Secondary metabolite biosynthetic gene clusters and their genomic localization in the fungal genusAspergillus

Abstract

Fungi are well-known producers of bioactive secondary metabolites (SMs), which have been exploited for centuries by humankind for various medical applications like therapeutics and antibiotics. SMs are synthesized by biosynthetic gene clusters (BGCs) – physically co-localized and co-regulated genes. Because BGCs are often regulated by histone post-translational modifications (PTMs), it was suggested that their chromosomal location is important for their expression. Studies in a few fungal species indicated an enrichment of BGCs in sub-telomeric regions, however, there is no evidence that BGCs with distinct genomic localization are regulated by different histone PTMs. Here, we used 174Aspergillusspecies covering 22 sections to determine the correlation between BGC genomic localization, gene expression, and histone PTMs. We found a high abundance and diversity of SM backbone genes across theAspergillusgenus, with notable diversity increases between sections. Being unique or conserved in many species, BGCs showed a strong bias for being localized in low-synteny regions, regardless of their position in chromosomes. Using chromosome-level assemblies, we also confirmed a significantly biased localization in sub-telomeric regions. Notably, SM backbone genes in sub-telomeric regions and about half of those in low-synteny regions exhibit higher gene expression variability, likely due to the similar higher variability in H3K4me3 and H3K36me3 histone PTMs. In contrast, variations in histone H3 acetylation and H3K9me3 are not correlated to genomic localization and expression variation. Overall, our results indicate that BGCs tend to be located in low-synteny regions and that regulation of expression in those regions likely involves different histone PTMs than the most commonly studied modifications.SignificanceFungi are known for producing a myriad of bioactive compounds with medical benefits, yet our understanding of how the production of these compounds is regulated remains limited. Here, we focused on the fungal genusAspergillus, containing many species known to be prolific producers of bioactive compounds, to systematically uncover the diversity and genomic localization of biosynthetic pathways. By expanding our knowledge beyond the few commonly studied fungal species, this research offers novel insights into how the genomic localization of biosynthetic pathways matters for the regulation of their expression. Our results pave the way for the discovery and harnessing of new fungal metabolites for medical and industrial applications.