Abstract
Filamentous fungi are frequently used as hosts for heterologous production of industrial enzymes and bioactive secondary metabolites. This role will likely increase in the post-genomic era as a multitude of fungal genome sequences are mined for new valuable products. The trend for constructing fungal cell factories is to use synthetic biology approaches. In simplicity, this includes puzzling available bio-blocks together using seamless DNA fusions to generate vectors, gene-expression cassettes, and protein fusions. Moreover, it also sets the stage to expand natural enzymatic functions and chemistry by combining functional domains into synthetic proteins with novel enzymatic properties or by combining enzymes from different organisms in a common host to establish new biosynthetic pathways. In this chapter, we describe the components of a modern synthetic biology toolbox and how they have been used to construct and optimize fungal cell factories for heterologous production of natural and synthetic enzymes and secondary metabolites.
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References
Adav SS, Ravindran A, Chao LT, Tan L, Singh S, Sze SK (2011) Proteomic analysis of pH and strains dependent protein secretion of Trichoderma reesei. J Proteome Res 10:4579–4596
Adeniran A, Sherer M, Tyo KEJ (2015) Yeast-based biosensors: design and applications. FEMS Yeast Res 15:1–15
Adney WS, Chou YC, Decker SR, Ding SY, Baker JO, Kunkel G, Vinzant TB, Himmel ME (2003) Heterologous expression of Trichoderma reesei 1,4-β-D-glucan cellobiohydrolase (Cel 7A). In: Mansfield SD, Saddler JN (eds) Applications of enzymes to lignocellulosics, vol 855. American Chemical Society, Washington, DC, pp 403–437
Adney WS, Jeoh T, Beckham GT, Chou YC, Baker JO, Michener W, Brunecky R, Himmel ME (2009) Probing the role of N-linked glycans in the stability and activity of fungal cellobiohydrolases by mutational analysis. Cellulose 16:699–709
Ahmed SM, Nishida-Fukuda H, Li Y, McDonald WH, Gradinaru CC, Macara IG (2018) Exocyst dynamics during vesicle tethering and fusion. Nat Commun 9:1–17
Alberti A, Ferrero I, Lodi T (2003) LYS2 gene and its mutation in Kluyveromyces lactis. Yeast 20:1171–1175
Aleksenko A, Clutterbuck AJ (1997) Autonomous plasmid replication in Aspergillus nidulans: AMA1 and MATE elements. Fungal Genet Biol 21:373–387
An X, Lu J, Huang J, Zhang B, Liu D, Zhang X, Chen J, Zhou Y, Tong Y (2007) Rapid assembly of multiple-exon cDNA directly from genomic DNA. PLoS One 2:1–7
Andersen MR, Vongsangnak W, Panagiotou G, Salazar MP, Lehmann L, Nielsen J (2008) A trispecies Aspergillus microarray: comparative transcriptomics of three Aspergillus species. Proc Natl Acad Sci USA 105:4387–4392
Andersen MR, Salazar MP, Schaap PJ, Van De Vondervoort PJI, Culley D, Thykaer J, Frisvad JC, Nielsen KF, Albang R, Albermann K, Berka RM, Braus GH, Braus-Stromeyer SA, Corrochano LM, Dai Z, Van Dijck PWM, Hofmann G, Lasure LL, Magnuson JK, Menke H, Meijer M, Meijer SL, Nielsen JB, Nielsen ML, Van Ooyen AJJ, Pel HJ, Poulsen L, Samson RA, Stam H, Tsang A, Van Den Brink JM, Atkins A, Aerts A, Shapiro H, Pangilinan J, Salamov A, Lou Y, Lindquist E, Lucas S, Grimwood J, Grigoriev IV, Kubicek CP, Martinez D, van Peij NNME, Roubos JA, Nielsen J, Baker SE (2011) Comparative genomics of citric-acid-producing Aspergillus niger ATCC 1015 versus enzyme-producing CBS 513.88. Genome Res 21:885–897
Anyaogu DC, Mortensen UH (2015) Manipulating the glycosylation pathway in bacterial and lower eukaryotes for production of therapeutic proteins. Curr Opin Biotechnol 36:122–128
Archer D, Jeenes D, MacKenzie D, Brightwell G, Lambert N, Lowe G, Radford S, Dobson C (1990) Hen egg white lysozyme expressed in, and secreted from, Aspergillus niger is correctly processed and folded. Biotechnology 8:741–745
Austin B, Hail RM, Tyler BM (1990) Optimized vectors and selection for transformation of Neurospora crassa and Aspergillus nidulans to bleomycin and phleomycin. Gene 93:157–162
Avalos J, Geever RF, Case ME (1989) Bialaphos resistance as a dominant selectable marker in Neurospora crassa. Curr Genet 16:369–372
Barlowe C, Miller EA (2013) Secretory protein biogenesis and traffic in the early secretory pathway. Genetics 193:383–410
Barredo JL, Cantoral JM, Alvarez E, Díez B, Martín JF (1989) Cloning, sequence analysis and transcriptional study of the isopenicillin N synthase of Penicillium chrysogenum AS-P-78. Mol Gen Genet 216:91–98
Beck J, Ripka S, Siegner A, Schiltz E, Schweizer E (1990) The multifunctional 6-methylsalicylic acid synthase gene of Penicillium patulum. Its gene structure relative to that of other polyketide synthases. Eur J Biochem 192:487–498
Bentley DL (2014) Coupling mRNA processing with transcription in time and space. Nat Rev Genet 15:163–175
Bergquist PL, Te’o VSJ, Gibbs MD, Curach NC, Nevalainen KMH (2004) Recombinant enzymes from thermophilic micro-organisms expressed in fungal hosts. Biochem Soc Trans 32:293–297
Bitinaite J, Rubino M, Varma KH, Schildkraut I, Vaisvila R, Vaiskunaite R (2007) USER friendly DNA engineering and cloning method by uracil excision. Nucleic Acids Res 35:1992–2002
Bleichrodt RJ, Read ND (2019) Flow cytometry and FACS applied to filamentous fungi. Fungal Biol Rev 33:1–15
Blumhoff M, Steiger MG, Marx H, Mattanovich D, Sauer M (2013) Six novel constitutive promoters for metabolic engineering of Aspergillus niger. Appl Microbiol Biotechnol 97:259–267
Boeke J, Lacroute F, Fink G (1984) A positive selection for mutants lacking orotidine-5′ phosphate decarboxylase activity in yeast: 5-fluoro-orotic acid resistance. Mol Gen Genet 197:346–346
Boel E, Hansen MT, Hjort I, Høegh I, Fiil NP (1984) Two different types of intervening sequences in the glucoamylase gene from Aspergillus niger. Eur Mol Biol Organ 3:1581–1585
Bok JW, Ye R, Clevenger KD, Mead D, Wagner M, Krerowicz A, Albright JC, Goering AW, Thomas PM, Kelleher NL, Keller NP, Wu CC (2015) Fungal artificial chromosomes for mining of the fungal secondary metabolome. BMC Genomics 16:1–10
Breakspear A, Momany M (2007) The first fifty microarray studies in filamentous fungi. Microbiology 153:7–15
Brochado AR, Matos C, Møller BL, Hansen J, Mortensen UH, Patil KR (2010) Improved vanillin production in baker’s yeast through in silico design. Microb Cell Factories 9:1–15
Bulakhov AG, Volkov PV, Rozhkova AM, Gusakov AV, Nemashkalov VA, Satrutdinov AD, Sinitsyn AP (2017) Using an inducible promoter of a gene encoding Penicillium verruculosum glucoamylase for production of enzyme preparations with enhanced cellulase performance. PLoS One 12:1–13
Buxton FP, Gwynne DI, Davies RW (1985) Transformation of Aspergillus niger using the argB gene of Aspergillus nidulans. Gene 37:207–214
Cairns TC, Nai C, Meyer V (2018) How a fungus shapes biotechnology: 100 years of Aspergillus niger research. Fungal Biol Biotechnol 5:1–14
Cairns TC, Zheng X, Zheng P, Sun J, Meyer V (2019) Moulding the mould: understanding and reprogramming filamentous fungal growth and morphogenesis for next generation cell factories. Biotechnol Biofuels 12:1–18
Carrington JC, Dougherty WG (1988) A viral cleavage site cassette: identification of amino acid sequences required for tobacco etch virus polyprotein processing. Biochemistry 85:3391–3395
Carvalho NDSP, Arentshorst M, Kooistra R, Stam H, Sagt CM, Van Den Hondel CAMJJ, Ram AFJ (2011) Effects of a defective ERAD pathway on growth and heterologous protein production in Aspergillus niger. Appl Microbiol Biotechnol 89:357–373
Chaga G, Bochkariov DE, Jokhadze GG, Hopp J, Nelson P (1999) Natural poly-histidine affinity tag for purification of recombinant proteins on cobalt(II)-carboxymethylaspartate crosslinked agarose. J Chromatogr A 864:247–256
Chanda A, Roze LV, Kang S, Artymovich KA, Hicks GR, Raikhel NV, Calvo AM, Linz JE (2009) A key role for vesicles in fungal secondary metabolism. Proc Natl Acad Sci USA 106:19533–19538
Chang KY, Georgianna RD, Heber S, Payne GA, Muddiman DC (2010) Detection of alternative splice variants at the proteome level in Aspergillus flavus. J Proteome Res 9:1209–1217
Chen X, Zaro J, Shen WC (2013) Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev 65:1357–1369
Cheng AW, Wang H, Yang H, Shi L, Katz Y, Theunissen TW, Rangarajan S, Shivalila CS, Dadon DB, Jaenisch R (2013) Multiplexed activation of endogenous genes by CRISPR-on, an RNA-guided transcriptional activator system. Cell Res 23:1163–1171
Cherry JR, Fidantsef AL (2003) Directed evolution of industrial enzymes: an update. Curr Opin Biotechnol 14:438–443
Chiang YM, Szewczyk E, Davidson AD, Keller N, Oakley BR, Wang CCC (2009) A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus nidulans. J Am Chem Soc 131:2965–2970
Chiang Y-M, Oakley CE, Ahuja M, Entwistle R, Schultz A, Chang S-L, Sung CT, Wang CCC, Oakley BR (2013) An efficient system for heterologous expression of secondary metabolite genes in Aspergillus nidulans. J Am Chem Soc 135:7720–7731
Chiang YM, Ahuja M, Oakley CE, Entwistle R, Asokan A, Zutz C, Wang CCC, Oakley BR (2016) Development of genetic dereplication strains in Aspergillus nidulans results in the discovery of aspercryptin. Angew Chem Int Ed 55:1662–1665
Chou YC, Adney WS, Decker SR, Baker JO, Kunkel G, Templeton DW, Himmel ME (2004) Cloning and heterologous expression of the gene encoding a family 7 glycosyl hydrolase from Penicillium funiculosum. In: Saha BC, Hayashi K (eds) Lignocellulose biodegradation, vol 889. American Chemical Society, Washington, DC, pp 170–193
Clevenger KD, Bok JW, Ye R, Miley GP, Verdan MH, Velk T, Chen C, Yang K, Robey MT, Gao P, Lamprecht M, Thomas PM, Islam MN, Palmer JM, Wu CC, Keller NP, Kelleher NL (2017) A scalable platform to identify fungal secondary metabolites and their gene clusters. Nat Chem Biol 13:895–901
Collis CM, Hall RM (1985) Identification of a Tn5 determinant conferring resistance to phleomycins, bleomycins, and tallysomycins. Plasmid 14:143–151
Cullen D, Leong SA, Wilson LJ, Henner DJ (1987) Transformation of Aspergillus nidulans with the hygromycin-resistance gene, hph. Gene 57:21–26
Curran KA, Karim AS, Gupta A, Alper HS (2013) Use of high capacity terminators in Saccharomyces cerevisiae to increase mRNA half-life and improve gene expression control for metabolic engineering applications. Metab Eng 19:88–97
Curran KA, Morse NJ, Markham KA, Wagman AM, Gupta A, Alper HS (2015) Short synthetic terminators for improved heterologous gene expression in yeast. ACS Synth Biol 4:824–832
Czymmek KJ, Bourett TM, Howard RJ (2005) Fluorescent protein probes in fungi. In: Savidge T, Pothulakis C (eds) Microbial imaging, vol 34. Academic, San Diego, pp 27–62
Dave K, Prabha VL, Ahuja M, Dave K, Tejaswini S, Punekar NS (2015) Expanding the repertoire of selectable markers for Aspergillus transformation. In: van den Berg MA, Maruthachalam K (eds) Genetic transformation systems in fungi, vol 1. Springer International Publishing, Cham, pp 141–153
de Graaff L, Visser J (1988) Structure of the Aspergillus nidulans pyruvate kinase gene. Curr Genet 14:553–560
de Vries RP, Grigoriev IV, Tsang A (2018) Introduction: overview of fungal genomics. In: de Vries RP, Tsang A, Grigoriev IV (eds) Fungal genomics. Methods in molecular biology, vol 1775. Humana Press, New York, NY
Deaner M, Alper HS (2017) Systematic testing of enzyme perturbation sensitivities via graded dCas9 modulation in Saccharomyces cerevisiae. Metab Eng 40:14–22
Díez B, Mellado E, Rodríguez M, Bernasconi E, Barredo JL (1999) The NADP-dependent glutamate dehydrogenase gene from Penicillium chrysogenum and the construction of expression vectors for filamentous fungi. Appl Microbiol Biotechnol 52:196–207
dos Santos Castro S, de Paula RG, Antoniêto ACC, Persinoti GF, Silva-Rocha R, Silva RN (2016) Understanding the role of the master regulator XYR1 in Trichoderma reesei by global transcriptional analysis. Front Microbiol 7:1–16
Du D, Roguev A, Gordon DE, Chen M, Chen SH, Shales M, Shen JP, Ideker T, Mali P, Qi LS, Krogan NJ (2017) Genetic interaction mapping in mammalian cells using CRISPR interference. Nat Methods 14:577–583
Eberle J, Russo V (1994) Neurospora crassa blue light-inducible gene bli-3. Biochem Mol Biol Int 34:737–744
Engler C, Marillonnet S (2014) Golden gate cloning. In: Valla S, Lale R (eds) DNA cloning and assembly methods, vol 1116. Springer Science Business Media, New York, pp 119–131
Fiedler MRM, Barthel L, Kubisch C, Nai C, Meyer V (2018) Construction of an improved Aspergillus niger platform for enhanced glucoamylase secretion. Microb Cell Factories 17:1–12
Fierro F, Kosalková K, Gutiérrez S, Martín JF (1996) Autonomously replicating plasmids carrying the AMA1 region in Penicillium chrysogenum. Curr Genet 29:482–489
Finnigan GC, Thorner J (2015) Complex in vivo ligation using homologous recombination and high-efficiency plasmid rescue from Saccharomyces cerevisiae. Bio-protocol 5:1–13
Fisch KM, Skellam E, Ivison D, Cox RJ, Bailey AM, Lazarus CM, Simpson TJ (2010) Catalytic role of the C-terminal domains of a fungal non-reducing polyketide synthase. Chem Commun 46:5331–5333
Fitz E, Wanka F, Seiboth B (2018) The promoter toolbox for recombinant gene expression in Trichoderma reesei. Front Bioeng Biotechnol 6:1–15
Fleissner A, Dersch P (2010) Expression and export: recombinant protein production systems for Aspergillus. Appl Microbiol Biotechnol 87:1255–1270
Ford KL, Baumgartner K, Henricot B, Bailey AM, Foster GD (2016) A native promoter and inclusion of an intron is necessary for efficient expression of GFP or mRFP in Armillaria mellea. Sci Rep 6:1–10
Foster AJ, Martin-Urdiroz M, Yan X, Wright HS, Soanes DM, Talbot NJ (2018) CRISPR-Cas9 ribonucleoprotein-mediated co-editing and counterselection in the rice blast fungus. Sci Rep 8:1–12
Foureau E, Clastre M, Millerioux Y, Simkin AJ, Cornet L, Dutilleul C, Besseau S, Marais E, Melin C, Guillard J, Crèche J, Giglioli-Guivarc’h N, Courdavault V, Papon N (2012) A TRP5/5-fluoroanthranilic acid counter-selection system for gene disruption in Candida guilliermondii. Curr Genet 58:245–254
Frandsen RJ, Khorsand-Jamal P, Kongstad KT, Nafisi M, Kannangara RM, Staerk D, Okkels FT, Binderup K, Madsen B, Lindberg Møller B, Thrane U, Mortensen UH (2018) Heterologous production of the widely used natural food colorant carminic acid in Aspergillus nidulans. Nat Sci Rep 8:1–10
Frohman MA, Dush MK, Martin GR (1988) Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc Natl Acad Sci USA 85:8998–9002
Fujii T, Yamaoka H, Gomi K, Kitamoto K, Kumaga C (1995) Cloning and nucleotide sequence of the ribonuclease T1 gene (rntA) from Aspergillus oryzae and its expression in Saccharomyces cerevisiae and Aspergillus oryzae. Biosci Biotechnol Biochem 59:1869–1874
Fujii I, Ono Y, Tada H, Gomi K, Ebizuka Y, Sankawa U (1996) Cloning of the polyketide synthase gene atX from Aspergillus terreus and its identification as the 6-methylsalicylic acid synthase gene by heterologous expression. Mol Gen Genomics 253:1–10
Fujii I, Yoshida N, Shimomaki S, Oikawa H, Ebizuka Y (2005) An iterative type I polyketide synthase PKSN catalyzes synthesis of the decaketide alternapyrone with regio-specific octa-methylation. Chem Biol 12:1301–1309
Gao F, Hao Z, Sun X, Qin L, Zhao T, Liu W, Luo H, Yao B, Su X (2018) A versatile system for fast screening and isolation of Trichoderma reesei cellulase hyperproducers based on DsRed and fluorescence-assisted cell sorting. Biotechnol Biofuels 11:1–13
Gardiner DM, Jarvis RS, Howlett BJ (2005) The ABC transporter gene in the sirodesmin biosynthetic gene cluster of Leptosphaeria maculans is not essential for sirodesmin production but facilitates self-protection. Fungal Genet Biol 42:257–263
Garneau-Tsodikova S, Labby KJ (2016) Mechanisms of resistance to aminoglycoside antibiotics: overview and perspectives. Medchemcomm 7:11–27
Gems D, Johnstone IL, Clutterbuck AJ (1991) An autonomously replicating plasmid transforms Aspergillus nidulans at high frequency. Gene 98:61–67
Gibson DG, Young L, Chuang RY, Craig Venter J, Hutchison CA III, Smith HO (2009) Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods 6:343–347
Giles NH, Case ME, Baum J, Geever R, Huiet L, Patel V, Tyler B (1985) Gene organization and regulation in the qa (quinic acid) gene cluster of Neurospora crassa. Microbiol Rev 49:338–358
Gomi K, Akeno T, Minetoki T, Ozeki K, Kumagai C, Okazaki N, Iimura Y (2000) Molecular cloning and characterization of a transcriptional activator gene, amyR, involved in the amylolytic gene expression in Aspergillus oryzae. Biosci Biotechnol Biochem 64:816–827
Goosen T, Bloemheuvel G, Gysler C, de Bie DA, van den Broek HWJ, Swart K (1987) Transformation of Aspergillus niger using the homologous orotidine-5′-phosphate-decarboxylase gene. Curr Genet 11:499–503
Goosen T, van Engelenburg F, Debets F, Swart K, Bos K, van den Broek H (1989) Tryptophan auxotrophic mutants in Aspergillus niger: inactivation of the trpC gene by cotransformation mutagenesis. Mol Gen Genet 219:282–288
Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551
Gossen M, Freundlieb S, Bender G, Müller G, Hillen W, Bujardt H (1995) Transcriptional activation by tetracyclines in mammalian cells. Science 268:1766–1769
Gouka RJ, Punt PJ, Van Den Hondel CAMJJ (1997) Glucoamylase gene fusions alleviate limitations for protein production in Aspergillus awamori at the transcriptional and (post)translational levels. Appl Environ Microbiol 63:488–497
Gould N, Hendy O, Papamichail D (2014) Computational tools and algorithms for designing customized synthetic genes. Front Bioeng Biotechnol 2:1–14
Gressler M, Hortschansky P, Geib E, Brock M (2015) A new high-performance heterologous fungal expression system based on regulatory elements from the Aspergillus terreus terrein gene cluster. Front Microbiol 6:1–16
Grigoriev IV, Nikitin R, Haridas S, Kuo A, Ohm R, Otillar R, Riley R, Salamov A, Zhao X, Korzeniewski F, Smirnova T, Nordberg H, Dubchak I, Shabalov I (2014) MycoCosm portal: gearing up for 1000 fungal genomes. Nucleic Acids Res 42:D699–D704
Gupta SK, Shukla P (2018) Glycosylation control technologies for recombinant therapeutic proteins. Appl Microbiol Biotechnol 102:10457–10468
Haas H, Redl B, Friedlin E, Stöffler G (1992) Isolation and analysis of the Penicillium chrysogenum phoA gene encoding a secreted phosphate-repressible acid phosphatase. Gene 113:129–133
Halo LM, Marshall JW, Yakasai AA, Song Z, Butts CP, Crump MP, Heneghan M, Bailey AM, Simpson TJ, Lazarus CM, Cox RJ (2008) Authentic heterologous expression of the tenellin iterative polyketide synthase nonribosomal peptide synthetase requires coexpression with an enoyl reductase. Chembiochem 9:585–594
Hansen BG, Genee HJ, Kaas CS, Nielsen JB, Regueira TB, Mortensen UH, Frisvad JC, Patil KR (2011a) A new class of IMP dehydrogenase with a role in self-resistance of mycophenolic acid producing fungi. BMC Microbiol 11:1–7
Hansen BG, Salomonsen B, Nielsen MT, Nielsen JB, Hansen NB, Nielsen KF, Regueira TB, Nielsen J, Patil KR, Mortensen UH (2011b) Versatile enzyme expression and characterization system for Aspergillus nidulans, with the Penicillium brevicompactum polyketide synthase gene from the mycophenolic acid gene cluster as a test case. Appl Environ Microbiol 77:3044–3051
Hanson G, Coller J (2018) Codon optimality, bias and usage in translation and mRNA decay. Nat Rev Mol Cell Biol 19:20–30
He Y, Cox RJ (2016) The molecular steps of citrinin biosynthesis in fungi. Chem Sci 7:2119–2127
Herr A, Fischer R (2014) Improvement of Aspergillus nidulans penicillin production by targeting AcvA to peroxisomes. Metab Eng 25:131–139
Hess GT, Frésard L, Han K, Lee CH, Li A, Cimprich KA, Montgomery SB, Bassik MC (2016) Directed evolution using dCas9-targeted somatic hypermutation in mammalian cells. Nat Methods 13:1036–1042
Hoang HD, Maruyama JI, Kitamoto K (2015) Modulating endoplasmic reticulum-Golgi cargo receptors for improving secretion of carrier-fused heterologous proteins in the filamentous fungus Aspergillus oryzae. Appl Environ Microbiol 81:533–543
Hoefgen S, Lin J, Fricke J, Stroe MC, Mattern DJ, Kufs JE, Hortschansky P, Brakhage AA, Hoffmeister D, Valiante V (2018) Facile assembly and fluorescence-based screening method for heterologous expression of biosynthetic pathways in fungi. Metab Eng 48:44–51
Holm DMK (2013) Development and implementation of novel genetic tools for investigation of fungal secondary metabolism. PhD thesis, Technical University of Denmark
Holm DK, Petersen LM, Klitgaard A, Knudsen PB, Jarczynska ZD, Nielsen KF, Gotfredsen CH, Larsen TO, Mortensen UH (2014) Molecular and chemical characterization of the biosynthesis of the 6-MSA-derived meroterpenoid yanuthone D in Aspergillus niger. Chem Biol 21:519–529
Hoover DM, Lubkowski J (2002) DNAWorks: an automated method for designing oligonucleotides for PCR-based gene synthesis. Nucleic Acids Res 30:1–7
Hopp TP, Prickett KS, Price VL, Libby RT, March CJ, Cerretti DP, Urdal DL, Conlon PJ (1988) A short polypeptide marker sequence useful for recombinant protein identification and purification. Bio/Technology 6:1204–1210
Hoshida H, Fujita T, Murata K, Kubo K, Akada R (2005) Copper-dependent production of a Pycnoporus coccineus extracellular laccase in Aspergillus oryzae and Saccharomyces cerevisiae. Biosci Biotechnol Biochem 69:1090–1097
Hoskins I, Roberts C (1994) Expression of the 3-phosphoglycerate kinase gene (pgkA) of Penicillium chrysogenum. Mol Gen Genet 243:270–276
Hurley JM, Chen CH, Loros JJ, Dunlap JC (2012) Light-inducible system for tunable protein expression in Neurospora crassa. G3 2:1207–1212
Hynes MJ, Pateman JAJ (1970) The genetic analysis of regulation of amidase synthesis in Aspergillus nidulans. Mol Gen Genet 108:107–116
Ilmén M, Onnela ML, Klemsdal S, Keränen S, Penttilä M (1998) Functional analysis of the cellobiohydrolase I promoter of the filamentous fungus Trichoderma reesei. Mol Gen Genet 253:303–314
Iriarte A, Sanguinetti M, Fernández-Calero T, Naya H, Ramón A, Musto H (2012) Translational selection on codon usage in the genus Aspergillus. Gene 506:98–105
Ishida H, Hata Y, Kawato A, Abe Y, Kashiwagi Y (2004) Isolation of a novel promoter for efficient protein production in Aspergillus oryzae. Biosci Biotechnol Biochem 68:1849–1857
Ishii N, Minami N, Chen EY, Medina AL, Chico MM, Kasamatsu H (1996) Analysis of a nuclear localization signal of simian virus 40 major capsid protein Vp1. J Virol 70:1317–1322
Jackson DC, Tang XL, Brown LE, Murray JM, White DO, Tregear GW (1986) Antigenic determinants of influenza virus hemagglutinin XII. Virology 155:625–632
Jalving R, Van De Vondervoort PJI, Visser J, Schaap PJ (2000) Characterization of the kexin-like maturase of Aspergillus niger. Appl Environ Microbiol 66:363–368
Jensen ED, Ferreira R, Jakočiunas T, Arsovska D, Zhang J, Ding L, Smith JD, David F, Nielsen J, Jensen MK, Keasling JD (2017) Transcriptional reprogramming in yeast using dCas9 and combinatorial gRNA strategies. Microb Cell Factories 16:1–16
Jin FJ, Maruyama J, Juvvadi PR, Arioka M, Kitamoto K (2004) Adenine auxotrophic mutants of Aspergillus oryzae: development of a novel transformation system with triple auxotrophic hosts. Biosci Biotechnol Biochem 68:656–662
Jin FJ, Watanabe T, Juvvadi PR, Maruyama JI, Arioka M, Kitamoto K (2007) Double disruption of the proteinase genes, tppA and pepE, increases the production level of human lysozyme by Aspergillus oryzae. Appl Microbiol Biotechnol 76:1059–1068
Johnstone IL, Hughes SG, Clutterbuck AJ (1985) Cloning an Aspergillus nidulans developmental gene by transformation. EMBO J 4:1307–1311
Jørgensen TR, Park J, Arentshorst M, van Welzen AM, Lamers G, VanKuyk PA, Damveld RA, van den Hondel CAM, Nielsen KF, Frisvad JC, Ram AFJ (2011) The molecular and genetic basis of conidial pigmentation in Aspergillus niger. Fungal Genet Biol 48:544–553
Kamaruddin N, Storms R, Mahadi NM, Illias RM, Bakar FDA, Murad AMA (2018) Reduction of extracellular proteases increased activity and stability of heterologous protein in Aspergillus niger. Arab J Sci Eng 43:3327–3338
Keller NP (2019) Fungal secondary metabolism: regulation, function and drug discovery. Nat Rev Microbiol 17:167–180
Keller NP, Turner G, Bennett JW (2005) Fungal secondary metabolism—from biochemistry to genomics. Nat Rev Microbiol 3:937–947
Kelly JM, Hynes MJ (1985) Transformation of Aspergillus niger by the amdS gene of Aspergillus nidulans. EMBO J 4:475–479
Kempken F (2013) Alternative splicing in ascomycetes. Appl Microbiol Biotechnol 97:4235–4241
Kempken F, Windhofer F (2004) Alternative splicing of transcripts of the transposon Restless is maintained in the foreign host Neurospora crassa and can be modified by introducing mutations at the 5′ and 3′ splice sites. Curr Genet 46:59–65
Kipriyanov SM, Kupriyanova OA, Little M, Moldenhauer G (1996) Rapid detection of recombinant antibody fragments directed against cell-surface antigens by flow cytometry. J Immunol Methods 196:51–62
Kistler HC, Broz K (2015) Cellular compartmentalization of secondary metabolism. Front Microbiol 6:68
Kitamoto N, Matsui J, Kawai Y, Kato A, Yoshino S, Ohmiya K, Tsukagoshi N (1998) Utilization of the TEF1-α gene (TEF1) promoter for expression of polygalacturonase genes, pgaA and pgaB, in Aspergillus oryzae. Appl Microbiol Biotechnol 50:85–92
Kitamoto N, Ono N, Yoshino Yasuda S (2015) Construction of quintuple protease and double amylase gene deletant for heterologous protein production in Aspergillus oryzae KBN616. Food Sci Technol Res 21:297–307
Kluge J, Terfehr D, Kück U (2018) Inducible promoters and functional genomic approaches for the genetic engineering of filamentous fungi. Appl Microbiol Biotechnol 102:6357–6372
Knudsen PB (2015) Development of scalable high throughput fermentation approaches for physiological characterisation of yeast and filamentous fungi. PhD thesis, Technical University of Denmark (DTU)
Krappmann S (2007) Gene targeting in filamentous fungi: the benefits of impaired repair. Fungal Biol Rev 21:25–29
Krishnan K, Askew DS (2014) The fungal UPR: a regulatory hub for virulence traits in the mold pathogen Aspergillus fumigatus. Virulence 5:334–340
Krügel H, Fiedler G, Smith C, Baumberg S (1993) Sequence and transcriptional analysis of the nourseothricin acetyltransferase-encoding gene nat1 from Streptomyces noursei. Gene 127:127–131
Kubodera T, Yamashita N, Nishimura A (2002) Transformation of Aspergillus sp. and Trichoderma reesei using the pyrithiamine resistance gene (ptrA) of Aspergillus oryzae. Biosci Biotechnol Biochem 66:404–406
Kupfer DM, Drabenstot SD, Buchanan KL, Hongshing L, Zhu H, Dyer DW, Roe BA, Murphy JW (2004) Introns and splicing elements of five diverse fungi. Eukaryot Cell 3:1088–1100
Kurzatkowski W, Törrönen A, Filipek J, Mach RL, Herzog P, Sowka S, Kubicek CP (1996) Glucose-induced secretion of Trichoderma reesei xylanases. Appl Environ Microbiol 62:2859–2865
Kwon MJ, Arentshorst M, Roos ED, Van Den Hondel CAMJJ, Meyer V, Ram AFJ (2011) Functional characterization of Rho GTPases in Aspergillus niger uncovers conserved and diverged roles of Rho proteins within filamentous fungi. Mol Microbiol 79:1151–1167
Lamb TM, Vickery J, Bell-Pedersen D (2013) Regulation of gene expression in Neurospora crassa with a copper responsive promoter. G3 3:2273–2280
Landowski CP, Huuskonen A, Wahl R, Westerholm-Parvinen A, Kanerva A, Hänninen AL, Salovuori N, Penttilä M, Natunen J, Ostermeier C, Helk B, Saarinen J, Saloheimo M (2015) Enabling low cost biopharmaceuticals: a systematic approach to delete proteases from a well-known protein production host Trichoderma reesei. PLoS One 10:1–28
Landowski CP, Mustalahti E, Wahl R, Croute L, Sivasiddarthan D, Westerholm-Parvinen A, Sommer B, Ostermeier C, Helk B, Saarinen J, Saloheimo M (2016) Enabling low cost biopharmaceuticals: high level interferon alpha-2b production in Trichoderma reesei. Microb Cell Factories 15:1–15
Leach DRF (1994) Long DNA palindromes, cruciform structures, genetic instability and secondary structure repair. BioEssays 16:893–900
Ley A, Coumou HC, Frandsen RJN (2015) Heterologous expression of MlcE in Saccharomyces cerevisiae provides resistance to natural and semi-synthetic statins. Metab Eng Commun 2:117–123
Li H, d’Anjou M (2009) Pharmacological significance of glycosylation in therapeutic proteins. Curr Opin Biotechnol 20:678–684
Li J, Wang J, Wang S, Xing M, Yu S, Liu G (2012) Achieving efficient protein expression in Trichoderma reesei by using strong constitutive promoters. Microb Cell Factories 11:1–10
Li W, Yu J, Li Z, Yin WB (2018) Rational design for fungal laccase production in the model host Aspergillus nidulans. Sci China Life Sci 61:1–11
Lin C, Baldwin T, Estell D, Fung J, Lin C, Pucci J, Razo J, Rider B, Throndset W, Trimbur D, Gastel F Van Ward M (2006) Develop systems for manufacturing 100,000,000 doses of an emergency pharmaceutical (e.g. vaccine or monoclonal antibody) within 2 months of product identification. Progress report, Genencor International, pp 1–21
Linder MB, Qiao M, Laumen F, Selber K, Hyytiä T, Nakari-Setälä T, Penttilä ME (2004) Efficient purification of recombinant proteins using hydrophobins as tags in surfactant-based two-phase systems. Biochemistry 43:11873–11882
Liu R, Chen L, Jiang Y, Zhou Z, Zou G (2015) Efficient genome editing in filamentous fungus Trichoderma reesei using the CRISPR/Cas9 system. Cell Discov 1:1–11
Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338
Lorang JM, Tuori RP, Martinez JP, Sawyer TL, Redman RS, Rollins JA, Wolpert TJ, Johnson KB, Rodriguez RJ, Dickman MB, Ciuffetti LM (2001) Green fluorescent protein is lighting up fungal biology. Appl Environ Microbiol 67:1987–1994
Lubertozzi D, Keasling JD (2006) Marker and promoter effects on heterologous expression in Aspergillus nidulans. Appl Microbiol Biotechnol 72:1014–1023
Lupton SD, Brunton LL, Kalberg VA, Overell RW (1991) Dominant positive and negative selection using a hygromycin phosphotransferase-thymidine kinase fusion gene. Mol Cell Biol 11:3374–3378
Ma Y, Zhang J, Yin W, Zhang Z, Song Y, Chang X (2016) Targeted AID-mediated mutagenesis (TAM) enables efficient genomic diversification in mammalian cells. Nat Methods 13:1029–1035
Maruyama J, Nakajima H, Kitamoto K (2001) Visualization of nuclei in Aspergillus oryzae with EGFP and analysis of the number of nuclei in each conidium by FACS. Biosci Biotechnol Biochem 65:1504–1510
Marx F, Haas H, Reindl M, Stöffler G, Lottspeich F, Redl B (1995) Cloning, structural organization and regulation of expression of the Penicillium chrysogenum paf gene encoding an abundantly secreted protein with antifungal activity. Gene 167:167–171
Masai K, Marumaya J, Nakajima H, Kitamoto K (2003) In vivo visualization of the distribution of a secretory protein in Aspergillus oryzae hyphae using the RntA-EGFP fusion protein. Biosci Biotechnol Biochem 67:455–459
Matsuda Y, Mitsuhashi T, Lee S, Hoshino M, Mori T, Okada M, Zhang H, Hayashi F, Fujita M, Abe I (2016) Astellifadiene: structure determination by NMR spectroscopy and crystalline sponge method, and elucidation of its biosynthesis. Angew Chem 128:5879–5882
McNally MT, Free SJ (1988) Isolation and characterization of a Neurospora glucose-repressible gene. Curr Genet 14:545–551
Meyer V, Arentshorst M, El-Ghezal A, Drews AC, Kooistra R, van den Hondel CAMJJ, Ram AFJ (2007) Highly efficient gene targeting in the Aspergillus niger kusA mutant. J Biotechnol 128:770–775
Meyer V, Wanka F, van Gent J, Arentshorst M, van den Hondel CAMJJ, Ram AFJ (2011) Fungal gene expression on demand: an inducible, tunable, and metabolism-independent expression system for Aspergillus niger. Appl Environ Microbiol 77:2975–2983
Meyer V, Andersen MR, Brakhage AA, Braus GH, Caddick MX, Cairns TC, de Vries RP, Haarmann T, Hansen K, Hertz-Fowler C, Krappmann S, Mortensen UH, Peñalva MA, Ram AFJ, Head RM (2016) Current challenges of research on filamentous fungi in relation to human welfare and a sustainable bio-economy: a white paper. Fungal Biol Biotechnol 3:1–17
Miyauchi S, Te’o VS, Bergquist PL, Nevalainen KMH (2013) Expression of a bacterial xylanase in Trichoderma reesei under the egl2 and cbh2 glycosyl hydrolase gene promoters. New Biotechnol 30:523–530
Moralejo FJ, Watson AJ, Jeenes DJ, Archer DB, Martín JF (2001) A defined level of protein disulfide isomerase expression is required for optimal secretion of thaumatin by Aspergillus awamori. Mol Gen Genomics 266:246–253
Morris MC (2010) Fluorescent biosensors of intracellular targets from genetically encoded reporters to modular polypeptide probes. Cell Biochem Biophys 56:19–37
Morse NJ, Gopal MR, Wagner JM, Alper HS (2017) Yeast terminator function can be modulated and designed on the basis of predictions of nucleosome occupancy. ACS Synth Biol 6:2086–2095
Muller C, Hjort CM, Hansen K, Nielsen J (2002) Altering the expression of two chitin synthase genes differentially affects the growth and morphology of Aspergillus oryzae. Microbiology 148:4025–4033
Munawar A, Marshall JW, Cox RJ, Bailey AM, Lazarus CM (2013) Isolation and characterisation of a ferrirhodin synthetase gene from the sugarcane pathogen Fusarium sacchari. Chembiochem 14:388–394
Nagamine S, Liu C, Nishishita J, Kozaki T, Sogahata K, Sato Y, Minami A, Ozaki T, Schmidt-Dannert C, Maruyama J, Oikawa H (2019) Ascomycota Aspergillus oryzae is an efficient expression host for production of basidiomycota terpenes using genomic DNA sequences. Appl Environ Microbiol 85:1–21
Nakajima KI, Asakura T, Maruyama JI, Morita Y, Oike H, Shimizu-Ibuka A, Misaka T, Sorimachi H, Arai S, Kitamoto K, Abe K (2006) Extracellular production of neoculin, a sweet-tasting heterodimeric protein with taste-modifying activity, by Aspergillus oryzae. Appl Environ Microbiol 72:3716–3723
Nakano ET, Fox RD, Clements DE, Koo K, Stuart WD, Ivy JM (1993) Expression vectors for Neurospora crassa and expression of a bovine preprochymosin cDNA. Fungal Genet Rep 40:54–56
Nakari-Setälä T, Penttilä M (1995) Production of Trichoderma reesei cellulases glucose-containing media. Appl Environ Microbiol 61:3650–3655
Nakazato L, Dutra V, Broetto L, Staats CC, Vainstein MH, Schrank A (2006) Development of an expression vector for Metarhizium anisopliae based on the tef-1α homologous promoter. Appl Microbiol Biotechnol 72:521–528
Nielsen ML, Albertsen L, Lettier G, Nielsen JB, Mortensen UH (2006) Efficient PCR-based gene targeting with a recyclable marker for Aspergillus nidulans. Fungal Genet Biol 43:54–64
Nielsen MT, Nielsen JB, Anyaogu DC, Holm DK, Nielsen KF, Larsen TO, Mortensen UH (2013) Heterologous reconstitution of the intact geodin gene cluster in Aspergillus nidulans through a simple and versatile PCR based approach. PLoS One 8:e72871
Nielsen ML, Isbrandt T, Rasmussen KB, Thrane U, Hoof JB, Larsen TO, Mortensen UH (2017) Genes linked to production of secondary metabolites in Talaromyces atroroseus revealed using CRISPR-Cas9. PLoS One 12:1–9
Nødvig CS, Nielsen JB, Kogle ME, Mortensen UH (2015) A CRISPR-Cas9 system for genetic engineering of filamentous fungi. PLoS One 10:1–18
Nødvig CS, Hoof JB, Kogle ME, Jarczynska ZD, Lehmbeck J, Klitgaard DK, Mortensen UH (2018) Efficient oligo nucleotide mediated CRISPR-Cas9 gene editing in Aspergilli. Fungal Genet Biol 115:78–89
Oda K, Terado S, Toyoura R, Fukuda H, Kawauchi M, Iwashita K (2016) Development of a promoter shutoff system in Aspergillus oryzae using a sorbitol-sensitive promoter. Biosci Biotechnol Biochem 80:1792–1801
Ohno A, Maruyama JI, Nemoto T, Arioka M, Kitamoto K (2011) A carrier fusion significantly induces unfolded protein response in heterologous protein production by Aspergillus oryzae. Appl Microbiol Biotechnol 92:1197–1206
Okada M, Saito K, Wong CP, Li C, Wang D, Iijima M, Taura F, Kurosaki F, Awakawa T, Abe I (2017) Combinatorial biosynthesis of (+)-daurichromenic acid and its halogenated analogue. Org Lett 19:3183–3186
Osmani AH, May GS, Osmani SA (1999) The extremely conserved pyroA gene of Aspergillus nidulans is required for pyridoxine synthesis and is required indirectly for resistance to photosensitizers. J Biol Chem 274:23565–23569
Ouedraogo JP, Arentshorst M, Nikolaev I, Barends S, Ram AFJ (2016) I-SceI enzyme mediated integration (SEMI) for fast and efficient gene targeting in Trichoderma reesei. J Biotechnol 222:25–28
Pahirulzaman KAK, Williams K, Lazarus CM (2012) A toolkit for heterologous expression of metabolic pathways in Aspergillus oryzae. In: Hopwood D (ed) Methods in enzymology, vol 517. Academic, San Diego, pp 241–260
Paloheimo M, Haarmann T, Mäkinen S, Vehmaanperä J (2016) Production of industrial enzymes in Trichoderma reesei. In: Schmoll M, Dattenböck C (eds) Gene expression systems in fungi: advancements and applications, vol 1. Springer International Publishing, Cham, pp 23–57
Pantazopoulou A, Pinar M, Xiang X, Peñalva MA (2014) Maturation of late Golgi cisternae into RabERAB11 exocytic post-Golgi carriers visualized in vivo. Mol Biol Cell 25:2428–2443
Perez-Pinera P, Ousterout DG, Brunger JM, Farin AM, Glass KA, Guilak F, Crawford GE, Hartemink AJ, Gersbach CA (2013) Synergistic and tunable human gene activation by combinations of synthetic transcription factors. Nat Methods 10:239–244
Peters JM, Colavin A, Shi H, Czarny TL, Larson MH, Wong S, Hawkins JS, Lu CHS, Koo BM, Marta E, Shiver AL, Whitehead EH, Weissman JS, Brown ED, Qi LS, Huang KC, Gross CA (2016) A comprehensive, CRISPR-based functional analysis of essential genes in bacteria. Cell 165:1493–1506
Petersen LM, Holm DK, Gotfredsen CH, Mortensen UH, Larsen TO (2015) Investigation of a 6-MSA synthase gene cluster in Aspergillus aculeatus reveals 6-MSA-derived aculinic acid, aculins A-B and epi-aculin A. Chembiochem 16:2200–2204
Petes T (1988) Recombination between repeated genes in microorganisms. Annu Rev Genet 22:147–168
Pohl C, Kiel J, Driessen A, Bovenberg R, Nygård Y (2016) CRISPR/Cas9 based genome editing of Penicillium chrysogenum. ACS Synth Biol 5:754–764
Polli F, Meijrink B, Bovenberg RAL, Driessen AJM (2016) New promoters for strain engineering of Penicillium chrysogenum. Fungal Genet Biol 89:62–71
Pop C, Rouskin S, Ingolia NT, Han L, Phizicky EM, Weissman JS, Koller D (2014) Causal signals between codon bias, mRNA structure, and the efficiency of translation and elongation. Mol Syst Biol 10:1–15
Prasher DC, Eckenrode VK, Ward WW, Prendergast FG, Cormier MJ (1992) Primary structure of the Aequorea victoria green-fluorescent protein. Gene 111:229–233
Pretorius IS, Boeke JD (2018) Yeast 2.0-connecting the dots in the construction of the world’s first functional synthetic eukaryotic genome. FEMS Yeast Res 18:1–15
Punt PJ, van den Hondel CAMJJ (1992) Transformation of filamentous fungi based on hygromycin b and phleomycin resistance markers. In: Wu R (ed) Methods in enzymology, vol 216. Academic, San Diego, pp 447–457
Punt PJ, Seiboth B, Weenink XO, Van Zeijl C, Lenders M, Konetschny C, Ram AFJ, Montijn R, Kubicek CP, Van Den Hondel CAMJJ (2001) Identification and characterization of a family of secretion-related small GTPase-encoding genes from the filamentous fungus Aspergillus niger: a putative SEC4 homologue is not essential for growth. Mol Microbiol 41:513–525
Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152:1173–1183
Qin LN, Cai FR, Dong XR, Huang ZB, Tao Y, Huang JZ, Dong ZY (2012) Improved production of heterologous lipase in Trichoderma reesei by RNAi mediated gene silencing of an endogenic highly expressed gene. Bioresour Technol 109:116–122
Qin H, Xiao H, Zou G, Zhou Z, Zhong J (2017) CRISPR-Cas9 assisted gene disruption in the higher fungus Ganoderma species. Process Biochem 56:57–61
Rahman Z, Shida Y, Furukawa T, Suzuki Y, Okada H, Ogasawara W, Morikawa Y (2009) Evaluation and characterization of Trichoderma reesei cellulase and xylanase promoters. Appl Microbiol Biotechnol 82:899–908
Rantasalo A, Landowski CP, Kuivanen J, Korppoo A, Reuter L, Koivistoinen O, Valkonen M, Penttilä M, Jäntti J, Mojzita D (2018) A universal gene expression system for fungi. Nucleic Acids Res 1:1–15
Rantasalo A, Vitikainen M, Paasikallio T, Jäntti J, Landowski CP, Mojzita D (2019) Novel genetic tools that enable highly pure protein production in Trichoderma reesei. Sci Rep 9:1–12
Read G, Vining LC (1968) The biosynthesis of terreic acid. Chem Commun 16:935–937
Record E, Punt PJ, Chamkha M, Labat M, Van Den Hondel CAMJJ, Asther M (2002) Expression of the Pycnoporus cinnabarinus laccase gene in Aspergillus niger and characterization of the recombinant enzyme. Eur J Biochem 269:602–609
Rendsvig JKH, Workman CT, Hoof JB (2019) Bidirectional histone-gene promoters in Aspergillus: characterization and application for multi-gene expression. Fungal Biol Biotechnol 6:1–14
Riquelme M, Sánchez-León E (2014) The Spitzenkörper: a choreographer of fungal growth and morphogenesis. Curr Opin Microbiol 20:27–33
Rogers JK, Taylor ND, Church GM (2016) Biosensor-based engineering of biosynthetic pathways. Curr Opin Biotechnol 42:84–91
Rokas A, Wisecaver JH, Lind AL (2018) The birth, evolution and death of metabolic gene clusters in fungi. Nat Rev Microbiol 16:731–744
Roller S, Covill N (1999) The antifungal properties of chitosan in laboratory media and apple juice. Int J Food Microbiol 47:67–77
Romero B, Turner G, Olivas I, Laborda F, Ramón De Lucas J (2003) The Aspergillus nidulans alcA promoter drives tightly regulated conditional gene expression in Aspergillus fumigatus permitting validation of essential genes in this human pathogen. Fungal Genet Biol 40:103–114
Roze LV, 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
Ryan MD, King AMQ, Thomas GP (1991) Cleavage of FMDV polyprotein is mediated by residues located within a 19 amino acid sequence. J Gen Virol 72:2727–2732
Sakai K, Kinoshita H, Shimizu T, Nihira T (2008) Construction of a citrinin gene cluster expression system in heterologous Aspergillus oryzae. J Biosci Bioeng 106:466–472
Sandermann H Jr (1992) Plant metabolism of xenobiotics. Trends Biochem Sci 17:82–84
Schalén M, Anyaogu DC, Hoof JB, Workman M (2016) Effect of secretory pathway gene overexpression on secretion of a fluorescent reporter protein in Aspergillus nidulans. Fungal Biol Biotechnol 3:1–14
Schäpe P, Kwon MJ, Baumann B, Gutschmann B, Jung S, Lenz S, Nitsche B, Paege N, Schütze T, Cairns TC, Meyer V (2019) Updating genome annotation for the microbial cell factory Aspergillus niger using gene co-expression networks. Nucleic Acids Res 47:559–569
Schuetze T, Meyer V (2017) Polycistronic gene expression in Aspergillus niger. Microb Cell Factories 16:1–8
Shi TQ, Gao J, Wang WJ, Wang KF, Xu GQ, Huang H, Ji XJ (2019) CRISPR/Cas9-based genome editing in the filamentous fungus Fusarium fujikuroi and its application in strain engineering for gibberellic acid production. ACS Synth Biol 8:445–454
Shimizu T, Ito T, Kanematsu S (2012) Transient and multivariate system for transformation of a fungal plant pathogen, Rosellinia necatrix, using autonomously replicating vectors. Curr Genet 58:129–138
Shoji J, Maruyama J, Arioka M, Kitamoto K (2005) Development of Aspergillus oryzae thiA promoter as a tool for molecular biological studies. FEMS Microbiol Lett 244:41–46
Sibthorp C, Wu H, Cowley G, Wong PWH, Palaima P, Morozov IY, Weedall GD, Caddick MX (2013) Transcriptome analysis of the filamentous fungus Aspergillus nidulans directed to the global identification of promoters. BMC Genomics 14:1–18
Song Z, Bakeer W, Marshall JW, Yakasai AA, Khalid RM, Collemare J, Skellam E, Tharreau D, Lebrun M-H, Lazarus CM, Bailey AM, Simpson TJ, Cox RJ (2015) Heterologous expression of the avirulence gene ACE1 from the fungal rice pathogen Magnaporthe oryzae. Chem Sci 6:4837–4845
Stajich JE, Dietrich FS, Roy SW (2007) Comparative genomic analysis of fungal genomes reveals intron-rich ancestors. Genome Biol 8:1–13
Steinberg G, Peñalva MA, Riquelme M, Wösten HA, Harris SD (2017) Cell biology of hyphal growth. Microbiol Spectr 5:231–265
Sticha KRK, Sieg CA, Bergstrom CP, Hanna PE, Wagner CR (1997) Overexpression and large-scale purification of recombinant hamster polymorphic arylamine N-acetyltransferase as a dihydrofolate reductase fusion protein. Protein Expr Purif 10:141–153
Stone PJ, Makoff AJ, Parish JH, Radford A (1993) Cloning and sequence analysis of the glucoamylase gene of Neurospora crassa. Curr Genet 24:205–211
Stricker AR, Grosstessner-Hain K, Würleitner E, Mach RL (2006) Xyr1 (xylanase regulator 1) regulates both the hydrolytic enzyme system and d-xylose metabolism in Hypocrea jecorina. Eukaryot Cell 5:2128–2137
Sun A, Peterson R, Te’o J, Nevalainen H (2016) Expression of the mammalian peptide hormone obestatin in Trichoderma reesei. New Biotechnol 33:99–106
Tada S, Gomi K, Kitamoto K, Takahashi K, Tamura G, Hara S (1991) Construction of a fusion gene comprising the Taka-amylase a promoter and the Escherichia coli β-glucuronidase gene and analysis of its expression in Aspergillus oryzae. Mol Gen Genet 229:301–306
Tanaka M, Tokuoka M, Gomi K (2014) Effects of codon optimization on the mRNA levels of heterologous genes in filamentous fungi. Appl Microbiol Biotechnol 98:3859–3867
Taylor DL, Hollingsworth TN, McFarland JW, Lennon NJ, Nusbaum C, Ruess RW (2014) A first comprehensive census of fungi in soil reveals both hyperdiversity and fine-scale niche partitioning. Ecol Monogr 84:3–20
Throndset W, Kim S, Bower B, Lantz S, Kelemen B, Pepsin M, Chow N, Mitchinson C, Ward M (2010) Flow cytometric sorting of the filamentous fungus Trichoderma reesei for improved strains. Enzym Microb Technol 47:335–341
Tian Y, Tan Y, Liu N, Yan Z, Liao Y, Chen J, De Saeger S, Yang H, Zhang Q, Wu A (2016) Detoxification of deoxynivalenol via glycosylation represents novel insights on antagonistic activities of Trichoderma when confronted with Fusarium graminearum. Toxins 8:1–15
Till P, Pucher ME, Mach RL, Mach-Aigner AR (2018) A long noncoding RNA promotes cellulase expression in Trichoderma reesei. Biotechnol Biofuels 11:1–16
Unkles SE, Campbell EI, Carrez D, Grieve C, Contreras R, Fiers W, van den Hondel CAMJJ, Kinghorn JR (1989) Transformation of Aspergillus niger with the homologous nitrate reductase gene. Gene 78:157–166
Urlinger S, Baron U, Thellmann M, Hasan MT, Bujard H, Hillen W (2000) Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc Natl Acad Sci USA 97:7963–7968
Valkonen M, Ward M, Wang H, Penttilä M, Saloheimo M (2003) Improvement of foreign-protein production in Aspergillus niger var. awamori by constitutive induction of the unfolded-protein response. Appl Environ Microbiol 69:6979–6986
van den Brink HJM, Petersen SG, Rahbek-Nielsen H, Hellmuth K, Harboe M (2006) Increased production of chymosin by glycosylation. J Biotechnol 125:304–310
Vanegas KG, Lehka BJ, Mortensen UH (2017) SWITCH: a dynamic CRISPR tool for genome engineering and metabolic pathway control for cell factory construction in Saccharomyces cerevisiae. Microb Cell Factories 16:1–12
Vesth TC, Nybo JL, Theobald S, Frisvad JC, Larsen TO, Nielsen KF, Hoof JB, Brandl J, Salamov A, Riley R, Gladden JM, Phatale P, Nielsen MT, Lyhne EK, Kogle ME, Strasser K, McDonnell E, Barry K, Clum A, Chen C, LaButti K, Haridas S, Nolan M, Sandor L, Kuo A, Lipzen A, Hainaut M, Drula E, Tsang A, Magnuson JK, Henrissat B, Wiebenga A, Simmons BA, Mäkelä MR, de Vries RP, Grigoriev IV, Mortensen UH, Baker SE, Andersen MR (2018) Investigation of inter- and intraspecies variation through genome sequencing of Aspergillus section Nigri. Nat Genet 50:1688–1695
Vlaardingerbroek I, Beerens B, Shahi S, Rep M (2015) Fluorescence assisted selection of Transformants (FAST): using flow cytometry to select fungal transformants. Fungal Genet Biol 76:104–109
Wang B, Guo G, Wang C, Lin Y, Wang X, Zhao M, Guo Y, He M, Zhang Y, Pan L (2010) Survey of the transcriptome of Aspergillus oryzae via massively parallel mRNA sequencing. Nucleic Acids Res 38:5075–5087
Wanka F, Cairns T, Boecker S, Berens C, Happel A, Zheng X, Sun J, Krappmann S, Meyer V (2016) Tet-on, or Tet-off, that is the question: advanced conditional gene expression in Aspergillus. Fungal Genet Biol 89:72–83
Ward M, Wilson LJ, Carmona CL, Turner G (1988) The oliC3 gene of Aspergillus niger: isolation, sequence and use as a selectable marker for transformation. Curr Genet 14:37–42
Waring RB, May GS, Morris NR (1989) Characterization of an inducible expression system in Aspergillus nidulans using alcA and tubulin coding genes. Gene 79:119–130
Watanabe A, Ono Y, Fujii I, Sankawa U, Mayorga ME, Timberlake WE, Ebizuka Y (1998) Product identification of polyketide synthase coded by Aspergillus nidulans wA gene. Tetrahedron Lett 39:7733–7736
Watanabe A, Fujii I, Sankawa U, Mayorga ME, Timberlake WE, Ebizuka Y (1999) Re-identification of Aspergillus nidulans wA gene to code for a polyketide synthase of naphthopyrone. Tetrahedron Lett 40:91–94
Wei W, Chen L, Zou G, Wang Q, Yan X, Zhang J, Wang C, Zhou Z (2013) N-glycosylation affects the proper folding, enzymatic characteristics and production of a fungal β-glucosidase. Biotechnol Bioeng 110:3075–3084
Wernars K, Goosen T, Wennekes LMJ, Visser J, Bos CJ, van den Broek HWJ, van Gorcom RFM, van den Hondel CAMJJ, Pouwels PH (1985) Gene amplification in Aspergillus nidulans by transformation with vectors containing the amdS gene. Curr Genet 9:361–368
Wiemann P, Soukup AA, Folz JS, Wang PM, Noack A, Keller NP (2018) CoIN:co-inducible nitrate expression system for secondary metabolites in Aspergillus nidulans. Fungal Biol Biotechnol 5:1–10
Willis KJ (ed) (2018) State of the world’s fungi 2018. Report. Royal Botanic Gardens, Kew
Wu Y, Sun X, Xue X, Luo H, Yao B, Xie X, Su X (2017) Overexpressing key component genes of the secretion pathway for enhanced secretion of an Aspergillus niger glucose oxidase in Trichoderma reesei. Enzym Microb Technol 106:83–87
Xie X, Meehan MJ, Xu W, Dorrestein PC, Tang Y (2009) Acyltransferase mediated polyketide release from a fungal megasynthase. J Am Chem Soc 131:8388–8389
Xu J, Gong ZZ (2003) Intron requirement for AFP gene expression in Trichoderma viride. Microbiology 149:3093–3097
Xu W, Chooi Y-H, Choi JW, Li S, Vederas JC, Da Silva NA, Tang Y (2013) LovG: the thioesterase required for dihydromonacolin L release and lovastatin nonaketide synthase turnover in lovastatin biosynthesis. Angew Chem Int Ed 52:6472–6475
Yang S, Kuang Y, Li H, Liu Y, Hui X, Li P, Jiang Z, Zhou Y, Wang Y, Xu A, Li S, Liu P, Wu D (2013) Enhanced production of recombinant secretory proteins in Pichia pastoris by optimizing Kex2 P1’ site. PLoS One 8:1–11
Yoon J, Aishan T, Maruyama JI, Kitamoto K (2010) Enhanced production and secretion of heterologous proteins by the filamentous fungus Aspergillus oryzae via disruption of vacuolar protein sorting receptor gene AoVps10. Appl Environ Microbiol 76:5718–5727
Yoshino-Yasuda S, Karita S, Kato M, Kitamoto N (2012) Sequence analysis and heterologous expression of rhamnogalacturonan lyase A gene (AsrglA) from Shoyu koji mold, Aspergillus sojae KBN1340. Food Sci Technol Res 18:901–909
Yu CH, Dang Y, Zhou Z, Wu C, Zhao F, Sachs MS, Liu Y (2015) Codon usage influences the local rate of translation elongation to regulate co-translational protein folding. Mol Cell 59:744–754
Yuill E (1950) The numbers of nuclei in conidia of Aspergilli. Trans Br Mycol Soc 33:324–331
Zadra I, Abt B, Parson W, Haas H (2000) xylP promoter-based expression system and its use for antisense downregulation of the Penicillium chrysogenum nitrogen regulator NRE. Appl Environ Microbiol 66:4810–4816
Zeilinger S, Mach RL, Schindler M, Herzog P, Kubicek CP (1996) Different inducibility of expression of the two xylanase genes xyn1 and xyn2 in Trichoderma reesei. J Biol Chem 271:25624–25629
Zeilinger S, Mach R, Kubicek C (1998) Two adjacent protein binding motifs in the cbh2 (Cellobiohydrolase II-encoding) promoter of the fungus Hypocrea jecorina (Trichoderma reesei) cooperate in the induction by cellulose. J Biol Chem 273:34463–34471
Zhang F, Keasling J (2011) Biosensors and their applications in microbial metabolic engineering. Trends Microbiol 19:323–329
Zhang DX, Lu HL, Liao X, St Leger RJ, Nuss DL (2013) Simple and efficient recycling of fungal selectable marker genes with the Cre-loxP recombination system via anastomosis. Fungal Genet Biol 61:1–9
Zhang XH, Tee LY, Wang XG, Huang QS, Yang SH (2015) Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol Ther Nucleic Acids 4:1–8
Zhang C, Meng X, Wei X, Lu L (2016a) Highly efficient CRISPR mutagenesis by microhomology-mediated end joining in Aspergillus fumigatus. Fungal Genet Biol 86:47–57
Zhang H, Wang S, Zhang XX, Ji W, Song F, Zhao Y, Li J (2016b) The amyR-deletion strain of Aspergillus niger CICC2462 is a suitable host strain to express secreted protein with a low background. Microb Cell Factories 15:1–11
Zhang J, Zhang G, Wang W, Wei D (2018) Enhanced cellulase production in Trichoderma reesei RUT C30 via constitution of minimal transcriptional activators. Microb Cell Factories 17:1–14
Zhao C, Waalwijk C, de Wit PJGM, Tang D, van der Lee T (2013) RNA-Seq analysis reveals new gene models and alternative splicing in the fungal pathogen Fusarium graminearum. BMC Genomics 14:1–16
Zheng YM, Lin FL, Gao H, Zou G, Zhang JW, Wang GQ, Chen GD, Zhou ZH, Yao XS, Hu D (2017) Development of a versatile and conventional technique for gene disruption in filamentous fungi based on CRISPR-Cas9 technology. Sci Rep 7:1–10
Zhou M, Wang T, Fu J, Xiao G, Liu Y (2015) Nonoptimal codon usage influences protein structure in intrinsically disordered regions. Mol Microbiol 97:974–987
Zhou Z, Dang Y, Zhou M, Li L, Yu C, Fu J, Chen S, Liu Y (2016) Codon usage is an important determinant of gene expression levels largely through its effects on transcription. Proc Natl Acad Sci USA 113:E6117–E6125
Zhou Z, Dang Y, Zhou M, Yuan H, Liu Y (2018) Codon usage biases co-evolve with transcription termination machinery to suppress premature cleavage and polyadenylation. Elife 7:1–29
Zhu H, Choi S, Johnston AK, Wing RA, Dean RA (1997) A large-insert (130 kbp) bacterial artificial chromosome library of the rice blast fungus Magnaporthe grisea: genome analysis, contig assembly, and gene cloning. Fungal Genet Biol 21:337–347
Zhu B, Cai G, Hall EO, Freeman GJ (2007) In-FusionTM assembly: seamless engineering of multidomain fusion proteins, modular vectors, and mutations. BioTechniques 43:354–359
Zubieta MP, Contesini FJ, Rubio MV, Gonçalves AEDSS, Gerhardt JA, Prade RA, Damasio ARDL (2018) Protein profile in Aspergillus nidulans recombinant strains overproducing heterologous enzymes. Microb Biotechnol 11:346–358
Acknowledgments
We are grateful to Michael Lynge Nielsen for carefully reading and editing this book chapter. This work has been supported by Innovation Fund Denmark, grant no.: 6150-00031B.
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Rendsvig, J.K.H., Futyma, M.E., Jarczynska, Z.D., Mortensen, U.H. (2020). Filamentous Fungi as Hosts for Heterologous Production of Proteins and Secondary Metabolites in the Post-Genomic Era. In: Benz, J.P., Schipper, K. (eds) Genetics and Biotechnology. The Mycota, vol 2. Springer, Cham. https://doi.org/10.1007/978-3-030-49924-2_10
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