Epigentic Gene Silencing Can Fuel Antifungal Resistance

S. pombe yeast, SEM
Coloured scanning electron micrograph (SEM) of Schizosaccharomyces pombe yeast. S. pombe is a single-celled fungus that is studied widely as a model organism for eukaryotic cell division. It is a rod-shaped yeast that grows by elongation at its ends. It replicates by binary fission. Magnification: x6500 when printed at 10 centimetres wide.

Each year fungal diseases affect billions of people globally, causing an estimated 1.6 million deaths. Infections resistant to treatment are a growing problem, particularly in patients with weakened immune systems, such as those with HIV. Since few effective antifungal drugs exist, it is imperative to understand the nature of fungal resistance and how it develops. Thankfully, investigators at the University of Edinburgh have just made a discovery that could be the key to how resistance mechanisms grow over time.

Amazingly, the research team discovered that fungi could develop drug resistance without changes to their DNA. The findings from the new research—published recently in Nature through an article entitled “Epigenetic gene silencing by heterochromatin primes fungal resistance“—finds that resistance can emerge in fungi without genetic changes. Instead, the fungi exhibit epigenetic changes suggesting that many causes and cases of antifungal resistance could have been previously missed.

The team of scientists from the University of Edinburgh’s Wellcome Centre for Cell Biology studied the emergence of resistance in yeast, Schizosaccharomyces pombe, by treating it with caffeine to mimic the activity of antifungal drugs.

“Our team is excited about the possible implications that these findings may have for understanding how plant, animal, and human fungal pathogens develop resistance to the very limited number of available and effective antifungal drug treatments,” noted senior study investigator Robin Allshire, Ph.D., a professor at the Wellcome Centre for Cell Biology.

The researchers discovered that the resulting resistant yeast had alterations in special chemical tags that affect how their DNA is organized. Some genes became packed into structures known as heterochromatin, which silences or inactivates underlying genes, causing resistance as a result of this epigenetic change.

“We show that heterochromatin-dependent epimutants resistant to caffeine arise in fission yeast grown with threshold levels of caffeine,” the authors wrote. “Isolates with unstable resistance have distinct heterochromatin islands with reduced expression of embedded genes, including some whose mutation confers caffeine resistance. Forced heterochromatin formation at implicated loci confirms that resistance results from heterochromatin-mediated silencing. Our analyses reveal that epigenetic processes promote phenotypic plasticity, letting wild-type cells adapt to unfavorable environments without genetic alteration. In some isolates, subsequent or coincident gene-amplification events augment resistance.”

The authors went on to state that caffeine affects two anti-silencing factors: Epe1 is downregulated, reducing its chromatin association, and a shortened isoform of Mst2 histone acetyltransferase is expressed. Thus, heterochromatin-dependent epimutation provides a bet-hedging strategy allowing cells to adapt transiently to insults while remaining genetically wild type. Isolates with unstable caffeine resistance show cross-resistance to antifungal agents, suggesting that related heterochromatin-dependent processes may contribute to resistance of plant and human fungal pathogens to such agents.”

This discovery could pave the way for new therapies to treat resistant infections by modifying existing epigenetic drugs or developing new drugs that interfere with fungal heterochromatin.

Improved fungicides to treat food crops could limit agricultural losses and also reduce the number of resistant fungal strains in the environment that continue to fuel increased infections in humans.

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