Metabolic and regulatory insights from the experimental horizontal gene transfer of the aurofusarin and bikaverin gene clusters to Aspergillus nidulans

• Published in: Molecular microbiology 2019-12, Vol.112 (6), p.1684-1700
• Main Authors: Reus, Elise, Nielsen, Mikkel Rank, Frandsen, Rasmus John Normand
• Format: Article
• Language: English
• Subjects: Aspergillus nidulans; Conservation; Environmental regulations; Fusarium fujikuroi; Gene clusters; Gene transfer; Horizontal transfer; Metabolism; Metabolites; Nitrogen; Regulatory sequences; Transcription
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/mmi.14376

Summary We staged the transfer of the aurofusarin and bikaverin biosynthetic gene clusters (BGCs) to Aspergillus nidulans with the aim of gaining functional insights into dynamics immediately following a horizontal gene transfer (HGT) event. While the introduction of both BGCs resulted in the production of detectable pathway metabolites in A. nidulans, the transferred aurofusarin BGC formed dimeric shunt products instead of aurofusarin. This was linked to low transcription of the cluster activator and insufficient activity of tailoring enzymes, demonstrating how a shift of the pathway bottleneck after HGT can result in metabolic innovation. The transferred bikaverin BGC readily produced bikaverin, providing a model system for studying the conservation of regulatory responses to environmental cues. Conserved PacC‐mediated pH regulation of the bikaverin BGC was observed between original host Fusarium fujikuroi and A. nidulans. Contrary to strong nitrogen responses described in other hosts, the BGC appeared unresponsive to environmental nitrogen in A. nidulans. While F. fujikuroi and A. nidulans both form chlamydospore‐like structures when exposed to ralsolamycin, specific induction of the bikaverin BGC was not observed in A. nidulans. We propose that the presence of compatible cis‐regulatory elements in BGCs facilitates regulatory conservation after transfer, without which the chromosomal context would dictate expression. Comparative genomics identifies widespread horizontal gene transfer (HGT) of biosynthetic gene clusters between fungi. We experimentally transfer the bikaverin and aurofusarin gene clusters to Aspergillus nidulans and study the immediate functional implications on different levels. Based on our findings, we describe how a shift in the pathway bottleneck can lead to metabolite innovation following HGT, and put forward factors that influence whether the regulatory logic of a gene cluster is conserved in the new host.