Natural products from plants and microorganisms play a pivotal role in modern medicine and show a wide range of pharmacological properties including anti-inflammatory, anticancer, antioxidant, and antiplasmodial properties [1], [2], [3], [4], [5], [6]. Microbial secondary metabolites, one of the main sources of natural products, are synthesized after an organism has reached a certain stage of growth, which aids in increasing its competitiveness. In the past several decades, microorganisms have produced many structurally diverse metabolites with significant biological activity and contributed greatly to the health and well-being of all humanity [7], [8], [9]. The concern in some quarters is that the decline in compound novelty and the rediscovery of known natural product structures are increasing challenges for microbial secondary metabolite research with the long-term use of existing fermentation methods [10]. In addition, the rise in resistance to antibiotics and cancer chemotherapeutics is a major threat to modern health care. Despite good intentions to control antibiotic use, there is no doubt that the situation with antibiotic resistance is grim. Antimicrobial resistance has been regarded as one of the major threats facing humanity and will threaten the lives of ∼ 10 million people by 2050 if no effective measures are taken [8], [11], [12], [13]. Consequently, to alleviate this challenge, a universally applicable alternative to rationally induce the silencing of natural product biosynthetic pathway expression is needed.

Genetically, microbial secondary metabolites are biologically synthesized by microorganism gene clusters. With the exception of yeast, the number of estimated natural product biosynthetic pathways exceeds the total number of natural products observed under laboratory culture conditions in fungi [14]. In the early 2000 s, whole-genome sequences of actinobacteria and filamentous fungi began to be identified, revealing greater potential to produce structurally diverse metabolites than traditional bioactivity-based screening methods had revealed [11]. The arrival of the genomic era resulted in the realization that the secondary metabolic production potential of these microorganisms was much broader than anyone had appreciated, and the overwhelming majority of secondary metabolite biosynthetic gene clusters (BGCs) are expressed at low levels in laboratory environments. Only a subset of the biosynthetic pathways that encode secondary metabolite production is expressed because traditional fungal fermentation methods poorly mimic the organism's native habitat [14], [15]. To mitigate this challenge, a series of experimental methods have been promoted to determine the metabolites of these clusters. Epigenetic manipulation, which exists at the crossroads of chemistry, biology, and medicine, is an effective method to meet this challenge [16].

In classical genetics, believes changes in the phenotype of any species are considered to be caused by changes in the DNA sequence and can be stably passed on to offspring. With the development of genomics came the gradual realization that gene expression is affected by many other heritable factors in addition to the sequence of DNA itself. There is a complex set of developmental processes between genotypes and phenotypes. Epigenetic manipulation, first proposed by the British scientist Dr. Waddington [17], refers to heritable alterations caused by reversible changes in the chromatin structure between euchromatin and heterochromatin. The complete analysis of the fungal genome shows that many putative biosynthetic gene clusters exist in a heterochromatin state in the distal regions of chromosomes, and the constituent genes are usually transcriptionally controlled by epigenetic regulation such as histone deacetylation and DNA methylation (Fig. 1) [17], [18]. Epigenetic modifiers cause a transition between active and silent chromatin, resulting in altered gene expression and further activating clusters of biosynthetic genes associated with secondary metabolites.

Epigenetic modification modifiers are chemicals that activate genes by changing the epigenetic state [19]. DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis) are the most common epigenetic modifiers that modify the function of microbial DNA. DNA methyltransferases (DNMTs) in fungi regulate posttranslational modifications of DNA and lead to cytosine conversion to the corresponding 5-methylcytosine product. DNA methylation is related to gene silencing, and the introduction of DNMTis is conducive to the activation of silent genes [19], [20]. Histone acetylation is arguably the most widely studied and well-understood histone modification, and its state is dynamic and controlled by the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Generally, hyperacetylation of histones tends to be more commonly associated with euchromatin and gene activation. Therefore, HDACis increase the acetylation level of histones and activate silenced genes [21]. Commonly used epigenetic modifiers (Fig. 2) have successfully induced microorganisms to produce unknown bioactive metabolites [8], [22], [23]. Epigenetic manipulation of fungi can promote the production of complex skeletons, which has attracted widespread attention from scholars. To exploit secondary metabolites from the epigenetic manipulation of microbes and reveal their active value, this review summarizes successful examples of epigenetically induced products of fungi from 2008 to 2022.