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Overexpression of the RNA-Binding Protein Nrda Affects Global Gene Expression

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Overexpression of the RNA-Binding Protein Nrda Affects Global Gene Expression bioRxiv preprint doi: https://doi.org/10.1101/2021.03.15.435561; this version posted March 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Overexpression of the RNA-binding protein NrdA affects global gene expression 2 and secondary metabolism in Aspergillus species 3 4 Chihiro Kadooka1,2*, Kosuke Izumitsu3, Teigo Asai4, Kazuki Mori5, Kayu Okutsu2, 5 Yumiko Yoshizaki1,2, Kazunori Takamine1,2, Masatoshi Goto1,6, Hisanori Tamaki1,2, 6 Taiki Futagami1,2# 7 8 1 United Graduate School of Agricultural Sciences, Kagoshima University, 1-21-24 9 Korimoto, Kagoshima, 890-0065, Japan 10 2 Education and Research Centre for Fermentation Studies, Faculty of Agriculture, 11 Kagoshima University, 1-21-24 Korimoto, Kagoshima, 890-0065, Japan. 12 3 Graduate School of Environmental Science, University of Shiga Prefecture, 2500 13 Hassaka-cho, Hikone, Shiga, 522-8533, Japan. 14 4 Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, 15 Aoba-ku, Sendai, Miyagi, 980-8578, Japan 16 5 Cell Innovator Co., Ltd., 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. 17 6 Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga 18 University, 1 Honjo-machi, Saga, 840-8502, Japan. 19 20 Running title: RNA-binding protein NrdA in Aspergillus 21 22 * Present address: Chihiro Kadooka, Faculty of Life and Environmental Sciences, 23 University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan. 24 # Address correspondence to Taiki Futagami, [email protected] 25 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.15.435561; this version posted March 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 26 ABSTRACT 27 RNA-binding protein Nrd1 plays a role in RNA polymerase II transcription termination. 28 In this study, we showed that the orthologous NrdA is important in global mRNA 29 expression and secondary metabolism in Aspergillus species. We constructed an nrdA 30 conditional expression strain using the Tet-On system in Aspergillus luchuenesis mut. 31 kawachii. Downregulation of nrdA caused a severe growth defect, indicating that NrdA 32 is essential for the proliferation of A. kawachii. Parallel RNA-sequencing and RNA 33 immunoprecipitation-sequencing analysis identified potential NrdA-interacting 34 transcripts, corresponding to 32% of the predicted protein coding genes of A. kawachii. 35 Subsequent gene ontology analysis suggested that overexpression of NrdA affects the 36 production of secondary metabolites. To clarify this, we constructed 37 NrdA-overexpressing strains of Aspergillus nidulans, Aspergillus fumigatus, and 38 Aspergillus oryzae. Overexpression of NrdA reduced the production of sterigmatocystin 39 and penicillin in A. nidulans, as well as that of helvolic acid and pyripyropene A in A. 40 fumigatus. Moreover, it increased the production of kojic acid and reduced production 41 of penicillin in A. oryzae. These effects were accompanied by almost consistent 42 transcriptional changes in the relevant genes. Collectively, these results suggest that 43 NrdA is the essential RNA-binding protein, which plays a significant role in global gene 44 expression and secondary metabolism in Aspergillus species. 45 46 IMPORTANCE 47 Nrd1, a component of the Nrd1–Nab3–Sen1 complex, is an essential RNA-binding 48 protein involved in transcriptional termination in yeast. However, its role in filamentous 49 fungi has not been studied. In this study, we characterized an orthologous NrdA in the 50 Aspergillus species, identified potential NrdA-interacting mRNA, and investigated the 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.15.435561; this version posted March 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 51 effect of overexpression of NrdA on mRNA expression in Aspergillus luchuensis mut. 52 kawachii. The results indicated that NrdA controls global gene expression involved in 53 versatile metabolic pathways, including the secondary metabolic process. We 54 demonstrated that NrdA overexpression significantly affected the production of 55 secondary metabolites in Aspergillus nidulans, Aspergillus oryzae, and Aspergillus 56 fumigatus. Our findings are of importance to the fungal research community because the 57 secondary metabolism is an industrially and clinically important aspect for the 58 Aspergillus species. 59 60 KEYWORDS 61 Aspergillus, RNA-binding protein, NrdA, gene expression, secondary metabolism 62 63 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.15.435561; this version posted March 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 64 INTRODUCTION 65 There are at least two pathways for transcription termination in the budding yeast 66 Saccharomyces cerevisiae, namely the RNA polymerase II cleavage/polyadenylation 67 factor-related pathway and the Nrd1–Nab3–Sen1 (NNS)-related pathway (1, 2). The 68 former cleavage/polyadenylation factor pathway is required for polyadenylation of the 3’ 69 end of precursor mRNA. The latter pathway is required for the early termination of 70 transcripts to produce the shorter polyadenylated transcripts. Moreover, it is involved in 71 the subsequent production of non-coding transcripts, such as small nucleolar RNAs, 72 small nuclear RNAs, cryptic unstable transcripts, and stable uncharacterized transcripts 73 with largely unknown functions. The Nrd1 and Nab3 are essential RNA-binding 74 proteins and bind specific sequences in target RNA, whereas Sen1 is a helicase 75 responsible for the termination of transcription. The NNS complex has been extensively 76 studied from the view point of non-coding RNA production. However, it has been 77 recently suggested that the NNS-related pathway also plays a significant role in 78 protein-coding mRNA involved in response to nutrient starvation (3, 4). It was proposed 79 that binding of Nrd1 and Nab3 led to premature transcription termination, resulting in 80 the downregulation of mRNA levels. In S. cerevisiae, it was estimated that Nrd1 and 81 Nab3 directly regulate a variety of protein-coding genes, representing 20%–30% of 82 protein-coding transcripts (5). In addition, the Nrd1 ortholog Seb1 drives transcription 83 termination for both protein-coding and non-coding sequences in the fission yeast 84 Schizosaccharomyces pombe (6, 7). 85 We have investigated the mechanism of citric acid accumulation by the white koji 86 fungus Aspergillus luchuensis mut. kawachii, which is used for the production of 87 shochu, a Japanese traditional distilled spirit. A. kawachii is used as a producer of 88 starch-degrading enzymes, such as α-amylase and glucoamylase (8, 9). In addition, A. 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.15.435561; this version posted March 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 89 kawachii also produces a large amount of citric acid, which prevents the growth of 90 microbial contaminants during the fermentation process (10). During the course of the 91 study, we found that the Nrd1 ortholog encoding nrdA was located in a syntenic region 92 together with mitochondrial citrate synthase-encoding citA and mitochondrial citrate 93 transporter encoding yhmA in the subdivision Pezizomycotina (including genus 94 Aspergillus). However, it was not found in the subdivisions Saccharomycotina 95 (including genus Saccharomyces) and Taphrinomycotina (including genus 96 Schizosaccharomyces) (11). Considering the numerous examples of metabolic gene 97 clusters in fungi and plants (12, 13), this finding motivated us to study the function of 98 NrdA in Aspergillus species in terms of metabolic activity. 99 In this study, we showed that NrdA is an essential RNA-binding protein involved 100 in the production of citric acid in A. kawachii using the nrdA conditional expression 101 strain. Nevertheless, whether nrdA is functionally related to citA and yhmA remains 102 unclear. By combining RNA-sequencing (RNA-seq) and RNA 103 immunoprecipitation-sequencing (RIP-seq) analyses, we identified potential NrdA– 104 mRNA interactions, corresponding to approximately 32% of protein-coding genes of the 105 A. kawachii genome. In addition, we showed that overexpression of nrdA causes 106 significant changes in the expression levels of NrdA-interacting mRNA involved in 107 secondary metabolism. Furthermore, we demonstrated that overexpression of nrdA also 108 caused changes in the production of secondary metabolites in Aspergillus nidulans, 109 Aspergillus fumigatus, and Aspergillus oryzae. These results suggested that the 110 NrdA-associated transcription termination pathway potentially regulates the secondary 111 metabolic process in the Aspergillus species. 112 113 RESULTS AND DISCUSSION 5 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.15.435561; this version posted March 16, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 114 Sequence feature of NrdA. The A. kawachii nrdA gene encodes a protein 115 composed of 742 amino acid residues. BLASTP analysis 116 (https://blast.ncbi.nlm.nih.gov/Blast.cgi) showed that the amino acid sequence percent 117 identities between A. kawachii NrdA and S.
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