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RNAi-dependent epimutation induces broad antifungal resistance in Mucor circinelloides

ABSTRACT: RNAi-dependent epimutation induces broad antifungal resistance in Mucor circinelloides

PROVIDER: PRJNA453739 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7068270.fastq.gz	Fastqsanger.gz
	SRR7068271.fastq.gz	Fastqsanger.gz
	SRR7068272.fastq.gz	Fastqsanger.gz
	SRR7068273.fastq.gz	Fastqsanger.gz
	SRR7068274.fastq.gz	Fastqsanger.gz

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RNAi-dependent epimutation induces broad antifungal resistance in Mucor circinelloides

Project description:To elucidate the role of epimutation in antifungal resistance of Mucor, epimutations were isolated that confer resistance to 5-fluoroorotic acid (5-FOA). We identified epimutant strains that exhibit resistance to 5-FOA without mutations in either of the 5-FOA target genes, pyrF or pyrG. Using sRNA sequencing, we demonstrate that these epimutants harbor sRNA against either pyrF or pyrG, and further show that this sRNA is lost after reversion to drug sensitivity.

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Antifungal drug resistance evoked via RNAi-dependent epimutations

Project description:Here we show that the human fungal pathogen Mucor circinelloides develops spontaneous resistance to the antifungal drug FK506 via two distinct mechanisms. One involves Mendelian mutations that confer stable drug resistance and the other via an epigenetic RNA interference (RNAi)-mediated pathway that results in unstable drug resistance. The peptidyl-prolyl isomerase FKBP12 interacts with FK506 to form a complex that inhibits the protein phosphatase calcineurin. In M. circinelloides, inhibition of calcineurin by FK506 blocks the transition to hyphae and enforces yeast growth. Mutations in the fkbA gene encoding FKBP12 or the calcineurin cnbR or cnaA genes confer FK506 resistance, restoring hyphal growth in the presence of this drug. In parallel, RNAi is spontaneously triggered to silence the FKBP12 fkbA gene, giving rise to drug-resistant epimutants. FK506-resistant epimutants readily reverted to the drug-sensitive wild type (WT) phenotype when selection was released by growth without drug. High-throughput small RNA (sRNA) sequencing showed abundant sRNA antisense to fkbA only in the epimutants and not in the WT or revertant strains. Analysis of RNAi mutants revealed components required for the establishment of drug resistant epimutants as well as other factors that constrain or reverse the epimutation pathway. Silencing involves generation of a double stranded RNA trigger intermediate using the fkbA mature mRNA as template. These results uncover 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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Project description:Mucormycosis-an emergent, deadly fungal infection-is difficult to treat, in part because the causative species demonstrate broad clinical antifungal resistance. However, the mechanisms underlying drug resistance in these infections remain poorly understood. Our previous work demonstrated that one major agent of mucormycosis, Mucor circinelloides, can develop resistance to the antifungal agents FK506 and rapamycin through a novel, transient RNA interference-dependent mechanism known as epimutation. Epimutations silence the drug target gene and are selected by drug exposure; the target gene is re-expressed and sensitivity is restored following passage without drug. This silencing process involves generation of small RNA (sRNA) against the target gene via core RNAi pathway proteins. To further elucidate the role of epimutation in the broad antifungal resistance of Mucor, epimutants were isolated that confer resistance to another antifungal agent, 5-fluoroorotic acid (5-FOA). We identified epimutant strains that exhibit resistance to 5-FOA without mutations in PyrF or PyrG, enzymes which convert 5-FOA into the active toxic form. Using sRNA hybridization as well as sRNA library analysis, we demonstrate that these epimutants harbor sRNA against either pyrF or pyrG, and further show that this sRNA is lost after reversion to drug sensitivity. We conclude that epimutation is a mechanism capable of targeting multiple genes, enabling Mucor to develop resistance to a variety of antifungal agents. Elucidation of the role of RNAi in epimutation affords a fuller understanding of mucormycosis. Furthermore, it improves our understanding of fungal pathogenesis and adaptation to stresses, including the evolution of drug resistance.

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