Sirtuin E is a fungal global transcriptional regulator that determines the transition from the primary growth to the stationary phase

Abstract

In response to limited nutrients, fungal cells exit the primary growth phase, enter the stationary phase, and cease proliferation. Although fundamental to microbial physiology in many environments, the regulation of this transition is poorly understood but likely involves many transcriptional regulators. These may include the sirtuins, which deacetylate acetyllysine residues of histones and epigenetically regulate global transcription. Therefore, we investigated the role of a nuclear sirtuin, sirtuin E (SirE), from the ascomycete fungus An strain with a disrupted gene (SirEΔ) accumulated more acetylated histone H3 during the stationary growth phase when was expressed at increased levels in the wild type. SirEΔ exhibited decreased mycelial autolysis, conidiophore development, sterigmatocystin biosynthesis, and production of extracellular hydrolases. Moreover, the transcription of the genes involved in these processes was also decreased, indicating that SirE is a histone deacetylase that up-regulates these activities in the stationary growth phase. Transcriptome analyses indicated that SirE repressed primary carbon and nitrogen metabolism and cell-wall synthesis. Chromatin immunoprecipitation demonstrated that SirE deacetylates acetylated Lys-9 residues in histone H3 at the gene promoters of α-1,3-glucan synthase (), glycolytic phosphofructokinase (), and glyceraldehyde 3-phosphate (), indicating that SirE represses the expression of these primary metabolic genes. In summary, these results indicate that SirE facilitates the metabolic transition from the primary growth phase to the stationary phase. Because the observed gene expression profiles in stationary phase matched those resulting from carbon starvation, SirE appears to control this metabolic transition via a mechanism associated with the starvation response.

On top of biosynthetic gene clusters: How epigenetic machinery influences secondary metabolism in fungi

“…A transcriptomic study of the sirA deletion mutant showed both up and down regulated secondary metabolite BGCs, and measured increases in austinol and sterigmatocystin production (Itoh et al, 2017b). Another class I sirtuin SirE (AN1226) has also been studied in A. nidulans, and was found to regulate both primary and secondary metabolism (Itoh et al, 2017a). Deletion of sirE led to an increase in H3K9ac, H3K18ac, as well as H3K56ac during various growth conditions (Itoh et al, 2017a).…”

“…Another class I sirtuin SirE (AN1226) has also been studied in A. nidulans, and was found to regulate both primary and secondary metabolism (Itoh et al, 2017a). Deletion of sirE led to an increase in H3K9ac, H3K18ac, as well as H3K56ac during various growth conditions (Itoh et al, 2017a).…”

NAD+/NADH homeostasis affects metabolic adaptation to hypoxia and secondary metabolite production in filamentous fungi*

“…Hypoxia induces biosynthesis of the secondary metabolite pseurotin A in the airborne fungal pathogen A. fumigatus [75]. SirE is a recently discovered NAD +dependent deacetylase that represses A. nidulans events during the stationary growth phase (that mammals and yeasts lack), autolysis, conidia development, secondary metabolites and extracellular hydrolase production [76].…”

5-Methylmellein is a novel inhibitor of fungal sirtuin and modulates fungal secondary metabolite production

“…We recently reported that the gene disruption of SirA increases sterigmatocystin production by A. nidulans cultured in liquid GMM medium (Itoh et al, 2017b). To determine the potential of 5-methylmellein to alter fungal secondary metabolism, A. nidulans was cultured in GMM medium with or without 100 mM 5-methylmellein for one week, and then the culture broth was extracted with ethyl acetate and analyzed by HPLC.…”

“…This result was unexpected since 5methylmellein inhibits SirA in vitro, and suggests that 5methylmellein targets another sirtuin isozyme(s) that regulates sterigmatocystin production. SirE of this fungus could be the most likely candidate since its gene disruption decreases sterigmatocystin production (Itoh et al, 2017b) and might cancel the possible positive effect of 5methylmellein on sterigmatocystin production through SirA inhibition. The amounts of metabolites at retention times of 6.9, 12.8, 18.2 and 19.8 min were increased > 1.5-fold by 5-methylmellein (P < 0.03) ("1" in Figs.…”