 80:25PubMedCentralPubMedGoogle Scholar
  32. 32.
    Hammond TM, Keller NP (2005) RNA silencing in Aspergillus nidulans is independent of RNA-dependent rna polymerases. Genetics 169(2):607–617PubMedCentralPubMedGoogle Scholar
  33. 33.
    Aramayo R, Metzenberg RL (1996) Meiotic transvection in fungi. Cell 86(1):103–113PubMedGoogle Scholar
  34. 34.
    Shiu PKT, Raju NB, Zickler D, Metzenberg RL (2001) Meiotic silencing by unpaired DNA. Cell 107(7):905–916PubMedGoogle Scholar
  35. 35.
    Keller NP, Hohn TM (1997) Metabolic pathway gene clusters in filamentous fungi. Fungal Genet Biol 21(1):17–29Google Scholar
  36. 36.
    Rosewich UL, Kistler HC (2000) Role of horizontal gene transfer in the evolution of fungi. Annu Rev Phytopathol 38(1):325–363PubMedGoogle Scholar
  37. 37.
    Khaldi N, Collemare J, Lebrun M-H, Wolfe KH (2008) Evidence for horizontal transfer of a secondary metabolite gene cluster between fungi. Genome Biol 9(1):R18PubMedCentralPubMedGoogle Scholar
  38. 38.
    Lawrence JG, Roth JR (1996) Selfish operons: horizontal transfer may drive the evolution of gene clusters. Genetics 143(4):1843–1860PubMedCentralPubMedGoogle Scholar
  39. 39.
    Lawrence JG (1999) Gene transfer, speciation, and the evolution of bacterial genomes. Curr Opin Microbiol 2(5):519–523PubMedGoogle Scholar
  40. 40.
    Smith MW, Feng D-F, Doolittle RF (1992) Evolution by acquisition: the case for horizontal gene transfers. Trends Biochem Sci 17(12):489–493PubMedGoogle Scholar
  41. 41.
    Tudzynski B, Hedden P, Carrera E, Gaskin P (2001) The p450–4 gene of Gibberella fujikuroi encodes ent-kaurene oxidase in the gibberellin biosynthesis pathway. Appl Environ Microbiol 67(8):3514–3522PubMedCentralPubMedGoogle Scholar
  42. 42.
    Wang X, Sena Filho JG, Hoover AR, King JB, Ellis TK, Powell DR et al (2010) Chemical epigenetics alters the secondary metabolite composition of guttate excreted by an atlantic-forest-soil-derived Penicillium citreonigrum. J Nat Prod 73(5):942–948PubMedCentralPubMedGoogle Scholar
  43. 43.
    Shilatifard A (2006) Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu Rev Biochem 75:243–269PubMedGoogle Scholar
  44. 44.
    Bok JW, Keller NP (2004) LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryotic cell 3(2):527–535PubMedCentralPubMedGoogle Scholar
  45. 45.
    Nützmann H-W, Reyes-Dominguez Y, Scherlach K, Schroeckh V, Horn F, Gacek A et al (2011) Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires saga/ada-mediated histone acetylation. Proc Natl Acad Sci 108(34):14282–14287PubMedCentralPubMedGoogle Scholar
  46. 46.
    Strauss J, Reyes-Dominguez Y (2011) Regulation of secondary metabolism by chromatin structure and epigenetic codes. Fungal Genet Biol 48(1):62–69PubMedCentralPubMedGoogle Scholar
  47. 47.
    Szewczyk E, Chiang Y-M, Oakley CE, Davidson AD, Wang CC, Oakley BR (2008) Identification and characterization of the asperthecin gene cluster of Aspergillus nidulans. Appl Environ Microbiol 74(24):7607–7612PubMedCentralPubMedGoogle Scholar
  48. 48.
    Kornberg RD (1974) Chromatin structure: a repeating unit of histones and DNA. Science 184(4139):868–871PubMedGoogle Scholar
  49. 49.
    de la Cruz X, Lois S, Sánchez‐Molina S, Martínez‐Balbás MA (2005) Do protein motifs read the histone code? Bioessays 27(2):164–175PubMedGoogle Scholar
  50. 50.
    Kosalková K, García-Estrada C, Ullán RV, Godio RP, Feltrer R, Teijeira F et al (2009) The global regulator LaeA controls penicillin biosynthesis, pigmentation and sporulation, but not roquefortine C synthesis in Penicillium chrysogenum. Biochimie 91(2):214–225PubMedGoogle Scholar
  51. 51.
    Smith KM, Phatale PA, Bredeweg EL, Pomraning KR, Freitag M (2012) Epigenetics of filamentous fungi. In: Meyers RA (ed) Epigenetic regulation and epigenomics (Current Topics from the Encyclopedia of Molecular Cell Biolo). Wiley-VCH Verlag GmbH & Co., pp 1063–1107Google Scholar
  52. 52.
    Reyes‐Dominguez Y, Bok JW, Berger H, Shwab EK, Basheer A, Gallmetzer A et al (2010) Heterochromatic marks are associated with the repression of secondary metabolism clusters in Aspergillus nidulans. Mol Microbiol 76(6):1376–1386PubMedCentralPubMedGoogle Scholar
  53. 53.
    Wang G, Ma A, Chow C-m, Horsley D, Brown NR, Cowell IG et al. (2000) Conservation of heterochromatin protein 1 function. Mol Cell Biol 20(18):6970–6983PubMedCentralPubMedGoogle Scholar
  54. 54.
    Cryderman DE, Cuaycong MH, Elgin SC, Wallrath LL (1998) Characterization of sequences associated with position-effect variegation at pericentric sites in Drosophila heterochromatin. Chromosoma 107(5):277–285PubMedGoogle Scholar
  55. 55.
    Holbert MA, Marmorstein R (2005) Structure and activity of enzymes that remove histone modifications. Curr Opin Struct Biol 15(6):673–680PubMedGoogle Scholar
  56. 56.
    Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun Z-W, Schmid M et al (2000) Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406(6796):593–599PubMedGoogle Scholar
  57. 57.
    Noma K-i, Allis CD, Grewal SI (2001) Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science 293(5532):1150–1155PubMedGoogle Scholar
  58. 58.
    Fanti L, Pimpinelli S (2008) HP1: a functionally multifaceted protein. Curr Opin Genet Dev 18(2):169–174PubMedGoogle Scholar
  59. 59.
    Freitag M, Hickey PC, Khlafallah TK, Read ND, Selker EU (2004) HP1 is essential for DNA methylation in Neurospora. Mol Cell 13(3):427–434PubMedGoogle Scholar
  60. 60.
    Lewis ZA, Honda S, Khlafallah TK, Jeffress JK, Freitag M, Mohn F et al (2009) Relics of repeat-induced point mutation direct heterochromatin formation in Neurospora crassa. Genome Res 19(3):427–437PubMedCentralPubMedGoogle Scholar
  61. 61.
    Sims RJ III, Nishioka K, Reinberg D (2003) Histone lysine methylation: a signature for chromatin function. TRENDS Genet 19(11):629–639PubMedGoogle Scholar
  62. 62.
    Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC et al (2001) Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410(6824):120–124PubMedGoogle Scholar
  63. 63.
    Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T (2001) Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410(6824):116–120PubMedGoogle Scholar
  64. 64.
    Ayyanathan K, Lechner MS, Bell P, Maul GG, Schultz DC, Yamada Y et al (2003) Regulated recruitment of hp1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev 17(15):1855–1869PubMedCentralPubMedGoogle Scholar
  65. 65.
    Li Y, Danzer JR, Alvarez P, Belmont AS, Wallrath LL (2003) Effects of tethering HP1 to euchromatic regions of the Drosophila genome. Development 130(9):1817–1824PubMedGoogle Scholar
  66. 66.
    Wiemann P, Brown DW, Kleigrewe K, Bok JW, Keller NP, Humpf HU et al (2010) FfVel1 and FfLae1, components of a velvet‐like complex in Fusarium fujikuroi, affect differentiation, secondary metabolism and virulence. Mol Microbiol 77(4):972–994PubMedCentralPubMedGoogle Scholar
  67. 67.
    Perrin RM, Fedorova ND, Bok JW, Cramer RA Jr, Wortman JR, Kim HS et al (2007) Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog 3(4):e50PubMedCentralPubMedGoogle Scholar
  68. 68.
    Bayram Ö, Krappmann S, Ni M, Bok JW, Helmstaedt K, Valerius O et al (2008) VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science 320(5882):1504–1506PubMedGoogle Scholar
  69. 69.
    Bok JW, Noordermeer D, Kale SP, Keller NP (2006) Secondary metabolic gene cluster silencing in Aspergillus nidulans. Mol Microbiol 61(6):1636–1645PubMedGoogle Scholar
  70. 70.
    Hoffmeister D, Keller NP. (2007) Natural products of filamentous fungi: enzymes, genes, and their regulation. Natural Product Reports 24(2):393–416PubMedGoogle Scholar
  71. 71.
    Kozbial PZ, Mushegian AR (2005) Natural history of s-adenosylmethionine-binding proteins. BMC Struct Biol 5(1):19PubMedCentralPubMedGoogle Scholar
  72. 72.
    Yin W, Keller NP (2011) Transcriptional regulatory elements in fungal secondary metabolism. J Microbiol 49(3):329–339PubMedCentralPubMedGoogle Scholar
  73. 73.
    Chiou C-H, Miller M, Wilson DL, Trail F, Linz JE (2002) Chromosomal location plays a role in regulation of aflatoxin gene expression in Aspergillus parasiticus. Appl Environ Microbiol 68(1):306–315PubMedCentralPubMedGoogle Scholar
  74. 74.
    Roze LV, Arthur AE, Hong SY, Chanda A, Linz JE. (2007) The initiation and pattern of spread of histone H4 acetylation parallel the order of transcriptional activation of genes in the aflatoxin cluster. Molecular Microbiol 66(3):713–726Google Scholar
  75. 75.
    Smith CA, Woloshuk CP, Robertson D, Payne GA (2007) Silencing of the aflatoxin gene cluster in a diploid strain of Aspergillus flavus is suppressed by ectopic aflR expression. Genetics 176(4):2077–2086PubMedCentralPubMedGoogle Scholar
  76. 76.
    Smith KM, Kothe GO, Matsen CB, Khlafallah TK, Adhvaryu KK, Hemphill M et al (2008) The fungus Neurospora crassa displays telomeric silencing mediated by multiple sirtuins and by methylation of histone H3 lysine 9. Epigenetics Chromatin 1(1):5PubMedCentralPubMedGoogle Scholar
  77. 77.
    Bok JW, Chiang Y-M, Szewczyk E, Reyes-Dominguez Y, Davidson AD, Sanchez JF et al (2009) Chromatin-level regulation of biosynthetic gene clusters. Nat Chem Biol 5(7):462–464PubMedCentralPubMedGoogle Scholar
  78. 78.
    Roguev A, Schaft D, Shevchenko A, Pijnappel WWM, Wilm M, Aasland R et al (2001) The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. EMBO J 20(24):7137–7148PubMedCentralPubMedGoogle Scholar
  79. 79.
    Krogan NJ, Dover J, Khorrami S, Greenblatt JF, Schneider J, Johnston M et al (2002) Compass, a histone H3 (lysine 4) methyltransferase required for telomeric silencing of gene expression. J Biol Chem 277(13):10753–10755PubMedGoogle Scholar
  80. 80.
    Nagy PL, Griesenbeck J, Kornberg RD, Cleary ML (2002) A trithorax-group complex purified from Saccharomyces cerevisiae is required for methylation of histone H3. Proc Natl Acad Sci 99(1):90–94PubMedCentralPubMedGoogle Scholar
  81. 81.
    Briggs SD, Bryk M, Strahl BD, Cheung WL, Davie JK, Dent SYR et al (2001) Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rdna silencing in Saccharomyces cerevisiae. Genes Dev 15(24):3286–3295PubMedCentralPubMedGoogle Scholar
  82. 82.
    Santos-Rosa H, Bannister AJ, Dehe PM, Géli V, Kouzarides T (2004) Methylation of H3 lysine 4 at euchromatin promotes Sir3p association with heterochromatin. J Biol Chem 279(46):47506–47512PubMedGoogle Scholar
  83. 83.
    Eissenberg JC, Shilatifard A (2010) Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev Biol 339(2):240–249PubMedCentralPubMedGoogle Scholar
  84. 84.
    Nedea E, Nalbant D, Xia D, Theoharis NT, Suter B, Richardson CJ et al (2008) The Glc7 phosphatase subunit of the cleavage and polyadenylation factor is essential for transcription termination on snorna genes. Mol Cell 29(5):577–587PubMedGoogle Scholar
  85. 85.
    Dichtl B, Aasland R, Keller W (2004) Functions for S. cerevisiae Swd2p in 3’ end formation of specific mrnas and snornas and global histone 3 lysine 4 methylation. RNA 10(6):965–977PubMedCentralPubMedGoogle Scholar
  86. 86.
    Cheng H, He X, Moore C (2004) The essential WD repeat protein Swd2 has dual functions in RNA polymerase ii transcription termination and lysine 4 methylation of histone H3. Mol Cell Biol 24(7):2932–2943PubMedCentralPubMedGoogle Scholar
  87. 87.
    Shilatifard A (2012) The compass family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem 81:65.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Meyers RA (2012) Epigenetic regulation and epigenomics: advances in molecular biology and medicine. Wiley-Blackwell, ChichesterGoogle Scholar
  89. 89.
    Mueller JE, Canze M, Bryk M (2006) The requirements for COMPASS and Paf1 transcriptional silencing and methylation of histone H3 in Saccharomyces cerevisiae. Genetics 173(2):557–567PubMedCentralPubMedGoogle Scholar
  90. 90.
    Nislow C, Ray E, Pillus L (1997) Set1, a yeast member of thetrithorax family, functions in transcriptional silencing and diverse cellular processes. Mol Biol Cell 8(12):2421–2436PubMedCentralPubMedGoogle Scholar
  91. 91.
    Schneider J, Wood A, Lee J-S, Schuster R, Dueker J, Maguire C et al (2005) Molecular regulation of histone H3 trimethylation by compass and the regulation of gene expression. Mol Cell 19(6):849–856PubMedGoogle Scholar
  92. 92.
    Palmer JM, Bok JW, Lee S, Dagenais TRT, Andes DR, Kontoyiannis DP et al (2013) Loss of CclA, required for histone 3 lysine 4 methylation, decreases growth but increases secondary metabolite production in Aspergillus fumigatus. PeerJ 1:e4PubMedCentralPubMedGoogle Scholar
  93. 93.
    Dokmanovic M, Clarke C, Marks PA (2007) Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 5(10):981–989PubMedGoogle Scholar
  94. 94.
    Robyr D, Suka Y, Xenarios I, Kurdistani SK, Wang A, Suka N et al (2002) Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases. Cell 109(4):437–446PubMedGoogle Scholar
  95. 95.
    Smith KM, Dobosy JR, Reifsnyder JE, Rountree MR, Anderson DC, Green GR et al (2010) H2B-and H3-specific histone deacetylases are required for DNA methylation in Neurospora crassa Genetics 186(4):1207–1216PubMedCentralPubMedGoogle Scholar
  96. 96.
    Tribus M, Bauer I, Galehr J, Rieser G, Trojer P, Brosch G et al (2010) A novel motif in fungal class 1 histone deacetylases is essential for growth and development of Aspergillus. Mol Biol Cell 21(2):345–353PubMedCentralPubMedGoogle Scholar
  97. 97.
    Shwab EK, Bok JW, Tribus M, Galehr J, Graessle S, Keller NP (2007) Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryotic Cell 6(9):1656–1664PubMedCentralPubMedGoogle Scholar
  98. 98.
    Lee I, Oh J-H, Keats Shwab E, Dagenais TR, Andes D, Keller NP (2009) Hdaa, a class 2 histone deacetylase of Aspergillus fumigatus, affects germination and secondary metabolite production. Fungal Genet Biol 46(10):782–790PubMedCentralPubMedGoogle Scholar
  99. 99.
    Baker S, Grant P (2007) The saga continues: Expanding the cellular role of a transcriptional co-activator complex. Oncogene 26(37):5329–5340PubMedCentralPubMedGoogle Scholar
  100. 100.
    Spröte P, Hynes MJ, Hortschansky P, Shelest E, Scharf DH, Wolke SM et al (2008) Identification of the novel penicillin biosynthesis gene aatB of Aspergillus nidulans and its putative evolutionary relationship to this fungal secondary metabolism gene cluster. Mol Microbiol 70(2):445–461PubMedGoogle Scholar
  101. 101.
    Barrios A, Selleck W, Hnatkovich B, Kramer R, Sermwittayawong D, Tan S (2007) Expression and purification of recombinant yeast Ada2/Ada3/Gcn5 and Piccolo NuA4 histone acetyltransferase complexes. Methods 41(3):271–277PubMedCentralPubMedGoogle Scholar
  102. 102.
    Marcus GA, Silverman N, Berger SL, Horiuchi J, Guarente L (1994) Functional similarity and physical association between Gcn5 and Ada2: putative transcriptional adaptors. EMBO J 13(20):4807PubMedCentralPubMedGoogle Scholar
  103. 103.
    Bayer P, Arndt A, Metzger S, Mahajan R, Melchior F, Jaenicke R et al (1998) Structure determination of the small ubiquitin-related modifier sumo-1. J Mol Biol 280(2):275–286PubMedGoogle Scholar
  104. 104.
    Harting R, Bayram Ö, Laubinger K, Valerius O, Braus GH (2013) Interplay of the fungal sumoylation network for control of multicellular development. Mol Microbiol 90(5):1125–1145PubMedGoogle Scholar
  105. 105.
    Pickart CM, Eddins MJ (2004) Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta 1695(1):55–72 ((BBA)-Molecular Cell Research)PubMedGoogle Scholar
  106. 106.
    Schwartz DC, Hochstrasser M (2003) A superfamily of protein tags: ubiquitin, SUMO and related modifiers. Trends Biochem Sci 28(6):321–328PubMedGoogle Scholar
  107. 107.
    Sampson DA, Wang M, Matunis MJ (2001) The small ubiquitin-like modifier-1 (SUMO-1) consensus sequence mediates Ubc9 binding and is essential for sumo-1 modification. J Biol Chem 276(24):21664–21669PubMedGoogle Scholar
  108. 108.
    Bernier-Villamor V, Sampson DA, Matunis MJ, Lima CD (2002) Structural basis for E2-mediated sumo conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell 108(3):345–356PubMedGoogle Scholar
  109. 109.
    Ohi MD, Vander Kooi CW, Rosenberg JA, Chazin WJ, Gould KL (2003) Structural insights into the U-box, a domain associated with multi-ubiquitination. Nat Struct Mol Biol 10(4):250–255Google Scholar
  110. 110.
    Swanson R, Locher M, Hochstrasser M (2001) A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matα2 repressor degradation. Genes Dev 15(20):2660–2674PubMedCentralPubMedGoogle Scholar
  111. 111.
    Pichler A, Gast A, Seeler JS, Dejean A, Melchior F (2002) The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108(1):109–120PubMedGoogle Scholar
  112. 112.
    Shiio Y, Eisenman RN (2003) Histone sumoylation is associated with transcriptional repression. Proceedings of the National Academy of Sciences 100(23):13225–13230Google Scholar
  113. 113.
    Shin JA, Choi ES, Kim HS, Ho JCY, Watts FZ, Park SD et al (2005) SUMO modification is involved in the maintenance of heterochromatin stability in fission yeast. Mol Cell 19(6):817–828PubMedGoogle Scholar
  114. 114.
    Sterner DE, Nathan D, Reindle A, Johnson ES, Berger SL (2006) Sumoylation of the yeast Gcn5 protein. BioChemistry 45(3):1035–1042PubMedGoogle Scholar
  115. 115.
    Harting R (2013) The sumoylation and neddylation networks in Aspergillus nidulans development. Dissertation, der Georg-August UniversityGoogle Scholar
  116. 116.
    Wong KH, Todd RB, Oakley BR, Oakley CE, Hynes MJ, Davis MA (2008) Sumoylation in Aspergillus nidulans: sumO inactivation, overexpression and live-cell imaging. Fungal Genet Biol 45(5):728–737PubMedCentralPubMedGoogle Scholar
  117. 117.
    Kobayashi E, Ando K, Nakano H, Iida T, Ohno H, Morimoto M et al (1989) Calphostins (UCN-1028), novel and specific inhibitors of protein kinase CI fermentation, isolation, physico-chemical properties and biological activities. J Antibiot (Tokyo) 42(10):1470–1474Google Scholar
  118. 118.
    Williams RB, Henrikson JC, Hoover AR, Lee AE, Cichewicz RH (2008) Epigenetic remodeling of the fungal secondary metabolome. Organic Biomol Chem 6(11):1895–1897Google Scholar
  119. 119.
    Fisch K, Gillaspy A, Gipson M, Henrikson J, Hoover A, Jackson L et al (2009) Chemical induction of silent biosynthetic pathway transcription in Aspergillus niger. J Ind Microbiol Biotechnol 36(9):1199–1213PubMedGoogle Scholar
  120. 120.
    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. Organic Biomol Chem 7(3):435–438Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Bacteriology and GeneticsUniversity of Wisconsin-MadisonMadisonUSA

Personalised recommendations