ArticleNature2014
Antifungal drug resistance evoked via RNAi-dependent epimutations.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.
What it found
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Who cites it
111 citing papers in PubMed, 190 citations in OpenAlex.
- Recurrent reversible mutations atMicrobiology spectrum · 2026Article
- Molecular Mechanisms, Diagnosis, and Therapeutic Strategies of Antifungal Resistance in Filamentous Fungi.Journal of fungi (Basel, Switzerland) · 2026Review
- Aneuploidy promotes transient stress adaptation and metabolic flexibility in the human fungal pathogen Aspergillus fumigatus.Current biology : CB · 2026Article
- Antifungal resistance: from classical mechanisms to the expanding role of acetyltransferases.Journal of biomedical science · 2026Review
- Variable ectopic heterochromatin islands provide an alternative route to antifungal heteroresistance inbioRxiv : the preprint server for biology · 2026Article
- Thermal adaptation crosstalk with azole response through lncRNA inbioRxiv : the preprint server for biology · 2026Article
- Genetic and Epigenetic Mechanisms Underlying Reversible Adaptive Responses in Fungi.Journal of fungi (Basel, Switzerland) · 2026Review
- Centromeres are hotspots of cytosine methylation epimutations in a filamentous fungus.bioRxiv : the preprint server for biology · 2026Article
- Epimutations: raw material for evolution?The EMBO journal · 2026Review
- Epimutations driven by RNAi or heterochromatin evoke transient antimicrobial drug resistance in pathogenic Mucor fungi.PLoS biology · 2026Article
- Coordinated gene family evolution shapes the genome of dimorphic Mucorales.Nature communications · 2026Article
- Heterochromatin epimutations impose mitochondrial dysfunction to confer antifungal resistance.The EMBO journal · 2026Article
- From Methylomes to CRISPR Epigenetic Editing: New Paths in Antibiotic Resistance.Pathogens (Basel, Switzerland) · 2025Review
- Stress-driven emergence of heritable non-genetic drug resistance.Research square · 2025Article
- Epimutations driven by RNAi or heterochromatin evoke transient antimicrobial drug resistance in fungi.bioRxiv : the preprint server for biology · 2025Article
- Whole-chromosome duplications drive antimicrobial resistance inbioRxiv : the preprint server for biology · 2025Article
- Tandem repeat-induced sexual silencing: A Rid-dependent RNAi mechanism for fungal genome defense via translational repression.Science advances · 2025Article
- RNAi epimutations conferring antifungal drug resistance are inheritable.Nature communications · 2025Article
- Celebrating the fifth edition of the International Symposium on Fungal Stress - ISFUS, a decade after its 2014 debut.Fungal biology · 2025Article
- The Fungal Kingdom as a Rosetta Stone for biological discovery.Current biology : CB · 2025Article
51 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Microorganisms evolve via a range of mechanisms that may include or involve sexual/parasexual reproduction, mutators, aneuploidy, Hsp90 and even prions. Mechanisms that may seem detrimental can be repurposed to generate diversity. Here we show that the human fungal pathogen Mucor circinelloides develops spontaneous resistance to the antifungal drug FK506 (tacrolimus) via two distinct mechanisms. One involves Mendelian mutations that confer stable drug resistance; the other occurs via an epigenetic RNA interference (RNAi)-mediated pathway resulting in unstable drug resistance. The peptidylprolyl isomerase FKBP12 interacts with FK506 forming a complex that inhibits the protein phosphatase calcineurin. Calcineurin inhibition by FK506 blocks M. circinelloides transition to hyphae and enforces yeast growth. Mutations in the fkbA gene encoding FKBP12 or the calcineurin cnbR or cnaA genes confer FK506 resistance and restore hyphal growth. In parallel, RNAi is spontaneously triggered to silence the fkbA gene, giving rise to drug-resistant epimutants. FK506-resistant epimutants readily reverted to the drug-sensitive wild-type phenotype when grown without exposure to the drug. The establishment of these epimutants is accompanied by generation of abundant fkbA small RNAs and requires the RNAi pathway as well as other factors that constrain or reverse the epimutant state. Silencing involves the generation of a double-stranded RNA trigger intermediate using the fkbA mature mRNA as a template to produce antisense fkbA RNA. This study uncovers a novel epigenetic RNAi-based epimutation mechanism controlling phenotypic plasticity, with possible implications for antimicrobial drug resistance and RNAi-regulatory mechanisms in fungi and other eukaryotes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.