Small Chemical Chromatin Effectors Alter Secondary Metabolite Production in Aspergillus clavatus

Abstract

The filamentous fungus Aspergillus clavatus is known to produce a variety of secondary metabolites (SM) such as patulin, pseurotin A, and cytochalasin E. In fungi, the production of most SM is strongly influenced by environmental factors and nutrients. Furthermore, it has been shown that the regulation of SM gene clusters is largely based on modulation of a chromatin structure. Communication between fungi and bacteria also triggers chromatin-based induction of silent SM gene clusters. Consequently, chemical chromatin effectors known to inhibit histone deacetylases (HDACs) and DNA-methyltransferases (DNMTs) influence the SM profile of several fungi. In this study, we tested the effect of five different chemicals, which are known to affect chromatin structure, on SM production in A. clavatus using two growth media with a different organic nitrogen source. We found that production of patulin was completely inhibited and cytochalasin E levels strongly reduced, whereas growing A. clavatus in media containing soya-derived peptone led to substantially higher pseurotin A levels. The HDAC inhibitors valproic acid, trichostatin A and butyrate, as well as the DNMT inhibitor 5-azacytidine (AZA) and N-acetyl-d-glucosamine, which was used as a proxy for bacterial fungal co-cultivation, had profound influence on SM accumulation and transcription of the corresponding biosynthetic genes. However, the repressing effect of the soya-based nitrogen source on patulin production could not be bypassed by any of the small chemical chromatin effectors. Interestingly, AZA influenced some SM cluster genes and SM production although no Aspergillus species has yet been shown to carry detectable DNA methylation.

Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores

“…Recently, the ability of small molecule effectors, like valproic acid (VPA), to inhibit the catalytic activity of HDACs and to modulate the subsequent “cryptic” expression profile of secondary metabolites has been shown in fungi ( Shwab et al, 2007 ; Cole, 2008 ; Cichewicz, 2010 ; Hagemann et al, 2011 ). Furthermore our previous study suggests that the effect of VPA seems to be target specific in fungi ( Zutz et al, 2013 ).…”

Large-Scale Metabolomics Reveals a Complex Response of Aspergillus nidulans to Epigenetic Perturbation

“…16 Like prior reports 12,17-20 we have used broad-spectrum chemical HDAC inhibitors; however, we have also reduced levels of a single HDAC, RpdA (AN4493) 7,21 and quantified the changes in expression of secondary metabolomes (Figure 1). Upon rpdA knockdown, we found that 61 compounds have >100 fold increases in their relative levels and 47 have >100 fold decreases.…”

Diversity of putatively toxigenic Aspergillus species in maize and soil samples in an aflatoxicosis hotspot in Eastern Kenya

“…Since it was not isolated from maize, human risks appear to be reduced. Earlier studies have reported this species to produce a variety of secondary metabolites (SM) such as patulin, pseurotin A and cytochalasin E (Zutz et al, 2013). On the other hand, other species which did not produce toxin in this study have been reported to be toxigenic in earlier studies for example; A. candidus was reported to produce a mycotoxin known as AcT1 (Chattopadhyay et al, 1987), whereas A. awamori has been reported to produce fumonisins (Storari et al, 2012) and aspochalamins A-D (Gebhardt et al, 2004).…”