RNAi epimutations conferring antifungal drug resistance are inheritable
Abstract Epimutations modify gene expression and lead to phenotypic variation while the encoding DNA sequence remains unchanged. Epimutations mediated by RNA interference (RNAi) and/or chromatin modifications can confer antifungal drug resistance and may impact virulence traits in fungi. However, wh...
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| Format: | Article |
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62572-6 |
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| author | Carlos Pérez-Arques María Isabel Navarro-Mendoza Ziyan Xu Grit Walther Joseph Heitman |
| author_facet | Carlos Pérez-Arques María Isabel Navarro-Mendoza Ziyan Xu Grit Walther Joseph Heitman |
| author_sort | Carlos Pérez-Arques |
| collection | DOAJ |
| description | Abstract Epimutations modify gene expression and lead to phenotypic variation while the encoding DNA sequence remains unchanged. Epimutations mediated by RNA interference (RNAi) and/or chromatin modifications can confer antifungal drug resistance and may impact virulence traits in fungi. However, whether these epigenetic modifications can be transmitted across generations following sexual reproduction was unclear. This study demonstrates that RNAi epimutations conferring antifungal drug resistance are transgenerationally inherited in the human fungal pathogen Mucor circinelloides. Our research reveals that RNAi-based antifungal resistance follows a DNA sequence-independent, non-Mendelian inheritance pattern. Small RNAs (sRNAs) are the exclusive determinants of inheritance, transmitting drug resistance independently of other known repressive epigenetic modifications. Unique sRNA signature patterns can be traced through inheritance from parent to progeny, further supporting RNA as an alternative molecule for transmitting information across generations. Understanding how epimutations occur, propagate, and confer resistance may enable their detection in other eukaryotic pathogens, provide solutions for challenges posed by rising antimicrobial drug resistance, and advance research on phenotypic adaptability and its evolutionary implications. |
| format | Article |
| id | doaj-art-e9fdeae2fe414aa388baaf45fe9071cf |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e9fdeae2fe414aa388baaf45fe9071cf2025-08-20T04:02:57ZengNature PortfolioNature Communications2041-17232025-08-0116111110.1038/s41467-025-62572-6RNAi epimutations conferring antifungal drug resistance are inheritableCarlos Pérez-Arques0María Isabel Navarro-Mendoza1Ziyan Xu2Grit Walther3Joseph Heitman4Department of Molecular Genetics and Microbiology, Duke University School of MedicineDepartment of Molecular Genetics and Microbiology, Duke University School of MedicineDepartment of Molecular Genetics and Microbiology, Duke University School of MedicineNational Reference Center for Invasive Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll InstituteDepartment of Molecular Genetics and Microbiology, Duke University School of MedicineAbstract Epimutations modify gene expression and lead to phenotypic variation while the encoding DNA sequence remains unchanged. Epimutations mediated by RNA interference (RNAi) and/or chromatin modifications can confer antifungal drug resistance and may impact virulence traits in fungi. However, whether these epigenetic modifications can be transmitted across generations following sexual reproduction was unclear. This study demonstrates that RNAi epimutations conferring antifungal drug resistance are transgenerationally inherited in the human fungal pathogen Mucor circinelloides. Our research reveals that RNAi-based antifungal resistance follows a DNA sequence-independent, non-Mendelian inheritance pattern. Small RNAs (sRNAs) are the exclusive determinants of inheritance, transmitting drug resistance independently of other known repressive epigenetic modifications. Unique sRNA signature patterns can be traced through inheritance from parent to progeny, further supporting RNA as an alternative molecule for transmitting information across generations. Understanding how epimutations occur, propagate, and confer resistance may enable their detection in other eukaryotic pathogens, provide solutions for challenges posed by rising antimicrobial drug resistance, and advance research on phenotypic adaptability and its evolutionary implications.https://doi.org/10.1038/s41467-025-62572-6 |
| spellingShingle | Carlos Pérez-Arques María Isabel Navarro-Mendoza Ziyan Xu Grit Walther Joseph Heitman RNAi epimutations conferring antifungal drug resistance are inheritable Nature Communications |
| title | RNAi epimutations conferring antifungal drug resistance are inheritable |
| title_full | RNAi epimutations conferring antifungal drug resistance are inheritable |
| title_fullStr | RNAi epimutations conferring antifungal drug resistance are inheritable |
| title_full_unstemmed | RNAi epimutations conferring antifungal drug resistance are inheritable |
| title_short | RNAi epimutations conferring antifungal drug resistance are inheritable |
| title_sort | rnai epimutations conferring antifungal drug resistance are inheritable |
| url | https://doi.org/10.1038/s41467-025-62572-6 |
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