Histone Modifications in Fungal Pathogenesis

Histone modifications constitute a dynamic layer of epigenetic regulation that shapes gene expression programmes central to fungal virulence, morphogenesis and drug resistance. In pathogenic fungi such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, covalent marks on histone tails – including acetylation, deacetylation, methylation, succinylation and crotonylation – alter chromatin accessibility at promoters and coding regions of genes involved in cell wall assembly, stress responses and secondary metabolism. These modifications coordinate the switch from benign commensal states to invasive growth forms, regulate immune‐evasion mechanisms and underpin the rapid emergence of antifungal resistance. By modulating transcriptional kinetics and enabling integration of environmental cues, histone modifiers and their reader proteins represent both fundamental determinants of fungal pathogenicity and promising targets for novel therapeutic strategies.

Research from Nature Portfolio

Recent studies have elucidated how specific histone-modifying enzymes govern virulence traits in major fungal pathogens. Work on Aspergillus fumigatus has revealed that a NAD+-dependent lysine deacetylase is essential for maintenance of cell wall integrity, thermotolerance and full pathogenicity in animal models. Loss of this deacetylase alters acetylation patterns on histones and non-histone substrates, leading to dysregulation of secondary metabolite clusters and cell wall biosynthetic genes, thus identifying deacetylase inhibition as a potential adjunct to existing antifungals. In Candida albicans, the histone acetyltransferase Gcn5 has been shown to orchestrate multiple pathways critical for infection, including morphogenetic transitions, cell wall-mediated signalling cascades and defence against host-derived oxidative stress. Genetic ablation of Gcn5 abolishes fungal virulence in murine models and sensitises cells to cell wall-targeting agents, underlining its promise as a drug target. Earlier foundational work established that selective inhibition of fungal bromodomain proteins disrupts chromatin recognition modules and impairs viability and virulence, laying the groundwork for highly selective epigenetic inhibitors as novel antifungal agents.

Histone Modifications in Fungal Pathogenesis publication trend

The graph below shows the total number of articles in histone modifications in fungal pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Histone acetylation: Addition of acetyl groups to lysine residues on histone tails, generally associated with transcriptional activation.

Histone deacetylase (HDAC): Enzyme that removes acetyl groups from histones and other proteins, often leading to chromatin compaction and gene repression.

Lysine succinylation: Post-translational addition of a succinyl group to lysine residues, affecting protein charge and function.

Lysine crotonylation: Post-translational addition of a crotonyl group to lysine residues, linked to metabolic state and gene regulation.

Bromodomain: Protein module that recognises acetylated lysine on histones and recruits transcriptional machinery.

Acetyltransferase (KAT): Enzyme that transfers acetyl groups to lysine residues on histones or other proteins, modulating chromatin structure.

Hyphal morphogenesis: Transition of fungal cells from yeast-like forms to filamentous hyphae, a key virulence determinant.

References

1. Post-translational modifications confer amphotericin B resistance in Candida krusei isolated from a neutropenic patient. Frontiers in Immunology (2023).
2. Sirtuin E deacetylase is required for full virulence of Aspergillus fumigatus. Communications Biology (2024).
3. The short-chain fatty acid crotonate reduces invasive growth and immune escape of Candida albicans by regulating hyphal gene expression. mBio (2023).
4. Post-Translational Modifications Drive Success and Failure of Fungal–Host Interactions. Journal of Fungi (2021).
5. The Fungal Histone Acetyl Transferase Gcn5 Controls Virulence of the Human Pathogen Candida albicans through Multiple Pathways. Scientific Reports (2019).
6. Selective BET bromodomain inhibition as an antifungal therapeutic strategy. Nature Communications (2017).