Epigenetic Regulation of Fungal Secondary Metabolism

Fungal secondary metabolism encompasses the synthesis of a vast array of non‐essential yet ecologically and pharmacologically vital compounds, including antibiotics, mycotoxins and pigments. These pathways are typically encoded within physically linked biosynthetic gene clusters (BGCs), which remain transcriptionally silent under standard conditions. Epigenetic regulation—comprising DNA methylation, histone post-translational modifications and chromatin remodelling—controls the accessibility of these BGCs to the transcriptional machinery. Under environmental or developmental cues, repressive chromatin marks such as histone deacetylation and heterochromatin formation are removed or remodelled into an active state via histone acetylation, methylation changes or nucleosome repositioning. Global regulatory proteins and RNA-binding factors further integrate signal transduction pathways with chromatin dynamics, coordinating cluster activation. Understanding these multilayered controls has illuminated strategies to awaken cryptic pathways for novel natural product discovery, enhance industrial fermentation yields and mitigate the production of harmful mycotoxins. Advances in genome editing, chemical epigenetic modifiers and multi-omics profiling continue to refine our capacity to manipulate epigenetic states for both basic research and biotechnological applications.

Research from Nature Portfolio

Recent studies have uncovered a novel mechanism by which an RNA-binding protein and its regulatory partner co-ordinate chromatin-level control of secondary metabolism. Through combined genetic deletion, transcriptome and metabolome analyses, researchers demonstrated that the RNA-binding protein CsdA physically interacts with the regulatory factor RsdA within the nucleus, modulating RsdA expression at a post-transcriptional level. This interaction influences global chromatin accessibility across multiple BGCs, leading to broad changes in metabolite profiles. The work exemplifies how RNA-protein complexes can serve as epigenetic switches, linking post-transcriptional gene regulation to chromatin remodelling and secondary metabolite synthesis in fungi.

Epigenetic Regulation of Fungal Secondary Metabolism publication trend

The graph below shows the total number of articles in epigenetic regulation of fungal secondary metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Epigenetics: Heritable changes in gene expression that occur without alteration of the underlying DNA sequence, often mediated by DNA methylation, histone modifications and chromatin remodelling.

Chromatin: The complex of DNA and histone proteins that packages eukaryotic genomes and whose structural state regulates access to genetic information.

Secondary Metabolites: Non-essential organic compounds produced by organisms that serve ecological functions such as defence, competition and signalling, including antibiotics and toxins.

Histone Modification: Covalent post-translational alterations of histone proteins (e.g. acetylation, methylation, phosphorylation) that influence chromatin structure and gene transcription.

Biosynthetic Gene Cluster (BGC): A contiguous set of genes encoding enzymes and regulators responsible for the production of a particular secondary metabolite pathway.

References

1. Fungal secondary metabolism is governed by an RNA-binding protein CsdA/RsdA complex. Nature Communications (2023).
2. Effects of Epigenetic Modification and High Hydrostatic Pressure on Polyketide Synthase Genes and Secondary Metabolites of Alternaria alternata Derived from the Mariana Trench Sediments. Marine Drugs (2023).
3. A Close View of the Production of Bioactive Fungal Metabolites Mediated by Chromatin Modifiers. Molecules (2024).
4. Epigenetic Induction of Secondary Metabolites Production in Endophytic Fungi Penicillium chrysogenum and GC-MS Analysis of Crude Metabolites with Anti-HIV-1 Activity. Microorganisms (2023).