Fungal infections are becoming harder to treat because the drugs that should kill them stop working. The standard explanation has been that fungi evolve resistance by mutating their DNA, but this team discovered that fungi can also become resistant through temporary, reversible changes in how their genes are packaged and silenced—so-called epimutations—without any change to the DNA sequence itself. This matters because antifungal resistance is rising in both human pathogens, such as the meningitis-causing *Cryptococcus neoformans*, and in crop pathogens like *Zymoseptoria tritici*, which devastates wheat harvests. Understanding this hidden epigenetic route to resistance could explain why some infections relapse after treatment and why resistance emerges so quickly in the field. The researchers will use fission yeast as a model system, then test whether the same mechanism operates in real fungal pathogens. If epimutations prove to be a general first step toward drug evasion, it would fundamentally change how scientists think about resistance—and open the door to new strategies that block the epigenetic switch before resistance becomes permanent. This is fundamental science, but with direct implications for medicine and global food security.
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Antifungal resistance is increasingly prevalent, raising fungal-borne disease frequencies in humans and crops important for human wellbeing. Conventional wisdom that resistance results solely from genetic mutations has been overturned by our landmark discovery that epigenetic gene repression can cause resistance via heterochromatin-island ‘epimutations’ that arise in fission yeast exposed to external insults. Transient ectopic methyl-H3K9-heterochromatin is normally rapidly erased by the counteracting Epe1-H3K9-demethylase. However, external insults/antifungals inactivate Epe1 via MAP Kinase-induced, proteasome-mediated cleavage, allowing heterochromatin-island formation. Epimutation-mediated repression of mitochondrial protein levels likely confers resistance through mitochondrial dysfunction. We propose that innate or imposed metabolic stress predisposes some cells in populations to form epimutations, and that heterochromatin islands increase mutation frequencies in underlying resistance genes. We will dedicate our expertise in chromatin-mediated epigenetic regulation to understanding how antifungals alter fungal epigenetic landscapes to promote resistance. We will determine how antifungals influence resistant epimutant emergence in human (Cryptococcus neoformans) and wheat (Zymoseptoria tritici) fungal pathogens. Using fission yeast as our workhorse alongside pathogenic fungi we will explore mechanistic conservation and divergence, and real-world impact. Evidence that heterochromatin-dependent epimutations provide a general pathway for initial antifungal evasion would dramatically alter understanding of resistance mechanisms in human and crop fungal pathogens, and beyond.
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