Examining the Evolution of the Regulatory Circuit Controlling Secondary Metabolism and Development in the Fungal Genus

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Filamentous fungi produce a highly diverse cadre of secondary metabolites, small molecules whose potent toxic activities are integral to the fungal lifestyle. Most secondary metabolites are narrowly taxonomically distributed, whereas the transcriptional regulators that control their production, alongside with controlling other key processes such as development, are broadly conserved. To gain insight into the evolution of the regulatory circuit governing secondary metabolism and development, we examined the evolution of the genes and pathways underlying these processes as well as the evolution of their transcriptional regulation in the filamentous fungal genus Aspergillus, a prolific and important producer of secondary metabolites. We discovered that although secondary metabolic genes and pathways are poorly conserved across Aspergillus, their regulation is largely conserved. In contrast, the regulation of highly conserved developmental genes is divergent. These results point to a new type of rewiring that has occurred during the evolution of the regulatory circuit governing secondary metabolism and development in Aspergillus in which conserved regulators control a conserved biological process (secondary metabolism), even though the underlying genes and pathways that make up the biological process are not themselves conserved.

Vyšlo v časopise: Examining the Evolution of the Regulatory Circuit Controlling Secondary Metabolism and Development in the Fungal Genus. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005096
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005096

Souhrn

Zdroje

1. Keller NP, Turner G, Bennett JW (2005) Fungal secondary metabolism—from biochemistry to genomics. Nat Rev Microbiol 3: 937–947. doi: 10.1038/nrmicro1286 16322742

2. Brakhage AA (1998) Molecular Regulation of β-Lactam Biosynthesis in Filamentous Fungi. Microbiol Mol Biol Rev 62: 547–585. 9729600

3. Kennedy J, Auclair K, Kendrew SG, Park C, Vederas JC, et al. (1999) Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science 284: 1368–1372. 10334994

4. Weber G, Schörgendorfer K, Schneider-Scherzer E, Leitner E (1994) The peptide synthetase catalyzing cyclosporine production in Tolypocladium niveum is encoded by a giant 45.8-kilobase open reading frame. Curr Genet 26: 120–125. doi: 10.1007/BF00313798 8001164

5. Chang PK, Ehrlich KC, Yu J, Bhatnagar D, Cleveland TE (1995) Increased expression of Aspergillus parasiticus aflR, encoding a sequence-specific DNA-binding protein, relieves nitrate inhibition of aflatoxin biosynthesis. Appl Environ Microbiol 61: 2372–2377. 7793958

6. Brown DW, Butchko RAE, Busman M, Proctor RH (2007) The Fusarium verticillioides FUM gene cluster encodes a Zn(II)2Cys6 protein that affects FUM gene expression and fumonisin production. Eukaryot Cell 6: 1210–1218. doi: 10.1128/EC.00400–06 17483290

7. Proctor RH, Brown DW, Plattner RD, Desjardins AE (2003) Co-expression of 15 contiguous genes delineates a fumonisin biosynthetic gene cluster in Gibberella moniliformis. Fungal Genet Biol 38: 237–249. 12620260

8. Yim G, Wang HH, Davies J (2007) Antibiotics as signalling molecules. Philos Trans R Soc Lond B Biol Sci 362: 1195–1200. doi: 10.1098/rstb.2007.2044 17360275

9. Rohlfs M, Albert M, Keller NP, Kempken F (2007) Secondary chemicals protect mould from fungivory. Biol Lett 3: 523–525. doi: 10.1098/rsbl.2007.0338 17686752

10. Vining LC (1990) Functions of secondary metabolites. Annu Rev Microbiol 44: 395–427. doi: 10.1146/annurev.mi.44.100190.002143 2252388

11. Demain AL, Fang A (2000) The natural functions of secondary metabolites. Adv Biochem Eng Biotechnol 69: 1–39. 11036689

12. Rohlfs M, Churchill ACL (2011) Fungal secondary metabolites as modulators of interactions with insects and other arthropods. Fungal Genet Biol 48: 23–34. doi: 10.1016/j.fgb.2010.08.008 20807586

13. Keller NP, Hohn TM (1997) Metabolic Pathway Gene Clusters in Filamentous Fungi. Fungal Genet Biol 21: 17–29. 9073477

14. Gardiner DM, Howlett BJ (2005) Bioinformatic and expression analysis of the putative gliotoxin biosynthetic gene cluster of Aspergillus fumigatus. FEMS Microbiol Lett 248: 241–248. doi: 10.1016/j.femsle.2005.05.046 15979823

15. Scharf DH, Heinekamp T, Remme N, Hortschansky P, Brakhage A a, et al. (2012) Biosynthesis and function of gliotoxin in Aspergillus fumigatus. Appl Microbiol Biotechnol 93: 467–472. doi: 10.1007/s00253–011–3689–1 22094977

16. Bennett J, Bentley R (1989) What’s in a name?—Microbial secondary metabolism. Adv Appl Microbiol 34. 2672724

17. Christensen M, Frisvad JC, Tuthill D (1999) Taxonomy of the Penicillium miczynskii group based on morphology and secondary metabolites. Mycol Res 103: 527–541. doi: 10.1017/S0953756298007515

18. McCowen MC, Callender ME, Lawlis JF (1951) Fumagillin (H-3), a new antibiotic with amebicidal properties. Science 113: 202–203. 14809278

19. Lin H-C, Chooi Y-H, Dhingra S, Xu W, Calvo AM, et al. (2013) The Fumagillin Biosynthetic Gene Cluster in Aspergillus fumigatus Encodes a Cryptic Terpene Cyclase Involved in the Formation of β-trans-Bergamotene. J Am Chem Soc 135: 4616–4619. doi: 10.1021/ja312503y 23488861

20. Asami Y, Kakeya H, Onose R, Chang Y-H, Toi M, et al. (2004) RK-805, an endothelial-cell-growth inhibitor produced by Neosartorya sp., and a docking model with methionine aminopeptidase-2. Tetrahedron 60: 7085–7091. doi: 10.1016/j.tet.2003.09.104

21. Wiemann P, Guo C-J, Palmer JM, Sekonyela R, Wang CCC, et al. (2013) Prototype of an intertwined secondary-metabolite supercluster. Proc Natl Acad Sci U S A 110: 17065–17070. doi: 10.1073/pnas.1313258110 24082142

22. Frisvad JC, Andersen B, Thrane U (2008) The use of secondary metabolite profiling in chemotaxonomy of filamentous fungi. Mycol Res 112: 231–240. doi: 10.1016/j.mycres.2007.08.018 18319145

23. Brakhage A a (2013) Regulation of fungal secondary metabolism. Nat Rev Microbiol 11: 21–32. doi: 10.1038/nrmicro2916 23178386

24. Bayram Ö, Krappmann S, Ni M, Bok JW, Helmstaedt K, et al. (2008) VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science (80-) 320: 1504–1506. doi: 10.1126/science.1155888

25. Kato N, Brooks W, Calvo AM (2003) The expression of sterigmatocystin and penicillin genes in Aspergillus nidulans is controlled by veA, a gene required for sexual development. Eukaryot Cell 2: 1178–1186. 14665453

26. Stinnett SM, Espeso EA, Cobeño L, Araújo-Bazán L, Calvo AM (2007) Aspergillus nidulans VeA subcellular localization is dependent on the importin alpha carrier and on light. Mol Microbiol 63: 242–255. doi: 10.1111/j.1365–2958.2006.05506.x 17163983

27. Purschwitz J, Müller S, Kastner C, Schöser M, Haas H, et al. (2008) Functional and physical interaction of blue- and red-light sensors in Aspergillus nidulans. Curr Biol 18: 255–259. doi: 10.1016/j.cub.2008.01.061 18291652

28. Dhingra S, Lind AL, Lin H-C, Tang Y, Rokas A, et al. (2013) The fumagillin gene cluster, an example of hundreds of genes under veA control in Aspergillus fumigatus. PLoS One 8: e77147. doi: 10.1371/journal.pone.0077147 24116213

29. Ramamoorthy V, Dhingra S, Kincaid A, Shantappa S, Feng X, et al. (2013) The Putative C2H2 Transcription Factor MtfA Is a Novel Regulator of Secondary Metabolism and Morphogenesis in Aspergillus nidulans. PLoS One 8: e74122. doi: 10.1371/journal.pone.0074122 24066102

30. Smith TD, Calvo AM (2014) The mtfA Transcription Factor Gene Controls Morphogenesis, Gliotoxin Production, and Virulence in the Opportunistic Human Pathogen Aspergillus fumigatus. Eukaryot Cell 13: 766–775. doi: 10.1128/EC.00075–14 24728192

31. Tsai HF, 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: 3031–3038. 9620950

32. Calvo AM, Wilson RA, Bok JW, Keller NP (2002) Relationship between secondary metabolism and fungal development. Microbiol Mol Biol Rev 66: 447–459, table of contents. 12208999

33. Calvo AM (2008) The VeA regulatory system and its role in morphological and chemical development in fungi. Fungal Genet Biol 45: 1053–1061. doi: 10.1016/j.fgb.2008.03.014 18457967

34. Roze L V, Chanda A, Linz JE (2011) Compartmentalization and molecular traffic in secondary metabolism: a new understanding of established cellular processes. Fungal Genet Biol 48: 35–48. doi: 10.1016/j.fgb.2010.05.006 20519149

35. Kroken S, Glass NL, Taylor JW, Yoder OC, Turgeon BG (2003) Phylogenomic analysis of type I polyketide synthase genes in pathogenic and saprobic ascomycetes. Proc Natl Acad Sci U S A 100: 15670–15675. doi: 10.1073/pnas.2532165100 14676319

36. Bayram O, Braus GH (2012) Coordination of secondary metabolism and development in fungi: the velvet family of regulatory proteins. FEMS Microbiol Rev 36: 1–24. doi: 10.1111/j.1574–6976.2011.00285.x 21658084

37. Martchenko M, Levitin A, Hogues H, Nantel A, Whiteway M (2007) Transcriptional rewiring of fungal galactose-metabolism circuitry. Curr Biol 17: 1007–1013. doi: 10.1016/j.cub.2007.05.017 17540568

38. Cain CW, Lohse MB, Homann OR, Sil A, Johnson AD (2012) A conserved transcriptional regulator governs fungal morphology in widely diverged species. Genetics 190: 511–521. doi: 10.1534/genetics.111.134080 22095082

39. Carroll SB (2005) Evolution at two levels: on genes and form. PLoS Biol 3: e245. doi: 10.1371/journal.pbio.0030245 16000021

40. Prud’homme B, Gompel N, Carroll SB (2007) Emerging principles of regulatory evolution. Proc Natl Acad Sci U S A 104 Suppl: 8605–8612. doi: 10.1073/pnas.0700488104 17494759

41. Tuch BB, Li H, Johnson AD (2008) Evolution of eukaryotic transcription circuits. Science (80-) 319: 1797–1799. doi: 10.1126/science.1152398

42. Tanay A, Regev A, Shamir R (2005) Conservation and evolvability in regulatory networks: the evolution of ribosomal regulation in yeast. Proc Natl Acad Sci U S A 102: 7203–7208. doi: 10.1073/pnas.0502521102 15883364

43. Carroll SB (2008) Evo-devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution. Cell 134: 25–36. doi: 10.1016/j.cell.2008.06.030 18614008

44. Thompson DA, Roy S, Chan M, Styczynsky MP, Pfiffner J, et al. (2013) Evolutionary principles of modular gene regulation in yeasts. Elife 2: e00603. doi: 10.7554/eLife.00603 23795289

45. Inglis DO, Binkley J, Skrzypek MS, Arnaud MB, Cerqueira GC, et al. (2013) Comprehensive annotation of secondary metabolite biosynthetic genes and gene clusters of Aspergillus nidulans, A. fumigatus, A. niger and A. oryzae. BMC Microbiol 13: 91. doi: 10.1186/1471–2180–13–91 23617571

46. Machida M, Asai K, Sano M, Tanaka T, Kumagai T, et al. (2005) Genome sequencing and analysis of Aspergillus oryzae. Nature 438: 1157–1161. doi: 10.1038/nature04300 16372010

47. Kiyota T, Hamada R, Sakamoto K, Iwashita K, Yamada O, et al. (2011) Aflatoxin non-productivity of Aspergillus oryzae caused by loss of function in the aflJ gene product. J Biosci Bioeng 111: 512–517. doi: 10.1016/j.jbiosc.2010.12.022 21342785

48. Gibbons JG, Salichos L, Slot JC, Rinker DC, McGary KL, et al. (2012) The evolutionary imprint of domestication on genome variation and function of the filamentous fungus Aspergillus oryzae. Curr Biol 22: 1403–1409. doi: 10.1016/j.cub.2012.05.033 22795693

49. Brown DW, Yu JH, Kelkar HS, Fernandes M, Nesbitt TC, et al. (1996) Twenty-five coregulated transcripts define a sterigmatocystin gene cluster in Aspergillus nidulans. Proc Natl Acad Sci U S A 93: 1418–1422. 8643646

50. Gibbons JG, Beauvais A, Beau R, McGary KL, Latgé J-P, et al. (2012) Global transcriptome changes underlying colony growth in the opportunistic human pathogen Aspergillus fumigatus. Eukaryot Cell 11: 68–78. doi: 10.1128/EC.05102–11 21724936

51. Dhingra S, Andes D, Calvo AM (2012) VeA Regulates Conidiation, Gliotoxin Production and Protease Activity in the Opportunistic Human Pathogen Aspergillus fumigatus. Eukaryot Cell 11: 1531–1543. doi: 10.1128/EC.00222–12 23087369

52. Ramamoorthy V, Shantappa S, Dhingra S, Calvo AM (2012) veA-dependent RNA-pol II transcription elongation factor-like protein, RtfA, is associated with secondary metabolism and morphological development in Aspergillus nidulans. Mol Microbiol 85: 795–814. doi: 10.1111/j.1365–2958.2012.08142.x 22783880

53. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, et al. (2000) Gene Ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25: 25–29. doi: 10.1038/75556 10802651

54. Arnaud MB, Chibucos MC, Costanzo MC, Crabtree J, Inglis DO, et al. (2010) The Aspergillus Genome Database, a curated comparative genomics resource for gene, protein and sequence information for the Aspergillus research community. Nucleic Acids Res 38: D420–D427. doi: 10.1093/nar/gkp751 19773420

55. Galagan JE, Calvo SE, Cuomo C, Ma L-J, Wortman JR, et al. (2005) Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae. Nature 438: 1105–1115. doi: 10.1038/nature04341 16372000

56. Khaldi N, Seifuddin FT, Turner G, Haft D, Nierman WC, et al. (2010) SMURF: Genomic mapping of fungal secondary metabolite clusters. Fungal Genet Biol 47: 736–741. doi: 10.1016/j.fgb.2010.06.003 20554054

57. Fedorova ND, Khaldi N, Joardar VS, Maiti R, Amedeo P, et al. (2008) Genomic islands in the pathogenic filamentous fungus Aspergillus fumigatus. PLoS Genet 4: e1000046. doi: 10.1371/journal.pgen.1000046 18404212

58. Andersen MR, Salazar MP, Schaap PJ, van de Vondervoort PJI, Culley D, et al. (2011) Comparative genomics of citric-acid-producing Aspergillus niger ATCC 1015 versus enzyme-producing CBS 513.88. Genome Res 21: 885–897. doi: 10.1101/gr.112169.110 21543515

59. Hoffmeister D, Keller NP (2007) Natural products of filamentous fungi: enzymes, genes, and their regulation. Nat Prod Rep 24: 393–416. doi: 10.1039/b603084j 17390002

60. Frisvad JC, Rank C, Nielsen KF, Larsen TO (2009) Metabolomics of Aspergillus fumigatus. Med Mycol 47 Suppl 1: S53–S71. doi: 10.1080/13693780802307720 18763205

61. Geiser DM, Klich MA, Frisvad JC, Peterson SW, Varga J, et al. (2007) The current status of species recognition and identification in Aspergillus. Stud Mycol 59: 1–10. doi: 10.3114/sim.2007.59.01 18490947

62. Wisecaver JH, Slot JC, Rokas A (2014) The Evolution of Fungal Metabolic Pathways. PLoS Genet. 10: e1004816 doi: 10.1371/journal.pgen.1004816 25474404

63. Bushley KE, Turgeon BG (2010) Phylogenomics reveals subfamilies of fungal nonribosomal peptide synthetases and their evolutionary relationships. BMC Evol Biol 10: 26. doi: 10.1186/1471–2148–10–26 20100353

64. Carvunis A-R, Rolland T, Wapinski I, Calderwood MA, Yildirim MA, et al. (2012) Proto-genes and de novo gene birth. Nature 487: 370–374. doi: 10.1038/nature11184 22722833

65. 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: R18. doi: 10.1186/gb-2008–9–1-r18 18218086

66. Slot JC, Rokas A (2011) Horizontal transfer of a large and highly toxic secondary metabolic gene cluster between fungi. Curr Biol 21: 134–139. doi: 10.1016/j.cub.2010.12.020 21194949

67. Campbell M a, Rokas A, Slot JC (2012) Horizontal transfer and death of a fungal secondary metabolic gene cluster. Genome Biol Evol 4: 289–293. doi: 10.1093/gbe/evs011 22294497

68. Proctor RH, Van Hove F, Susca A, Stea G, Busman M, et al. (2013) Birth, death and horizontal transfer of the fumonisin biosynthetic gene cluster during the evolutionary diversification of Fusarium. Mol Microbiol 90: 290–306. doi: 10.1111/mmi.12362 23937442

69. Khaldi N, Wolfe KH (2011) Evolutionary Origins of the Fumonisin Secondary Metabolite Gene Cluster in Fusarium verticillioides and Aspergillus niger. Int J Evol Biol 2011: 423821. doi: 10.4061/2011/423821 21716743

70. Sarikaya-Bayram O, Bayram O, Feussner K, Kim J-H, Kim H-S, et al. (2014) Membrane-bound methyltransferase complex VapA-VipC-VapB guides epigenetic control of fungal development. Dev Cell 29: 406–420. doi: 10.1016/j.devcel.2014.03.020 24871947

71. Ahmed YL, Gerke J, Park H-S, Bayram Ö, Neumann P, et al. (2013) The Velvet Family of Fungal Regulators Contains a DNA-Binding Domain Structurally Similar to NF-κB. PLoS Biol 11: e1001750. doi: 10.1371/journal.pbio.1001750 24391470

72. Tsong AE, Tuch BB, Li H, Johnson AD (2006) Evolution of alternative transcriptional circuits with identical logic. Nature 443: 415–420. doi: 10.1038/nature05099 17006507

73. Rokas A (2006) Evolution: different paths to the same end. Nature 443: 401–402. doi: 10.1038/443401a 17006502

74. Rokas A, Hittinger CT (2007) Transcriptional rewiring: the proof is in the eating. Curr Biol 17: R626–R628. doi: 10.1016/j.cub.2007.06.025 17714646

75. Galant R, Carroll SB (2002) Evolution of a transcriptional repression domain in an insect Hox protein. Nature 415: 910–913. doi: 10.1038/nature717 11859369

76. Ronshaugen M, McGinnis N, McGinnis W (2002) Hox protein mutation and macroevolution of the insect body plan. Nature 415: 914–917. doi: 10.1038/nature716 11859370

77. Tuch BB, Galgoczy DJ, Hernday AD, Li H, Johnson AD (2008) The evolution of combinatorial gene regulation in fungi. PLoS Biol 6: e38. doi: 10.1371/journal.pbio.0060038 18303948

78. Odom DT, Dowell RD, Jacobsen ES, Gordon W, Danford TW, et al. (2007) Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nat Genet 39: 730–732. doi: 10.1038/ng2047 17529977

79. Borneman AR, Gianoulis TA, Zhang ZD, Yu H, Rozowsky J, et al. (2007) Divergence of transcription factor binding sites across related yeast species. Science 317: 815–819. doi: 10.1126/science.1140748 17690298

80. O’Gorman CM, Fuller HT, Dyer PS (2009) Discovery of a sexual cycle in the opportunistic fungal pathogen Aspergillus fumigatus. Nature 457: 471–474. doi: 10.1038/nature07528 19043401

81. Crabtree J, Angiuoli S V, Wortman JR, White OR (2007) Sybil: methods and software for multiple genome comparison and visualization. Methods Mol Biol 408: 93–108. doi: 10.1007/978–1–59745–547–3_6 18314579

82. Enright AJ, Van Dongen S, Ouzounis CA (2002) An efficient algorithm for large-scale detection of protein families. Nucleic Acids Res 30: 1575–1584. 11917018

83. Carbon S, Ireland A, Mungall CJ, Shu S, Marshall B, et al. (2009) AmiGO: online access to ontology and annotation data. Bioinformatics 25: 288–289. doi: 10.1093/bioinformatics/btn615 19033274

84. Kim H-S, Han K-Y, Kim K-J, Han D-M, Jahng K-Y, et al. (2002) The veA gene activates sexual development in Aspergillus nidulans. Fungal Genet Biol 37: 72–80. doi: 10.1016/S1087–1845(02)00029–4 12223191

85. Szewczyk E, Nayak T, Oakley CE, Edgerton H, Xiong Y, et al. (2006) Fusion PCR and gene targeting in Aspergillus nidulans. Nat Protoc 1: 3111–3120. doi: 10.1038/nprot.2006.405 17406574

86. Shaaban M, Palmer JM, El-Naggar WA, El-Sokkary MA, Habib E-SE, et al. (2010) Involvement of transposon-like elements in penicillin gene cluster regulation. Fungal Genet Biol 47: 423–432. doi: 10.1016/j.fgb.2010.02.006 20219692

87. Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics: btu170 –. doi: 10.1093/bioinformatics/btu170 24695404

88. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, et al. (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14: R36. doi: 10.1186/gb-2013–14–4-r36 23618408

89. Anders S, Pyl PT, Huber W (2014) HTSeq—A Python framework to work with high-throughput sequencing data. bioRxiv. doi: 10.1101/002824

90. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-Seq data with DESeq2. bioRxiv. doi: 10.1101/002832

91. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, et al. (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13: 2498–2504. doi: 10.1101/gr.1239303 14597658

92. Maere S, Heymans K, Kuiper M (2005) BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21: 3448–3449. doi: 10.1093/bioinformatics/bti551 15972284

93. R Core Team (2014) R: A Language and Environment for Statistical Computing.

94. Benjamini Y, Hochberg Y (1995) Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc Ser B 57: pp. 289–300.

95. Wickham H (2009) ggplot2: elegant graphics for data analysis. Springer New York.

96. Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, et al. (2009) Circos: an information aesthetic for comparative genomics. Genome Res 19: 1639–1645. doi: 10.1101/gr.092759.109 19541911

97. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc 3: 1101–1108. doi: 10.1038/nprot.2008.73 18546601