In a study published online in Science Advances, researchers at the Institute of Microbiology of the Chinese Academy of Sciences screened out an endophytic fungus Epicoccum dendrobii (E. dendrobii) which stimulated global alteration in the secondary metabolic profile of Aspergillus nidulans (A. nidulans) during the exploration of interaction between the model fungus A. nidulans and other fungi.  

They found that E. dendrobii was able to induce SM changes of at least fungi from four genera during cocultivation, indicating that the donor fungus E. dendrobii might contribute a general mechanism to trigger the recipient fungi which produce novel SMs by global regulations on secondary metabolism as the responses. 

But how is this response achieved? Researchers demonstrated the response mechanism by chemical and genetic experiments during cocultivation of E. dendrobii and A. nidulans. Transcriptome and metabolome analysis showed the widespread alteration of transcription and secondary metabolism in A. nidulans triggered by E. dendrobii, leading to the up-regulated expression of 15.4% and down-regulated of 19.0% of the genes in A. nidulans, as well as the up-regulation of 22 SMs which includes eight novel polyketides (aspernidines) synthesized by the silent pkf BGC. 

Unprecedentedly, gene deletion and replacement proved that the partial loss-of-function VeA1 protein is crucial for the SM alteration in fungal-fungal cocultivation. Researchers proved that the velvet complex regulators VeA1, LaeA, and VelB but not VeA or VosA were involved in the positive regulation of aspernidine derivatives during cocultivation. Through transcriptome analysis and gene deletions of potential transcription factors, they confirmed that the sole Zn(II)₂Cys₆ transcription factor SclB affects SM production in A. nidulans under cocultivation conditions. 

In addition, researchers confirmed the generalizability of regulatory network in A. fumigatus and E. dendrobii cocultivation system by gene deletion and complementation. Cocultivation of E. dendrobii with A. nidulans carrying the veA1 allele led to widespread alteration of secondary metabolism, representing a new example for pathway activation. Partial loss-of-function of VeA (VeA1) is crucial for fungal chemical signal transduction triggered by cocultivation. Therefore, cocultivation with E. dendrobii stimulated the VelB-VeA1-LaeA complex in A. nidulans, which subsequently induced the expression of SclB for eventually activating the silent pkf BGC and leading to the discovery of cryptic SMs. 

This study presented a regulatory network mediated by partial loss-of-function mutation of VeA in a fungal-fungal interaction, and provided insights into understanding the mechanism of microbial communication.