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Annual Review of Genetics

Volume 52, 2018

Metabolic Gene Clusters in Eukaryotes

Abstract

In bacteria, more than half of the genes in the genome are organized in operons. In contrast, in eukaryotes, functionally related genes are usually dispersed across the genome. There are, however, numerous examples of functional clusters of nonhomologous genes for metabolic pathways in fungi and plants. Despite superficial similarities with operons (physical clustering, coordinate regulation), these clusters have not usually originated by horizontal gene transfer from bacteria, and (unlike operons) the genes are typically transcribed separately rather than as a single polycistronic message. This clustering phenomenon raises intriguing questions about the origins of clustered metabolic pathways in eukaryotes and the significance of clustering for pathway function. Here we review metabolic gene clusters from fungi and plants, highlight commonalities and differences, and consider how these clusters form and are regulated. We also identify opportunities for future research in the areas of large-scale genomics, synthetic biology, and experimental evolution.

Keyword(s): biosynthesis, fungi, genome architecture, natural products, plants, regulation
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2018-11-23
2024-04-19
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Literature Cited

  1. 1.  Aleksenko A, Liu W, Gojkovic Z, Nielsen J, Piskur J 1999. Structural and transcriptional analysis of the pyrABCN, pyrD and pyrF genes in Aspergillus nidulans and the evolutionary origin of fungal dihydroorotases. Mol. Microbiol. 33:599–611
     [Google Scholar]
  2. 2.  Alifano P, Fani R, Lio P, Lazcano A, Bazzicalupo M et al. 1996. Histidine biosynthetic pathway and genes: structure, regulation, and evolution. Microbiol. Rev. 60:44–69
     [Google Scholar]
  3. 3.  Ámon J, Fernández-Martín R, Bokor E, Cultrone A, Kelly JM et al. 2017. A eukaryotic nicotinate-inducible gene cluster: convergent evolution in fungi and bacteria. Open Biol 7:170199
     [Google Scholar]
  4. 4.  Arst HN Jr, MacDonald DW 1978. Reduced expression of a distal gene of the prn gene cluster in deletion mutants of Aspergillus nidulans: genetic evidence for a dicistronic messenger in a eukaryote. Mol. Gen. Genet. 163:17–22
     [Google Scholar]
  5. 5.  Avila J, Gonzalez C, Brito N, Machin F, Perez MD, Siverio JM 2002. A second Zn(II)2Cys6 transcriptional factor encoded by the YNA2 gene is indispensable for the transcriptional activation of the genes involved in nitrate assimilation in the yeast Hansenula polymorpha. Yeast 19:537–44
     [Google Scholar]
  6. 6.  Barlow DP 2011. Genomic imprinting: a mammalian epigenetic discovery model. Annu. Rev. Genet. 45:379–403
     [Google Scholar]
  7. 7.  Bayram O, 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 320:1504–6
     [Google Scholar]
  8. 8.  Boettger D, Hertweck C 2013. Molecular diversity sculpted by fungal PKS-NRPS hybrids. ChemBioChem 14:28–42
     [Google Scholar]
  9. 9.  Bok JW, Chiang YM, Szewczyk E, Reyes-Dominguez Y, Davidson AD et al. 2009. Chromatin-level regulation of biosynthetic gene clusters. Nat. Chem. Biol. 5:462–64
     [Google Scholar]
  10. 10.  Bok JW, Keller NP 2004. LaeA, a regulator of secondary metabolism in Aspergillus spp. Cell 3:527–35
     [Google Scholar]
  11. 11.  Bok JW, Soukup AA, Chadwick E, Chiang YM, Wang CC, Keller NP 2013. VeA and MvlA repression of the cryptic orsellinic acid gene cluster in Aspergillus nidulans involves histone 3 acetylation. Mol. Microbiol. 89:963–74
     [Google Scholar]
  12. 12.  Boutanaev AM, Moses T, Zi J, Nelson DR, Mugford ST et al. 2015. Investigation of terpene diversification across multiple sequenced plant genomes. PNAS 112:E81–88
     [Google Scholar]
  13. 13.  Boutanaev AM, Osbourn A 2018. Multigenome analysis implicates miniature inverted-repeat transposable elements (MITEs) in metabolic diversification in eudicots. PNAS 115:E6650–58
     [Google Scholar]
  14. 14.  Brakhage AA 2013. Regulation of fungal secondary metabolism. Nat. Rev. Microbiol. 11:21–32
     [Google Scholar]
  15. 15.  Brakhage AA, Sprote P, Al-Abdallah Q, Gehrke A, Plattner H, Tuncher A 2004. Regulation of penicillin biosynthesis in filamentous fungi. Adv. Biochem. Eng. 88:45–90
     [Google Scholar]
  16. 16.  Brickner DG, Cajigas I, Fondufe-Mittendorf Y, Ahmed S, Lee PC et al. 2007. H2A.Z-mediated localization of genes at the nuclear periphery confers epigenetic memory of previous transcriptional state. PLOS Biol 5:e81
     [Google Scholar]
  17. 17.  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. PNAS 93:1418–22
     [Google Scholar]
  18. 18.  Butchko RA, Brown DW, Busman M, Tudzynski B, Wiemann P 2012. Lae1 regulates expression of multiple secondary metabolite gene clusters in Fusarium verticillioides. Fungal Genet. Biol 49:602–12
     [Google Scholar]
  19. 19.  Cabal GG, Genovesio A, Rodriguez-Navarro S, Zimmer C, Gadal O et al. 2006. SAGA interacting factors confine sub-diffusion of transcribed genes to the nuclear envelope. Nature 441:770–73
     [Google Scholar]
  20. 20.  Cárdenas PD, Sonawane PD, Pollier J, Vanden Bossche R, Dewangan V et al. 2016. GAME9 regulates the biosynthesis of steroidal alkaloids and upstream isoprenoids in the plant mevalonate pathway. Nat. Commun. 7:10654
     [Google Scholar]
  21. 21.  Cary JW, Ehrlich KC 2006. Aflatoxigenicity in Aspergillus: molecular genetics, phylogenetic relationships and evolutionary implications. Mycopathologia 162:167–77
     [Google Scholar]
  22. 22.  Chiang YM, Ahuja M, Oakley CE, Entwistle R, Asokan A et al. 2016. Development of genetic dereplication strains in Aspergillus nidulans results in the discovery of aspercryptin. Angew. Chem. Int. Ed. 55:1662–65
     [Google Scholar]
  23. 23.  Chiba R, Minami A, Gomi K, Oikawa H 2013. Identification of ophiobolin F synthase by a genome mining approach: a sesterterpene synthase from Aspergillus clavatus. Org. Lett 15:594–97
     [Google Scholar]
  24. 24.  Chu CG, Friesen TL, Xu SS, Faris JD, Kolmer JA 2009. Identification of novel QTLs for seedling and adult plant leaf rust resistance in a wheat doubled haploid population. Theor. Appl. Genet. 119:263–69
     [Google Scholar]
  25. 25.  Chu HY, Wegel E, Osbourn A 2011. From hormones to secondary metabolism: the emergence of metabolic gene clusters in plants. Plant J 66:66–79
     [Google Scholar]
  26. 26.  Cimermancic P, Medema MH, Claesen J, Kurita K, Brown LCW et al. 2014. Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters. Cell 158:412–21
     [Google Scholar]
  27. 27.  Connolly LR, Smith KM, Freitag M 2013. The Fusarium graminearum histone H3 K27 methyltransferase KMT6 regulates development and expression of secondary metabolite gene clusters. PLOS Genet 9:e1003916
     [Google Scholar]
  28. 28.  Cooper TG 1996. Regulation of allantoin catabolism in Saccharomyces cerevisiae. The Mycota, Vol. 3: Biochemistry and Molecular Biology R Brambl, GA Marzluf 139–69 Berlin: Springer
     [Google Scholar]
  29. 29.  Cove DJ 1979. Genetic studies of nitrate assimilation in Aspergillus nidulans. Biol. Rev. Camb. Philos. Soc 54:291–327
     [Google Scholar]
  30. 30.  Cubero B, Scazzocchio C 1994. Two different, adjacent and divergent zinc finger binding sites are necessary for CREA-mediated carbon catabolite repression in the proline gene cluster of Aspergillus nidulans. EMBO J 13:407–15
     [Google Scholar]
  31. 31.  Dalal CK, Zuleta IA, Mitchell KF, Andes DR, El-Samad H, Johnson AD 2016. Transcriptional rewiring over evolutionary timescales changes quantitative and qualitative properties of gene expression. eLife 5:e18981
     [Google Scholar]
  32. 32.  Darbani B, Motawia MS, Olsen CE, Nour-Eldin HH, Moller BL, Rook F 2016. The biosynthetic gene cluster for the cyanogenic glucoside dhurrin in Sorghum bicolor contains its co-expressed vacuolar MATE transporter. Sci. Rep. 6:37079
     [Google Scholar]
  33. 33.  De Luca V, Salim V, Atsumi SM, Yu F 2012. Mining the biodiversity of plants: a revolution in the making. Science 336:1658–61
     [Google Scholar]
  34. 34.  de Vries RP, Riley R, Wiebenga A, Aguilar-Osorio G, Amillis S et al. 2017. Comparative genomics reveals high biological diversity and specific adaptations in the industrially and medically important fungal genus Aspergillus. Genome Biol 18:28
     [Google Scholar]
  35. 35.  Demain AL, Fang A 2000. The natural functions of secondary metabolites. Adv. Biochem. Eng. 69:1–39
     [Google Scholar]
  36. 36.  Demais S 2006. Recherche de mutants constitutifs de l'activateur transcriptionnel du métabolisme de la proline PhD Thesis, Univ. Paris Sud
  37. 37.  Diez B, Gutierrez S, Barredo JL, van Solingen P, van der Voort LH, Martin JF 1990. The cluster of penicillin biosynthetic genes: identification and characterization of the pcbAB gene encoding the alpha-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes. J. Biol. Chem. 265:16358–65
     [Google Scholar]
  38. 38.  Dultz E, Tjong H, Weider E, Herzog M, Young B et al. 2016. Global reorganization of budding yeast chromosome conformation in different physiological conditions. J. Cell Biol. 212:321–34
     [Google Scholar]
  39. 39.  Dutartre L, Hilliou F, Feyereisen R 2012. Phylogenomics of the benzoxazinoid biosynthetic pathway of Poaceae: gene duplications and origin of the Bx cluster. BMC Evol. Biol. 12:64
     [Google Scholar]
  40. 40.  Ehrlich KC, Yu JJ 2010. Aflatoxin-like gene clusters and how they evolved. Mycotoxins in Food, Feed and Bioweapons M Rai, A Varma 65–75 Berlin: Springer
     [Google Scholar]
  41. 41.  Elmore MH, McGary KL, Wisecaver JH, Slot JC, Geiser DM et al. 2015. Clustering of two genes putatively involved in cyanate detoxification evolved recently and independently in multiple fungal lineages. Genome Biol. Evol. 7:789–800
     [Google Scholar]
  42. 42.  Field B, Fiston-Lavier AS, Kemen A, Geisler K, Quesneville H, Osbourn AE 2011. Formation of plant metabolic gene clusters within dynamic chromosomal regions. PNAS 108:16116–21
     [Google Scholar]
  43. 43.  Field B, Osbourn AE 2008. Metabolic diversification—independent assembly of operon-like gene clusters in different plants. Science 320:543–47
     [Google Scholar]
  44. 44.  Fillinger S, Felenbok B 1996. A newly identified gene cluster in Aspergillus nidulans comprises five novel genes localized in the alc region that are controlled both by the specific transactivator AlcR and the general carbon-catabolite repressor CreA. Mol. Microbiol. 20:475–88
     [Google Scholar]
  45. 45.  Flipphi M, Sun J, Robellet X, Karaffa L, Fekete E et al. 2009. Biodiversity and evolution of primary carbon metabolism in Aspergillus nidulans and other Aspergillus spp. Fungal Genet. Biol. 46:Suppl. 1S19–44
     [Google Scholar]
  46. 46.  Frey M, Chomet P, Glawischnig E, Stettner C, Grun S et al. 1997. Analysis of a chemical plant defense mechanism in grasses. Science 277:696–99
     [Google Scholar]
  47. 47.  Gacek A, Strauss J 2012. The chromatin code of fungal secondary metabolite gene clusters. Appl. Microbiol. Biotechnol. 95:1389–404
     [Google Scholar]
  48. 48.  Gallmetzer A, Silvestrini L, Schinko T, Gesslbauer B, Hortschansky P et al. 2015. Reversible oxidation of a conserved methionine in the nuclear export sequence determines subcellular distribution and activity of the fungal nitrate regulator NirA. PLOS Genet 11:e1005297
     [Google Scholar]
  49. 49.  García I, Gonzalez R, Gómez D, Scazzocchio C 2004. Chromatin rearrangements in the prnD-prnB bidirectional promoter: dependence on transcription factors. Eukaryot. Cell 3:144–56
     [Google Scholar]
  50. 50.  Geever RF, Huiet L, Baum JA, Tyler BM, Patel VB et al. 1989. DNA-sequence, organization and regulation of the qa gene-cluster of Neurospora crassa. J. Mol. Biol 207:15–34
     [Google Scholar]
  51. 51.  Gerke J, Bayram O, Feussner K, Landesfeind M, Shelest E et al. 2012. Breaking the silence: protein stabilization uncovers silenced biosynthetic gene clusters in the fungus Aspergillus nidulans. Appl. Environ. Microbiol 78:8234–44
     [Google Scholar]
  52. 52.  Giles NH, Case ME, Partridge CW, Ahmed SI 1967. A gene cluster in Neurospora crassa coding for an aggregate of five aromatic synthetic enzymes. PNAS 58:1453–60
     [Google Scholar]
  53. 53.  Giles NH, Geever RF, Asch DK, Avalos J, Case ME 1991. The Wilhelmine E. Key 1989 invitational lecture. Organization and regulation of the qa (quinic acid) genes in Neurospora crassa and other fungi. J. Hered. 82:1–7
     [Google Scholar]
  54. 54.  Gómez D, Cubero B, Cecchetto G, Scazzocchio C 2002. PrnA, a Zn2Cys6 activator with a unique DNA recognition mode, requires inducer for in vivo binding. Mol. Microbiol. 44:585–97
     [Google Scholar]
  55. 55.  Grigoriev IV, Nikitin R, Haridas S, Kuo A, Ohm R et al. 2014. MycoCosm portal: gearing up for 1000 fungal genomes. Nucleic Acids Res 42:D699–704
     [Google Scholar]
  56. 56.  Gross J, Cho WK, Lezhneva L, Falk J, Krupinska K et al. 2006. A plant locus essential for phylloquinone (vitamin K-1) biosynthesis originated from a fusion of four eubacterial genes. J. Biol. Chem. 281:17189–96
     [Google Scholar]
  57. 57.  Gutierrez S, Velasco J, Fernandez FJ, Martin JF 1992. The cefG gene of Cephalosporium acremonium is linked to the cefEF gene and encodes a deacetylcephalosporin C acetyltransferase closely related to homoserine O-acetyltransferase. J. Bacteriol. 174:3056–64
     [Google Scholar]
  58. 58.  Hall C, Dietrich FS 2007. The reacquisition of biotin prototrophy in Saccharomyces cerevisiae involved horizontal gene transfer, gene duplication and gene clustering. Genetics 177:2293–307
     [Google Scholar]
  59. 59.  Hawkins AR, Moore JD, Lamb HK 1993. The molecular biology of the pentafunctional AROM protein. Biochem. Soc. Trans. 21:181–86
     [Google Scholar]
  60. 60.  Hen-Avivi S, Savin O, Racovita RC, Lee WS, Adamski NM et al. 2016. A metabolic gene cluster in the wheat W1 and the barley Cer-cqu loci determines β-diketone biosynthesis and glaucousness. Plant Cell 28:1440–60
     [Google Scholar]
  61. 61.  Henke MT, Soukup AA, Goering AW, McClure RA, Thomson RJ et al. 2016. New aspercryptins, lipopeptide natural products, revealed by HDAC inhibition in Aspergillus nidulans. ACS Chem. Biol 11:2117–23
     [Google Scholar]
  62. 62.  Houseley J, Rubbi L, Grunstein M, Tollervey D, Vogelauer M 2008. A ncRNA modulates histone modification and mRNA induction in the yeast GAL gene cluster. Mol. Cell 32:685–95
     [Google Scholar]
  63. 63.  Huang ACC, Kautsar SA, Hong YJ, Medema MH, Bond AD et al. 2017. Unearthing a sesterterpene biosynthetic repertoire in the Brassicaceae through genome mining reveals convergent evolution. PNAS 114:E6005–14
     [Google Scholar]
  64. 64.  Hull EP, Green PM, Arst HN Jr, Scazzocchio C 1989. Cloning and physical characterization of the L-proline catabolism gene cluster of Aspergillus nidulans. Mol. Microbiol 3:553–59
     [Google Scholar]
  65. 65.  Hurst LD, Pál C, Lercher MJ 2004. The evolutionary dynamics of eukaryotic gene order. Nat. Rev. Genet. 5:299–310
     [Google Scholar]
  66. 66.  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
     [Google Scholar]
  67. 67.  Itkin M, Heinig U, Tzfadia O, Bhide AJ, Shinde B et al. 2013. Biosynthesis of antinutritional alkaloids in solanaceous crops is mediated by clustered genes. Science 341:175–79
     [Google Scholar]
  68. 68.  Itkin M, Rogachev I, Alkan N, Rosenberg T, Malitsky S et al. 2011. GLYCOALKALOID METABOLISM1 is required for steroidal alkaloid glycosylation and prevention of phytotoxicity in tomato. Plant Cell 23:4507–25
     [Google Scholar]
  69. 69.  Jacob F, Monod J 1961. Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3:318–56
     [Google Scholar]
  70. 70.  Jacob F, Perrin D, Sanchez C, Monod J 1960. [The operon: a group of genes with the expression coordinated by an operator]. C. R. Hebd. Seances Acad. Sci. 250:1727–29 (In French)
    [Google Scholar]
  71. 71.  Johnstone IL, McCabe PC, Greaves P, Gurr SJ, Cole GE et al. 1990. Isolation and characterisation of the crnA-niiA-niaD gene cluster for nitrate assimilation in Aspergillus nidulans. Gene 90:181–92
     [Google Scholar]
  72. 72.  Jones SA, Arst HN Jr, Macdonald DW 1981. Gene roles in the prn cluster of Aspergillus nidulans. Curr. Genet 3:49–56
     [Google Scholar]
  73. 73.  Kappel L, Gaderer R, Flipphi M, Seidl-Seiboth V 2016. The N-acetylglucosamine catabolic gene cluster in Trichoderma reesei is controlled by the Ndt80-like transcription factor RON1. Mol. Microbiol. 99:640–57
     [Google Scholar]
  74. 74.  Kautsar SA, Suarez Duran HG, Blin K, Osbourn A, Medema MH 2017. plantiSMASH: automated identification, annotation and expression analysis of plant biosynthetic gene clusters. Nucleic Acids Res 45:W55–63
     [Google Scholar]
  75. 75.  Keller NP 2015. Translating biosynthetic gene clusters into fungal armor and weaponry. Nat. Chem. Biol. 11:671–77
     [Google Scholar]
  76. 76.  Keller NP, Turner G, Bennett JW 2005. Fungal secondary metabolism—from biochemistry to genomics. Nat. Rev. Microbiol. 3:937–47
     [Google Scholar]
  77. 77.  Kemen AC, Honkanen S, Melton RE, Findlay KC, Mugford ST et al. 2014. Investigation of triterpene synthesis and regulation in oats reveals a role for β-amyrin in determining root epidermal cell patterning. PNAS 111:8679–84
     [Google Scholar]
  78. 78.  Kempner ES, Cole KW, Gaertner FH 1982. The functional unit of the arom conjugate in Neurospora. J. Biol. Chem 257:8919–21
     [Google Scholar]
  79. 79.  Khaldi N, Collemare J, Lebrun MH, Wolfe KH 2008. Evidence for horizontal transfer of a secondary metabolite gene cluster between fungi. Genome Biol 9:R18
     [Google Scholar]
  80. 80.  Kimura N, Tsuge T 1993. Gene cluster involved in melanin biosynthesis of the filamentous fungus Alternaria alternata. J. Bacteriol 175:4427–35
     [Google Scholar]
  81. 81.  Koch BM, Sibbesen O, Halkier BA, Svendsen I, Moller BL 1995. The primary sequence of cytochrome P450tyr, the multifunctional N-hydroxylase catalyzing the conversion of L-tyrosine to p-hydroxyphenylacetaldehyde oxime in the biosynthesis of the cyanogenic glucoside dhurrin in Sorghum bicolor (L.) Moench. Arch. Biochem. Biophys. 323:177–86
     [Google Scholar]
  82. 82.  Krapp A 2015. Plant nitrogen assimilation and its regulation: a complex puzzle with missing pieces. Curr. Opin. Plant Biol. 25:115–22
     [Google Scholar]
  83. 83.  Krattinger SG, Lagudah ES, Spielmeyer W, Singh RP, Huerta-Espino J et al. 2009. A putative ABC transporter confers durable resistance to multiple fungal pathogens in wheat. Science 323:1360–63
     [Google Scholar]
  84. 84.  Kumar D, Barad S, Chen Y, Luo XY, Tannous J et al. 2017. LaeA regulation of secondary metabolism modulates virulence in Penicillium expansum and is mediated by sucrose. Mol. Plant Pathol. 18:1150–63
     [Google Scholar]
  85. 85.  Landolfo S, Ianiri G, Camiolo S, Porceddu A, Mulas G et al. 2018. CAR gene cluster and transcript levels of carotenogenic genes in Rhodotorula mucilaginosa. Microbiology 164:78–87
     [Google Scholar]
  86. 86.  Larimer FW, Morse CC, Beck AK, Cole KW, Gaertner FH 1983. Isolation of the ARO1 cluster gene of Saccharomyces cerevisiae. Mol. Cell. Biol 3:1609–14
     [Google Scholar]
  87. 87.  Lasko PF, Brandriss MC 1981. Proline transport in Saccharomyces cerevisiae. J. Bacteriol 148:241–47
     [Google Scholar]
  88. 88.  Lee IR, Lui EY, Chow EW, Arras SD, Morrow CA, Fraser JA 2013. Reactive oxygen species homeostasis and virulence of the fungal pathogen Cryptococcus neoformans requires an intact proline catabolism pathway. Genetics 194:421–33
     [Google Scholar]
  89. 89.  Lee JM, Sonnhammer ELL 2003. Genomic gene clustering analysis of pathways in eukaryotes. Genome Res 13:875–82
     [Google Scholar]
  90. 90.  Li J, Cocker JM, Wright J, Webster MA, McMullan M et al. 2016. Genetic architecture and evolution of the S locus supergene in Primula vulgaris. Nat. Plants 2:16188
     [Google Scholar]
  91. 91.  Lind AL, Wisecaver JH, Lameiras C, Wiemann P, Palmer JM et al. 2017. Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species. PLOS Biol 15:e2003583
     [Google Scholar]
  92. 92.  Lind AL, Wisecaver JH, Smith TD, Feng X, Calvo AM, Rokas A 2015. Examining the evolution of the regulatory circuit controlling secondary metabolism and development in the fungal genus Aspergillus. PLOS Genet 11:e1005096
     [Google Scholar]
  93. 93.  Liras P, Martin JF 2006. Gene clusters for beta-lactam antibiotics and control of their expression: Why have clusters evolved, and from where did they originate?. Int. Microbiol. 9:9–19
     [Google Scholar]
  94. 94.  Lo HC, Entwistle R, Guo CJ, Ahuja M, Szewczyk E et al. 2012. Two separate gene clusters encode the biosynthetic pathway for the meroterpenoids austinol and dehydroaustinol in Aspergillus nidulans. J. Am. Chem. Soc 134:4709–20
     [Google Scholar]
  95. 95.  Lohr D, Venkov P, Zlatanova J 1995. Transcriptional regulation in the yeast GAL gene family: a complex genetic network. FASEB J 9:777–87
     [Google Scholar]
  96. 96.  Luthra R, Kerr SC, Harreman MT, Apponi LH, Fasken MB et al. 2007. Actively transcribed GAL genes can be physically linked to the nuclear pore by the SAGA chromatin modifying complex. J. Biol. Chem. 282:3042–49
     [Google Scholar]
  97. 97.  Lynch M 2007. The Origins of Genome Architecture Sunderland, MA: Sinauer
  98. 98.  Magliano P, Flipphi M, Sanglard D, Poirier Y 2011. Characterization of the Aspergillus nidulans biotin biosynthetic gene cluster and use of the bioDA gene as a new transformation marker. Fungal Genet. Biol. 48:208–15
     [Google Scholar]
  99. 99.  Marsian J, Lomonossoff GP 2016. Molecular pharming—VLPs made in plants. Curr. Opin. Biotechnol. 37:201–6
     [Google Scholar]
  100. 100.  Marzluf GA 1981. Regulation of nitrogen metabolism and gene expression in fungi. Microbiol. Rev. 45:437–61
     [Google Scholar]
  101. 101.  McDonagh A, Fedorova ND, Crabtree J, Yu Y, Kim S et al. 2008. Sub-telomere directed gene expression during initiation of invasive aspergillosis. PLOS Pathog 4:e1000154
     [Google Scholar]
  102. 102.  McGary KL, Slot JC, Rokas A 2013. Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds. PNAS 110:11481–86
     [Google Scholar]
  103. 103.  Medema MH, Blin K, Cimermancic P, de Jager V, Zakrzewski P et al. 2011. antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res 39:W339–46
     [Google Scholar]
  104. 104.  Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB et al. 2015. Minimum information about a biosynthetic gene cluster. Nat. Chem. Biol. 11:625–31
     [Google Scholar]
  105. 105.  Medema MH, Osbourn A 2016. Computational genomic identification and functional reconstitution of plant natural product biosynthetic pathways. Nat. Prod. Rep. 33:951–62
     [Google Scholar]
  106. 106.  Meneghini MD, Wu M, Madhani HD 2003. Conserved histone variant H2A.Z protects euchromatin from the ectopic spread of silent heterochromatin. Cell 112:725–36
     [Google Scholar]
  107. 107.  Miyamoto K, Matsumoto T, Okada A, Komiyama K, Chujo T et al. 2014. Identification of target genes of the bZIP transcription factor OsTGAP1, whose overexpression causes elicitor-induced hyperaccumulation of diterpenoid phytoalexins in rice cells. PLOS ONE 9:e105823
     [Google Scholar]
  108. 108.  Mugford ST, Louveau T, Melton R, Qi X, Bakht S et al. 2013. Modularity of plant metabolic gene clusters: a trio of linked genes that are collectively required for acylation of triterpenes in oat. Plant Cell 25:1078–92
     [Google Scholar]
  109. 109.  Mullaney EJ, Hamer JE, Roberti KA, Yelton MM, Timberlake WE 1985. Primary structure of the trpC gene from Aspergillus nidulans. Mol. Gen. Genet 199:37–45
     [Google Scholar]
  110. 110.  Muralla R, Chen E, Sweeney C, Gray JA, Dickerman A et al. 2008. A bifunctional locus (BIO3-BIO1) required for biotin biosynthesis in Arabidopsis. Plant Physiol 146:60–73
     [Google Scholar]
  111. 111.  Muro-Pastor AM, Maloy S 1995. Proline dehydrogenase activity of the transcriptional repressor PutA is required for induction of the put operon by proline. J. Biol. Chem. 270:9819–27
     [Google Scholar]
  112. 112.  Muro-Pastor MI, Gonzalez R, Strauss J, Narendja F, Scazzocchio C 1999. The GATA factor AreA is essential for chromatin remodelling in a eukaryotic bidirectional promoter. EMBO J 18:1584–97
     [Google Scholar]
  113. 113.  Nehlin JO, Carlberg M, Ronne H 1991. Control of yeast GAL genes by MIG1 repressor: a transcriptional cascade in the glucose response. EMBO J 10:3373–77
     [Google Scholar]
  114. 114.  Noordermeer D, de Laat W 2008. Joining the loops: β-globin gene regulation. IUBMB Life 60:824–33
     [Google Scholar]
  115. 115.  Nützmann HW, Fischer J, Scherlach K, Hertweck C, Brakhage AA 2013. Distinct amino acids of histone H3 control secondary metabolism in Aspergillus nidulans. Appl. Environ. Microbiol 79:6102–9
     [Google Scholar]
  116. 116.  Nützmann HW, Huang A, Osbourn A 2016. Plant metabolic clusters—from genetics to genomics. New Phytol 211:771–89
     [Google Scholar]
  117. 117.  Nützmann HW, Osbourn A 2015. Regulation of metabolic gene clusters in Arabidopsis thaliana. New Phytol 205:503–10
     [Google Scholar]
  118. 118.  Nützmann HW, Reyes-Dominguez Y, Scherlach K, Schroeckh V, Horn F et al. 2011. Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation. PNAS 108:14282–87
     [Google Scholar]
  119. 119.  Okada A, Okada K, Miyamoto K, Koga J, Shibuya N et al. 2009. OsTGAP1, a bZIP transcription factor, coordinately regulates the inductive production of diterpenoid phytoalexins in rice. J. Biol. Chem. 284:26510–18
     [Google Scholar]
  120. 120.  Owen C, Patron NJ, Huang A, Osbourn A 2017. Harnessing plant metabolic diversity. Curr. Opin. Chem. Biol. 40:24–30
     [Google Scholar]
  121. 121.  Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K et al. 2013. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496:528–32
     [Google Scholar]
  122. 122.  Palmer JM, Bok JW, Lee S, Dagenais TRT, Andes DR 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:e4
     [Google Scholar]
  123. 123.  Palmer JM, Keller NP 2010. Secondary metabolism in fungi: Does chromosomal location matter?. Curr. Opin. Microbiol. 13:431–36
     [Google Scholar]
  124. 124.  Penalva MA 2001. A fungal perspective on human inborn errors of metabolism: alkaptonuria and beyond. Fungal Genet. Biol. 34:1–10
     [Google Scholar]
  125. 125.  Qi X, Bakht S, Leggett M, Maxwell C, Melton R, Osbourn A 2004. A gene cluster for secondary metabolism in oat: implications for the evolution of metabolic diversity in plants. PNAS 101:8233–38
     [Google Scholar]
  126. 126.  Qi X, Bakht S, Qin B, Leggett M, Hemmings A et al. 2006. A different function for a member of an ancient and highly conserved cytochrome P450 family: from essential sterols to plant defense. PNAS 103:18848–53
     [Google Scholar]
  127. 127.  Qin B, Matsuda Y, Mori T, Okada M, Quan ZY et al. 2016. An unusual chimeric diterpene synthase from Emericella variecolor and its functional conversion into a sesterterpene synthase by domain swapping. Angew. Chem. Int. Ed. 55:1658–61
     [Google Scholar]
  128. 128.  Ragoczy T, Bender MA, Telling A, Byron R, Groudine M 2006. The locus control region is required for association of the murine β-globin locus with engaged transcription factories during erythroid maturation. Genes Dev 20:1447–57
     [Google Scholar]
  129. 129.  Reed J, Osbourn A 2018. Engineering terpenoid production through transient expression in Nicotiana benthamiana. Plant Cell Rep https://doi.org/10.1007/s00299-018-2296-3
    [Crossref]
  130. 130.  Reed J, Stephenson MJ, Miettinen K, Brouwer B, Leveau A et al. 2017. A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules. Metab. Eng. 42:185–93
     [Google Scholar]
  131. 131.  Reynolds HT, Slot JC, Divon HH, Lysøe E, Proctor RH, Brown DW 2017. Differential retention of gene functions in a secondary metabolite cluster. Mol. Biol. Evol. 34:2002–15
     [Google Scholar]
  132. 132.  Riley R, Haridas S, Wolfe KH, Lopes MR, Hittinger CT et al. 2016. Comparative genomics of biotechnologically important yeasts. PNAS 113:9882–87
     [Google Scholar]
  133. 133.  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. Mol. Microbiol. 66:713–26
     [Google Scholar]
  134. 134.  Sanz-Luque E, Chamizo-Ampudia A, Llamas A, Galvan A, Fernandez E 2015. Understanding nitrate assimilation and its regulation in microalgae. Front. Plant Sci. 6:899
     [Google Scholar]
  135. 135.  Scazzocchio C 1994. The proline utilisation pathway, history and beyond. Prog. Ind. Microbiol. 29:259–77
     [Google Scholar]
  136. 136.  Scazzocchio C 2014. Fungal biology in the post-genomic era. Fungal Biol. Biotechnol. 1:7
     [Google Scholar]
  137. 137.  Schlapfer P, Zhang P, Wang C, Kim T, Banf M et al. 2017. Genome-wide prediction of metabolic enzymes, pathways, and gene clusters in plants. Plant Physiol 173:2041–59
     [Google Scholar]
  138. 138.  Schmelz EA, Huffaker A, Sims JW, Christensen SA, Lu X et al. 2014. Biosynthesis, elicitation and roles of monocot terpenoid phytoalexins. Plant J 79:659–78
     [Google Scholar]
  139. 139.  Schoenfelder S, Sugar R, Dimond A, Javierre BM, Armstrong H et al. 2015. Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome. Nat. Genet. 47:1179–86
     [Google Scholar]
  140. 140.  Schrettl M, Carberry S, Kavanagh K, Haas H, Jones GW et al. 2010. Self-protection against gliotoxin—a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLOS Pathog 6:e1000952
     [Google Scholar]
  141. 141.  Schroeckh V, Scherlach K, Nützmann HW, Shelest E, Schmidt-Heck W et al. 2009. Intimate bacterial-fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. PNAS 106:14558–63
     [Google Scholar]
  142. 142.  Schumacher J, Simon A, Cohrs KC, Traeger S, Porquier A et al. 2015. The VELVET complex in the gray mold fungus Botrytis cinerea: impact of BcLAE1 on differentiation, secondary metabolism, and virulence. Mol. Plant Microbe 28:659–74
     [Google Scholar]
  143. 143.  Seiboth B, Karaffa L, Sandor E, Kubicek CP 2002. The Hypocrea jecorina gal10 (uridine 5′-diphosphate-glucose 4-epimerase-encoding) gene differs from yeast homologues in structure, genomic organization and expression. Gene 295:143–49
     [Google Scholar]
  144. 144.  Sellick CA, Campbell RN, Reece RJ 2008. Galactose metabolism in yeast—structure and regulation of the Leloir pathway enzymes and the genes encoding them. Int. Rev. Cell Mol. Biol. 269:111–50
     [Google Scholar]
  145. 145.  Shaaban M, Palmer JM, El-Naggar WA, El-Sokkary MA, Habib e-S, Keller NP 2010. Involvement of transposon-like elements in penicillin gene cluster regulation. Fungal Genet. Biol. 47:423–32
     [Google Scholar]
  146. 146.  Shang Y, Ma Y, Zhou Y, Zhang H, Duan L et al. 2014. Biosynthesis, regulation, and domestication of bitterness in cucumber. Science 346:1084–88
     [Google Scholar]
  147. 147.  Shao J, Chen QW, Lv HJ, He J, Liu ZF et al. 2017. (+)-Thalianatriene and (−)-retigeranin B catalyzed by sesterterpene synthases from Arabidopsis thaliana. Org. Lett 19:1816–19
     [Google Scholar]
  148. 148.  Silvestrini L, Rossi B, Gallmetzer A, Mathieu M, Scazzocchio C et al. 2015. Interaction of Yna1 and Yna2 is required for nuclear accumulation and transcriptional activation of the nitrate assimilation pathway in the yeast Hansenula polymorpha. PLOS ONE 10:e0135416
     [Google Scholar]
  149. 149.  Simonis M, Klous P, Splinter E, Moshkin Y, Willemsen R et al. 2006. Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nat. Genet. 38:1348–54
     [Google Scholar]
  150. 150.  Sims JW, Fillmore JP, Warner DD, Schmidt EW 2005. Equisetin biosynthesis in Fusarium heterosporum. Chem. Commun 2005:186–88
     [Google Scholar]
  151. 151.  Siverio JM 2002. Assimilation of nitrate by yeasts. FEMS Microbiol. Rev. 26:277–84
     [Google Scholar]
  152. 152.  Slot JC 2017. Fungal gene cluster diversity and evolution. Adv. Genet. 100:141–78
     [Google Scholar]
  153. 153.  Slot JC, Hibbett DS 2007. Horizontal transfer of a nitrate assimilation gene cluster and ecological transitions in fungi: a phylogenetic study. PLOS ONE 2:e1097
     [Google Scholar]
  154. 154.  Slot JC, Rokas A 2010. Multiple GAL pathway gene clusters evolved independently and by different mechanisms in fungi. PNAS 107:10136–41
     [Google Scholar]
  155. 155.  Slot JC, Rokas A 2011. Horizontal transfer of a large and highly toxic secondary metabolic gene cluster between fungi. Curr. Biol. 21:134–39
     [Google Scholar]
  156. 156.  Smith DJ, Burnham MKR, Bull JH, Hodgson JE, Ward JM et al. 1990. Beta-lactam antibiotic biosynthetic genes have been conserved in clusters in prokaryotes and eukaryotes. EMBO J 9:741–47
     [Google Scholar]
  157. 157.  Smith MW, Feng DF, Doolittle RF 1992. Evolution by acquisition: the case for horizontal gene transfers. Trends Biochem. Sci. 17:489–93
     [Google Scholar]
  158. 158.  Song Z, Cox RJ, Lazarus CM, Simpson TJ 2004. Fusarin C biosynthesis in Fusarium moniliforme and Fusarium venenatum. ChemBioChem 5:1196–203
     [Google Scholar]
  159. 159.  Soukup AA, Chiang YM, Bok JW, Reyes-Dominguez Y, Oakley BR et al. 2012. Overexpression of the Aspergillus nidulans histone 4 acetyltransferase EsaA increases activation of secondary metabolite production. Mol. Microbiol. 86:314–30
     [Google Scholar]
  160. 160.  Spiteller P 2015. Chemical ecology of fungi. Nat. Prod. Rep. 32:971–93
     [Google Scholar]
  161. 161.  Sproul D, Gilbert N, Bickmore WA 2005. The role of chromatin structure in regulating the expression of clustered genes. Nat. Rev. Genet. 6:775–81
     [Google Scholar]
  162. 162.  Streit WR, Entcheva P 2003. Biotin in microbes, the genes involved in its biosynthesis, its biochemical role and perspectives for biotechnological production. Appl. Microbiol. Biotechnol. 61:21–31
     [Google Scholar]
  163. 163.  Studt L, Janevska S, Arndt B, Boedi S, Sulyok M et al. 2016. Lack of the COMPASS component Ccl1 reduces H3K4 trimethylation levels and affects transcription of secondary metabolite genes in two plant-pathogenic Fusarium species. Front. Microbiol. 7:2144
     [Google Scholar]
  164. 164.  Studt L, Rosler SM, Burkhardt I, Arndt B, Freitag M et al. 2016. Knock-down of the methyltransferase Kmt6 relieves H3K27me3 and results in induction of cryptic and otherwise silent secondary metabolite gene clusters in Fusarium fujikuroi. Environ. Microbiol 18:4037–54
     [Google Scholar]
  165. 165.  Takos AM, Knudsen C, Lai D, Kannangara R, Mikkelsen L et al. 2011. Genomic clustering of cyanogenic glucoside biosynthetic genes aids their identification in Lotus japonicus and suggests the repeated evolution of this chemical defence pathway. Plant J 68:273–86
     [Google Scholar]
  166. 166.  Takos AM, Rook F 2012. Why biosynthetic genes for chemical defense compounds cluster. Trends Plant Sci 17:383–88
     [Google Scholar]
  167. 167.  Topfer N, Fuchs LM, Aharoni A 2017. The PhytoClust tool for metabolic gene clusters discovery in plant genomes. Nucleic Acids Res 45:7049–63
     [Google Scholar]
  168. 168.  Trimborn T, Gribnau J, Grosveld F, Fraser P 1999. Mechanisms of developmental control of transcription in the murine α- and β-globin loci. Genes Dev 13:112–24
     [Google Scholar]
  169. 169.  Twyford AD 2018. The road to 10,000 plant genomes. Nat. Plants 4:312–13
     [Google Scholar]
  170. 170.  Valiante V, Mattern DJ, Schüffler A, Horn F, Walther G et al. 2017. Discovery of an extended austinoid biosynthetic pathway in Aspergillus calidoustus. ACS Chem. Biol 12:1227–34
     [Google Scholar]
  171. 171.  van der Merwe GK, van Vuuren HJ, Cooper TG 2001. Cis-acting sites contributing to expression of divergently transcribed DAL1 and DAL4 genes in S. cerevisiae: a word of caution when correlating cis-acting sequences with genome-wide expression analyses. Curr. Genet. 39:156–65
     [Google Scholar]
  172. 172.  Vieux-Rochas M, Fabre PJ, Leleu M, Duboule D, Noordermeer D 2015. Clustering of mammalian Hox genes with other H3K27me3 targets within an active nuclear domain. PNAS 112:4672–77
     [Google Scholar]
  173. 173.  von Rad U, Huttl R, Lottspeich F, Gierl A, Frey M 2001. Two glucosyltransferases are involved in detoxification of benzoxazinoids in maize. Plant J 28:633–42
     [Google Scholar]
  174. 174.  Wang SS, Brandriss MC 1986. Proline utilization in Saccharomyces cerevisiae: analysis of the cloned PUT1 gene. Mol. Cell. Biol. 6:2638–45
     [Google Scholar]
  175. 175.  Wei L, Gu L, Song X, Cui X, Lu Z et al. 2014. Dicer-like 3 produces transposable element-associated 24-nt siRNAs that control agricultural traits in rice. PNAS 111:3877–82
     [Google Scholar]
  176. 176.  Wiemann P, Guo CJ, Palmer JM, Sekonyela R, Wang CC, Keller NP 2013. Prototype of an intertwined secondary-metabolite supercluster. PNAS 110:17065–70
     [Google Scholar]
  177. 177.  Wijgerde M, Grosveld F, Fraser P 1995. Transcription complex stability and chromatin dynamics in vivo. Nature 377:209–13
     [Google Scholar]
  178. 178.  Wilderman PR, Xu MM, Jin YH, Coates RM, Peters RJ 2004. Identification of syn-pimara-7,15-diene synthase reveals functional clustering of terpene synthases involved in rice phytoalexin/allelochemical biosynthesis. Plant Physiol 135:2098–105
     [Google Scholar]
  179. 179.  Winzer T, Gazda V, He Z, Kaminski F, Kern M et al. 2012. A Papaver somniferum 10-gene cluster for synthesis of the anticancer alkaloid noscapine. Science 336:1704–8
     [Google Scholar]
  180. 180.  Winzer T, Kern M, King AJ, Larson TR, Teodor RI et al. 2015. Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein. Science 349:309–12
     [Google Scholar]
  181. 181.  Wisecaver JH, Slot JC, Rokas A 2014. The evolution of fungal metabolic pathways. PLOS Genet 10:e1004816
     [Google Scholar]
  182. 182.  Wolfe KH, Armisen D, Proux-Wera E, OhEigeartaigh SS, Azam H et al. 2015. Clade- and species-specific features of genome evolution in the Saccharomycetaceae. FEMS Yeast Res 15:fov035
     [Google Scholar]
  183. 183.  Wong S, Wolfe KH 2005. Birth of a metabolic gene cluster in yeast by adaptive gene relocation. Nat. Genet. 37:777–82
     [Google Scholar]
  184. 184.  Wurtzel ET, Kutchan TM 2016. Plant metabolism, the diverse chemistry set of the future. Science 353:1232–36
     [Google Scholar]
  185. 185.  Yeh HH, Ahuja M, Chiang YM, Oakley CE, Moore S et al. 2016. Resistance gene-guided genome mining: Serial promoter exchanges in Aspergillus nidulans reveal the biosynthetic pathway for fellutamide B, a proteasome inhibitor. ACS Chem. Biol. 11:2275–84
     [Google Scholar]
  186. 186.  Yu J 2012. Current understanding on aflatoxin biosynthesis and future perspective in reducing aflatoxin contamination. Toxins 4:1024–57
     [Google Scholar]
  187. 187.  Yu J, Chang PK, Cary JW, Wright M, Bhatnagar D et al. 1995. Comparative mapping of aflatoxin pathway gene clusters in Aspergillus parasiticus and Aspergillus flavus. Appl. Environ. Microbiol 61:2365–71
     [Google Scholar]
  188. 188.  Yu N, Nützmann HW, MacDonald JT, Moore B, Field B et al. 2016. Delineation of metabolic gene clusters in plant genomes by chromatin signatures. Nucleic Acids Res 44:2255–65
     [Google Scholar]
  189. 189.  Yue Q, Chen L, Li Y, Bills GF, Zhang X et al. 2015. Functional operons in secondary metabolic gene clusters in Glarea lozoyensis (Fungi, Ascomycota, Leotiomycetes). mBio 6:e00703
     [Google Scholar]
  190. 190.  Zheng L, McMullen MD, Bauer E, Schön CC, Gierl A, Frey M 2015. Prolonged expression of the BX1 signature enzyme is associated with a recombination hotspot in the benzoxazinoid gene cluster in Zea mays. J. Exp. Bot 66:3917–30
     [Google Scholar]
  191. 191.  Zhou Y, Ma Y, Zeng J, Duan L, Xue X et al. 2016. Convergence and divergence of bitterness biosynthesis and regulation in Cucurbitaceae. Nat. Plants 2:16183
     [Google Scholar]
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Metabolic Gene Clusters in Eukaryotes
Annual Review of Genetics 52, 159 (2018); https://doi.org/10.1146/annurev-genet-120417-031237
/content/journals/10.1146/annurev-genet-120417-031237
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