Research Progress on Epigenetic Regulation of Fungal Secondary Metabolism

Fungi are capable of synthesizing a wide array of secondary metabolites with diverse structures and biological activities, which have significant applications in agriculture, medicine, food, and industry. However, a large number of fungal secondary metabolite biosynthetic gene cluster (SM-BGC) remain transcriptionally silent under standard laboratory conditions, posing a major challenge for the discovery and utilization of their potential products. In recent years, epigenetic mechanisms such as DNA methylation, chromatin remodeling, non-coding RNAs, and RNA modifications have attracted increasing attention for their roles in regulating gene expression and secondary metabolism in fungi. This review summarizes the major epigenetic mechanisms regulating fungal gene expression, with a particular focus on histone acetylation, histone methylation, and the global regulatory factor LaeA in controlling the secondary metabolite biosynthesis. Histone modifications, as a core component of epigenetic regulation, modulate chromatin structure through chemical modifications such as acetylation and methylation, ultimately affecting the activation or silencing of gene clusters. Histone acetylation is generally associated with the activation of secondary metabolite gene clusters, whereas the effects of histone methylation depend heavily on specific methylation sites and the activity of the corresponding methyltransferases or demethylases. LaeA, a conserved S-adenosylmethionine (SAM)-dependent methyltransferase in filamentous fungi, plays a central role in modulating the chromatin landscape of multiple secondary metabolite gene clusters. Beyond its chromatin-modifying function, LaeA also cooperates with other transcription factors such as BrlA and CreA to coordinate complex metabolic networks. This review also discusses the potential applications of chemical epigenetic modifiers, including DNA methyltransferase inhibitors and histone deacetylase inhibitors, in activating silent gene clusters and modulating fungal secondary metabolism, promoting the biosynthesis of offering valuable strategies for fungal natural product discovery.