A Class 1 Histone Deacetylase as Major Regulator of Secondary Metabolite Production in Aspergillus nidulans.

Angelo Pidroni,Gerald Brosch,Birgit Faber,Stefan Graessle,Ingo Bauer

doi:10.3389/fmicb.2018.02212

Abstract

An outstanding feature of filamentous fungi is their ability to produce a wide variety of small bioactive molecules that contribute to their survival, fitness, and pathogenicity. The vast collection of these so-called secondary metabolites (SMs) includes molecules that play a role in virulence, protect fungi from environmental damage, act as toxins or antibiotics that harm host tissues, or hinder microbial competitors for food sources. Many of these compounds are used in medical treatment; however, biosynthetic genes for the production of these natural products are arranged in compact clusters that are commonly silent under growth conditions routinely used in laboratories. Consequently, a wide arsenal of yet unknown fungal metabolites is waiting to be discovered. Here, we describe the effects of deletion of hosA, one of four classical histone deacetylase (HDAC) genes in Aspergillus nidulans; we show that HosA acts as a major regulator of SMs in Aspergillus with converse regulatory effects depending on the metabolite gene cluster examined. Co-inhibition of all classical enzymes by the pan HDAC inhibitor trichostatin A and the analysis of HDAC double mutants indicate that HosA is able to override known regulatory effects of other HDACs such as the class 2 type enzyme HdaA. Chromatin immunoprecipitation analysis revealed a direct correlation between hosA deletion, the acetylation status of H4 and the regulation of SM cluster genes, whereas H3 hyper-acetylation could not be detected in all the upregulated SM clusters examined. Our data suggest that HosA has inductive effects on SM production in addition to its classical role as a repressor via deacetylation of histones. Moreover, a genome wide transcriptome analysis revealed that in addition to SMs, expression of several other important protein categories such as enzymes of the carbohydrate metabolism or proteins involved in disease, virulence, and defense are significantly affected by the deletion of HosA.

Highlights

In addition to their indispensable ecological role in the recycling of organic material, filamentous fungi produce of a variety of commercially used compounds such as pigments, polysaccharides, vitamins, organic acids, enzymes, and even foodstuff such as miso, sake, shoyu, or Quorn (Newman and Cragg, 2012; Harvey et al, 2015)
Novel Regulator of Secondary Metabolite Production bioactive molecules that aid these organisms to adapt to adverse environmental conditions or to repel predators or microbes competing for food sources or habitats
In yeast and certain molds it was shown recently that the class 1 histone deacetylase (HDAC) HOS2 contributes to resistance against antifungals such as voriconazole (Pfaller et al, 2009)

Summary

Introduction

In addition to their indispensable ecological role in the recycling of organic material, filamentous fungi produce of a variety of commercially used compounds such as pigments, polysaccharides, vitamins, organic acids, enzymes, and even foodstuff such as miso, sake, shoyu, or Quorn (Newman and Cragg, 2012; Harvey et al, 2015). Novel Regulator of Secondary Metabolite Production bioactive molecules that aid these organisms to adapt to adverse environmental conditions or to repel predators or microbes competing for food sources or habitats. Some of these molecules are dreaded mycotoxins that, if spoiled food is consumed, have a variety of detrimental effects on humans, ranging from allergic reactions and symptoms of poisoning to the triggering of cancer, if a low-dose exposure occurs over a longer time period (Pitt, 2000). An overview summarizing the multitude of emerging tools and technologies developed for the discovery of novel SMs was recently presented by Hautbergue et al (2018) in a comprehensive review

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