Deletion of the Histone Deacetylase HdaA in Endophytic Fungus Penicillium chrysogenum Fes1701 Induces the Complex Response of Multiple Bioactive Secondary Metabolite Production and Relevant Gene Cluster Expression.

Zhuang Ding,Ruiyan Zhang,Xiao Wang,Haotian Wang,Huiming Huang,Haibo Zhou,Zhengping Wang,Jun Han

doi:10.3390/molecules25163657

Zhuang Ding, Ruiyan Zhang + Show 6 more

Open Access

https://doi.org/10.3390/molecules25163657

Copy DOI

Abstract

Epigenetic regulation plays a critical role in controlling fungal secondary metabolism. Here, we report the pleiotropic effects of the epigenetic regulator HdaA (histone deacetylase) on secondary metabolite production and the associated biosynthetic gene clusters (BGCs) expression in the plant endophytic fungus Penicillium chrysogenum Fes1701. Deletion of the hdaA gene in strain Fes1701 induced a significant change of the secondary metabolite profile with the emergence of the bioactive indole alkaloid meleagrin. Simultaneously, more meleagrin/roquefortine-related compounds and less chrysogine were synthesized in the ΔhdaA strain. Transcriptional analysis of relevant gene clusters in ΔhdaA and wild strains indicated that disruption of hdaA had different effects on the expression levels of two BGCs: the meleagrin/roquefortine BGC was upregulated, while the chrysogine BGC was downregulated. Interestingly, transcriptional analysis demonstrated that different functional genes in the same BGC had different responses to the disruption of hdaA. Thereinto, the roqO gene, which encodes a key catalyzing enzyme in meleagrin biosynthesis, showed the highest upregulation in the ΔhdaA strain (84.8-fold). To our knowledge, this is the first report of the upregulation of HdaA inactivation on meleagrin/roquefortine alkaloid production in the endophytic fungus P. chrysogenum. Our results suggest that genetic manipulation based on the epigenetic regulator HdaA is an important strategy for regulating the productions of secondary metabolites and expanding bioactive natural product resources in endophytic fungi.

Highlights

Filamentous fungi are well-known producers of diverse secondary metabolites (SMs), which have a wide range of biological activities and can be beneficial or harmful to human beings [1,2]
Because the deletion of ∆hdaA greatly influenced the production of chrysogine (1) and meleagrin (2), Because the deletion of ΔhdaA greatly influenced the production of chrysogine (1) and meleagrin we further investigated the differences in the transcriptional levels of genes from two biosynthetic gene clusters (BGCs) encoding
Our results demonstrate protein Pga1 has been reported to upregulate the biosynthesis of roquefortine in P. chrysogenum that itWis54-1255 is important to reveal the different effects of epigenetic regulators in the same organism on

Summary

Introduction

Filamentous fungi are well-known producers of diverse secondary metabolites (SMs), which have a wide range of biological activities and can be beneficial or harmful to human beings [1,2]. Many beneficial fungi-derived SMs have long been clinically utilized as antibacterials (penicillin and cephalosporin), antifungals (anidulafungin and caspofungin), immunosuppressants (cyclosporin), and antihypercholesterolemic drugs (lovastatin) [3]. As an industrial microbial strain used for producing the β-lactam antibiotic penicillin, Penicillium chrysogenum has the capacity to synthesize many SMs with diverse chemical structures and significant bioactivities, such as alkaloids, polyketides, and terpenoids [5,6,7]. Genome sequencing and genetic studies of P. chrysogenum have led to the elucidation of many secondary metabolic pathways for SM production [8,9]. The regulatory factors PcRFX1 and PcFKH1 have been characterized to positively control penicillin biosynthesis in Penicillium chrysogenum [10,11]

Methods

Results

Conclusion