Antifungal drug resistance evoked via RNAi-dependent epimutations
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In M. circinelloides, RNAi-mediated epimutations can confer antifungal resistance via degradation of mRNAs of drug target genes.
“In Mucor circinelloides (causative agent of mucormycosis), RNAi (RNA interference)-mediated epimutations can confer antifungal resistance via degradation of mRNAs of drug target genes100,101.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [101]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
R: A Language and Environment for Statistical Computing
R Core Team (2000) · doi:10.32614/r.manuals · Cited by 355,706 · see citing works
Matplotlib: a 2D graphics environment
Hunter, J. D. (2007) · Computing in Science & Engineering · doi:10.1109/mcse.2007.55 · Cited by 39,249 · see citing works
HTSeq—a Python framework to work with high-throughput sequencing data
Anders, S., Pyl, P. T., & Huber, W. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btu638 · Cited by 21,464 · see citing works
Differential expression analysis for sequence count data
Anders, S., & Huber, W. (2010) · Genome Biology · doi:10.1186/gb-2010-11-10-r106 · Cited by 15,581 · see citing works
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository
Edgar, R. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.1.207 · Cited by 13,288 · see citing works
Kim, D., Pertea, G., Trapnell, C., Pimentel, H., Kelley, R., & Salzberg, S. L. (2013) · Genome Biology · doi:10.1186/gb-2013-14-4-r36 · Cited by 12,668 · see citing works
WebLogo: A Sequence Logo Generator: Figure 1Preprint
Crooks, G. E., Hon, G. C., Chandonia, J., & Brenner, S. E. (2004) · Genome Research · doi:10.1101/gr.849004 · Cited by 12,433 · see citing works
Biopython: freely available python tools for computational molecular biology and bioinformatics
Cock, P. J. A., Antao, T., Chang, J. T., Chapman, B. A., Cox, C. J., Dalke, A., Friedberg, I., Hamelryck, T., Kauff, F., Wilczynski, B., et al. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp163 · Cited by 6,080 · see citing works
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes
Liu, J., Farmer, J. D., Lane, W. S., Friedman, J., Weissman, I., & Schreiber, S. L. (1991) · Cell · doi:10.1016/0092-8674(91)90124-h · Cited by 4,116 · see citing works
Python for scientific computing
Oliphant, T. E. (2007) · Computing in Science & Engineering · doi:10.1109/mcse.2007.58 · Cited by 3,303 · see citing works
Targets for Cell Cycle Arrest by the Immunosuppressant Rapamycin in Yeast
Heitman, J., Movva, N. R., & Hall, M. N. (1991) · Science · doi:10.1126/science.1715094 · Cited by 2,010 · see citing works
Self-citationHTSeq – A Python framework to work with high-throughput sequencing dataPreprint
Anders, S., Pyl, P. T., & Huber, W. K. (2014) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/002824 · Cited by 1,286 · see citing works
An epigenetic mutation responsible for natural variation in floral symmetry
Cubas, P., Vincent, C. A., & Coen, E. (1999) · Nature · doi:10.1038/43657 · Cited by 1,247 · see citing works
Being Sensitive to Uncertainty
Arriola, L. M., & Hyman, J. M. (2007) · Computing in Science & Engineering · doi:10.1109/mcse.2007.27 · Cited by 975 · see citing works
A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans
Kennedy, S. G., Wang, D., & Ruvkun, G. (2004) · Nature · doi:10.1038/nature02302 · Cited by 595 · see citing works
The Genome Portal of the Department of Energy Joint Genome Institute
Grigoriev, I. V., Nordberg, H. P., Shabalov, I., Aerts, A. L., Cantor, M., Goodstein, D. M., Kuo, A., Minovitsky, S., Nikitin, R., Ohm, R. A., et al. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr947 · Cited by 546 · see citing works
Germline epimutation of MLH1 in individuals with multiple cancers
Suter, C. M., Martin, D. I. K., & Ward, R. L. (2004) · Nature Genetics · doi:10.1038/ng1342 · Cited by 475 · see citing works
Inheritance of a Cancer-Associated MLH1 Germ-Line Epimutation
Hitchins, M. P., Wong, J. J. L., Suthers, G., Suter, C. M., Martin, D. I. K., Hawkins, N. J., & Ward, R. L. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa064522 · Cited by 409 · see citing works
Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer
Chan, T. L., Yuen, S. T., Kong, C. K., Chan, Y. W., Chan, A. S., Ng, W. F., Tsui, W. Y., Lo, M. W., Tam, W. Y., Li, V. S., et al. (2006) · Nature Genetics · doi:10.1038/ng1866 · Cited by 324 · see citing works
A Link Between mRNA Turnover and RNA Interference in Arabidopsis
Gazzani, S., Lawrenson, T., Woodward, C. J. D. A., Headon, D., & Sablowski, R. W. M. (2004) · Science · doi:10.1126/science.1101092 · Cited by 322 · see citing works
Elmayan, T., & Vaucheret, H. (1996) · The Plant Journal · doi:10.1046/j.1365-313x.1996.9060787.x · Cited by 295 · see citing works
RNA as a target and an initiator of post-transcriptional gene silencing in trangenic plants
Baulcombe, D. C. (1996) · Plant Molecular Biology · doi:10.1007/bf00039378 · Cited by 285 · see citing works
A model for RNA-mediated gene silencing in higher plants
Wassenegger, M., & Pélissier, T. (1998) · Plant Molecular Biology · doi:10.1023/a:1005946720438 · Cited by 217 · see citing works
Distinct Phases of siRNA Synthesis in an Endogenous RNAi Pathway in C. elegans Soma
Gent, J. I., Lamm, A. T., Pavelec, D. M., Maniar, J. M., Parameswaran, P., Li, T., Kennedy, S. G., & Fire, A. Z. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.01.012 · Cited by 197 · see citing works
Lee, S. C., Li, A., Calo, S., & Heitman, J. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003625 · Cited by 172 · see citing works
Self-citationSporangiospore Size Dimorphism Is Linked to Virulence of Mucor circinelloides
Li, C. H., Cervantes, M., Springer, D. J., Boekhout, T., Ruiz‐Vázquez, R. M., Torres‐Martínez, S., Heitman, J., & Lee, S. C. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002086 · Cited by 151 · see citing works
Self-citationRNAi triggered by specialized machinery silences developmental genes and retrotransposons
Yamanaka, S., Mehta, S. S., Reyes‐Turcu, F. E., Zhuang, F., Fuchs, R. T., Rong, Y. S., Robb, G. B., & Grewal, S. I. S. (2012) · Nature · doi:10.1038/nature11716 · Cited by 148 · see citing works
Nicolás, F. E., de Haro, J. P., Torres‐Martínez, S., & Ruiz‐Vázquez, R. M. (2006) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2006.09.003 · Cited by 136 · see citing works
Self-citationEpimutation of repeated genes in Ascobolus immersus.
Rhounim, L., Rossignol, J., & Faugeron, G. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05546.x · Cited by 135 · see citing works
Colot, V., Maloisel, L., & Rossignol, J. (1996) · Cell · doi:10.1016/s0092-8674(00)80161-0 · Cited by 133 · see citing works
Lee, S. C., Billmyre, R. B., Li, A., Carson, S. A., Sykes, S. M., Huh, E. Y., Mieczkowski, P. A., Ko, D. C., Cuomo, C. A., & Heitman, J. (2014) · mBio · doi:10.1128/mbio.01390-14 · Cited by 133 · see citing works
Self-citationTwo classes of small antisense RNAs in fungal RNA silencing triggered by non‐integrative transgenes
Nicolás, F. E., Torres‐Martínez, S., & Ruiz‐Vázquez, R. M. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg384 · Cited by 132 · see citing works
Self-citationCardenas, M. E., & Heitman, J. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00277.x · Cited by 116 · see citing works
Self-citationOrlowski, M. (1991) · Microbiological Reviews · doi:10.1128/mr.55.2.234-258.1991 · Cited by 105 · see citing works
Nicolás, F. E., Moxon, S., de Haro, J. P., Calo, S., Grigoriev, I. V., Torres‐Martínez, S., Moulton, V., Ruiz‐Vázquez, R. M., & Dalmay, T. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq301 · Cited by 104 · see citing works
Self-citationOrlowski, M. (1991) · Microbiological Reviews · doi:10.1128/mmbr.55.2.234-258.1991 · Cited by 84 · see citing works
Reyes‐Turcu, F. E., & Grewal, S. I. S. (2012) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2011.12.004 · Cited by 81 · see citing works
Bastidas, R. J., Shertz, C. A., Lee, S. C., Heitman, J., & Cardenas, M. E. (2011) · Eukaryotic Cell · doi:10.1128/ec.05284-11 · Cited by 79 · see citing works
Self-citationHigh reliability transformation of the basal fungus Mucor circinelloides by electroporation
Gutiérrez, A., López‐García, S., & Garre, V. (2011) · Journal of Microbiological Methods · doi:10.1016/j.mimet.2011.01.002 · Cited by 77 · see citing works
de Haro, J. P., Calo, S., Cervantes, M., Nicolás, F. E., Torres‐Martínez, S., & Ruiz‐Vázquez, R. M. (2009) · Eukaryotic Cell · doi:10.1128/ec.00191-09 · Cited by 72 · see citing works
Self-citationCalo, S., Nicolás, F. E., Vila, A., Torres‐Martínez, S., & Ruiz‐Vázquez, R. M. (2011) · Molecular Microbiology · doi:10.1111/j.1365-2958.2011.07939.x · Cited by 69 · see citing works
Self-citationCervantes, M., Vila, A., Nicolás, F. E., Moxon, S., de Haro, J. P., Dalmay, T., Torres‐Martínez, S., & Ruiz‐Vázquez, R. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069283 · Cited by 59 · see citing works
Self-citationHigh-frequency heterokaryon formation by Mucor racemosus
Lasker, B. A., & Borgia, P. T. (1980) · Journal of Bacteriology · doi:10.1128/jb.141.2.565-569.1980 · Cited by 48 · see citing works
Wetzel, J., Burmester, A., Kolbe, M., & Wöstemeyer, J. (2012) · Microbiology · doi:10.1099/mic.0.054106-0 · Cited by 30 · see citing works
Endogenous inhibitors of RNA interference in Caenorhabditis elegans
Timmons, L. (2004) · BioEssays · doi:10.1002/bies.20078 · Cited by 22 · see citing works
Non-AUG Translation Initiation of a Fungal RING Finger Repressor Involved in Photocarotenogenesis
Murcia, L., Lorca‐Pascual, J. M., Garre, V., Torres‐Martínez, S., & Ruiz‐Vázquez, R. M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610366200 · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Molecular mechanisms of transgenerational epigenetic inheritance
Fitz-James, M. H., & Cavalli, G. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-021-00438-5 · Cited by 589 · see citing works
Ecological plant epigenetics: Evidence from model and non‐model species, and the way forward
Richards, C. L., Alonso, C., Becker, C., Bossdorf, O., Bucher, E., Colomé‐Tatché, M., Durka, W., Engelhardt, J., Gáspár, B. K., Gogol‐Döring, A., et al. (2017) · Ecology Letters · doi:10.1111/ele.12858 · Cited by 352 · see citing works
Molecular mechanisms governing antifungal drug resistance
Lee, Y., Robbins, N., & Cowen, L. E. (2023) · npj Antimicrobials and Resistance · doi:10.1038/s44259-023-00007-2 · Cited by 304 · see citing works
Fungicide Resistance: Progress in Understanding Mechanism, Monitoring, and Management
Yin, Y., Miao, J., Shao, W., Liu, X., Zhao, Y. F., & Ma, Z. (2023) · Phytopathology · doi:10.1094/phyto-10-22-0370-kd · Cited by 291 · see citing works
Chang, Z., & Heitman, J. (2019) · mBio · doi:10.1128/mbio.02579-19 · Cited by 202 · see citing works
Self-citationAbdolrasouli, A., Rhodes, J. L., Beale, M. A., Hagen, F., Rogers, T. R., Chowdhary, A., Meis, J. F. G. M., Armstrong-James, D. P. H., & Fisher, M. C. (2015) · mBio · doi:10.1128/mbio.00536-15 · Cited by 177 · see citing works
Epigenetic inheritance and reproductive mode in plants and animals
Anastasiadi, D., Venney, C. J., Bernatchez, L., & Wellenreuther, M. (2021) · Trends in Ecology & Evolution · doi:10.1016/j.tree.2021.08.006 · Cited by 162 · see citing works
Hoenigl, M., Arastehfar, A. A., Arendrup, M. C., Brüggemann, R. J. M., Carvalho, A., Chiller, T. M., Chen, W., Egger, M., Feys, S., Gangneux, J., et al. (2024) · Clinical Microbiology Reviews · doi:10.1128/cmr.00074-23 · Cited by 160 · see citing works
Mucormycosis in 2023: an update on pathogenesis and management
Alqarihi, A., Kontoyiannis, D. P., & Ibrahim, A. S. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1254919 · Cited by 145 · see citing works
Epigenetic gene silencing by heterochromatin primes fungal resistance
Torres-Garcia, S., Yaseen, I., Shukla, M. S., Audergon, P. N. C. B., White, S. A., Pidoux, A. L., & Allshire, R. C. (2020) · Nature · doi:10.1038/s41586-020-2706-x · Cited by 128 · see citing works
Trends and Challenges in Pesticide Resistance Detection
(2016) · Trends in Plant Science · doi:10.1016/j.tplants.2016.06.006 · Cited by 115 · see citing works
Navarro-Mendoza, M. I., Arques, C. P., Panchal, S., Nicolás, F. E., Mondo, S. J., Ganguly, P., Pangilinan, J. L., Grigoriev, I. V., Heitman, J., Sanyal, K., et al. (2019) · Current Biology · doi:10.1016/j.cub.2019.09.024 · Cited by 107 · see citing works
Self-citationNon-Target Site Mechanisms of Fungicide Resistance in Crop Pathogens: A Review
Hu, M., & Chen, S. (2021) · Microorganisms · doi:10.3390/microorganisms9030502 · Cited by 106 · see citing works
The RNAi Universe in Fungi: A Varied Landscape of Small RNAs and Biological Functions
Torres‐Martínez, S., & Ruiz‐Vázquez, R. M. (2017) · Annual Review of Microbiology · doi:10.1146/annurev-micro-090816-093352 · Cited by 105 · see citing works
Self-citationSmall RNAs in the Transgenerational Inheritance of Epigenetic Information
Duempelmann, L., Skribbe, M., & Bühler, M. (2020) · Trends in Genetics · doi:10.1016/j.tig.2019.12.001 · Cited by 94 · see citing works
Lee, S. C., Li, A., Calo, S., Inoue, M., Tonthat, N. K., Bain, J. M., Louw, J., Shinohara, M. L., Erwig, L. P., Schumacher, M. A., et al. (2015) · Molecular Microbiology · doi:10.1111/mmi.13071 · Cited by 90 · see citing works
Self-citationWang, L., Chen, H., Li, J., Shu, H., Zhang, X., Wang, Y., Tyler, B. M., & Dong, S. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz1160 · Cited by 89 · see citing works
Drug Resistance and Novel Therapeutic Approaches in Invasive Candidiasis
Murphy, S. E., & Bicanic, T. A. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.759408 · Cited by 85 · see citing works
Epigenetic mechanisms of drug resistance in fungi
Chang, Z., Yadav, V., Lee, S. C., & Heitman, J. (2019) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2019.103253 · Cited by 81 · see citing works
Self-citationMucorales Species and Macrophages
Nicolás, F. E., Murcia, L., Navarro, E., Navarro-Mendoza, M. I., Arques, C. P., & Garre, V. (2020) · Journal of Fungi · doi:10.3390/jof6020094 · Cited by 80 · see citing works
Self-citationSun, S., Hoy, M. J., & Heitman, J. (2020) · Current Biology · doi:10.1016/j.cub.2020.07.032 · Cited by 80 · see citing works
Self-citationAntifungal Resistance: An Emerging Reality and A Global Challenge
Kontoyiannis, D. P. (2017) · The Journal of Infectious Diseases · doi:10.1093/infdis/jix179 · Cited by 77 · see citing works
Genes, Pathways, and Mechanisms Involved in the Virulence of Mucorales
Lax, C., Arques, C. P., Navarro-Mendoza, M. I., Cánovas-Márquez, J. T., Tahiri, G., Pérez-Ruiz, J. A., Osorio-Concepción, M., Murcia, L., Navarro, E., Garre, V., et al. (2020) · Genes · doi:10.3390/genes11030317 · Cited by 76 · see citing works
Self-citationThe Evolutionary Significance of RNAi in the Fungal Kingdom
Lax, C., Tahiri, G., Patiño-Medina, J. A., Cánovas-Márquez, J. T., Pérez-Ruiz, J. A., Osorio-Concepción, M., Navarro, E., & Calo, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249348 · Cited by 76 · see citing works
Self-citationEmpirical evidence for epigenetic inheritance driving evolutionary adaptation
Stajic, D., & Jansen, L. E. T. (2021) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2020.0121 · Cited by 74 · see citing works
RNAi-Based Functional Genomics Identifies New Virulence Determinants in Mucormycosis
Trieu, T. A., Navarro-Mendoza, M. I., Arques, C. P., Sanchis, M., Capilla, J., Navarro-Rodríguez, P., López‐Fernández, L., Torres‐Martínez, S., Garre, V., Ruiz‐Vázquez, R. M., et al. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006150 · Cited by 73 · see citing works
Self-citationChang, Z., Billmyre, R. B., Lee, S. C., & Heitman, J. (2019) · PLOS Genetics · doi:10.1371/journal.pgen.1007957 · Cited by 72 · see citing works
Self-citationJanbon, G., Quintin, J., Lanternier, F., & d’Enfert, C. (2019) · Genes and Immunity · doi:10.1038/s41435-019-0071-2 · Cited by 71 · see citing works
Barber, A. E., Riedel, J., Sae-Ong, T., Kang, K., Brabetz, W., Panagiotou, G., Deising, H. B., & Kurzai, O. (2020) · mBio · doi:10.1128/mbio.02213-20 · Cited by 71 · see citing works
A One Health approach to overcoming fungal disease and antifungal resistance
Woods, M., McAlister, J. A., & Geddes‐McAlister, J. (2023) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1610 · Cited by 68 · see citing works
A Non-canonical RNA Silencing Pathway Promotes mRNA Degradation in Basal Fungi
Trieu, T. A., Calo, S., Nicolás, F. E., Vila, A., Moxon, S., Dalmay, T., Torres‐Martínez, S., Garre, V., & Ruiz‐Vázquez, R. M. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005168 · Cited by 64 · see citing works
Self-citationCalo, S., Nicolás, F. E., Lee, S. C., Vila, A., Cervantes, M., Torres-Martinez, S., Ruiz-Vazquez, R. M., Cardenas, M. E., & Heitman, J. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006686 · Cited by 65 · see citing works
Self-citationNavarro-Mendoza, M. I., Arques, C. P., Murcia, L., Martínez-García, P., Lax, C., Sanchis, M., Capilla, J., Nicolás, F. E., & Garre, V. (2018) · Scientific Reports · doi:10.1038/s41598-018-26051-x · Cited by 62 · see citing works
Self-citationJanbon, G., Quintin, J., Lanternier, F., & d’Enfert, C. (2019) · Microbes and Infection · doi:10.1016/j.micinf.2019.06.011 · Cited by 61 · see citing works
Nicolás, F. E., Vila, A., Moxon, S., Cascales, M. D., Torres‐Martínez, S., Ruiz‐Vázquez, R. M., & Garre, V. (2015) · BMC Genomics · doi:10.1186/s12864-015-1443-2 · Cited by 58 · see citing works
Self-citationMucormycosis: Pathogenesis and Pathology
Challa, S. (2019) · Current Fungal Infection Reports · doi:10.1007/s12281-019-0337-1 · Cited by 53 · see citing works
Mucor circinelloides : Growth, Maintenance, and Genetic Manipulation
Vellanki, S., Navarro-Mendoza, M. I., Garcia, A., Murcia, L., Arques, C. P., Garre, V., Nicolás, F. E., & Lee, S. C. (2018) · Current Protocols in Microbiology · doi:10.1002/cpmc.53 · Cited by 53 · see citing works
Self-citationMolecular bases of antifungal resistance in filamentous fungi
Sharma, C., & Chowdhary, A. (2017) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2017.06.018 · Cited by 51 · see citing works
Priest, S. J., Yadav, V., Roth, C., Dahlmann, T. A., Kück, U., Magwene, P. M., & Heitman, J. (2022) · Nature Microbiology · doi:10.1038/s41564-022-01183-z · Cited by 47 · see citing works
Self-citationVellanki, S., Billmyre, R. B., Lorenzen, A., Campbell, M., Turner, B., Huh, E. Y., Heitman, J., & Lee, S. C. (2020) · mBio · doi:10.1128/mbio.02949-19 · Cited by 47 · see citing works
Self-citationEmerging Issues in Antifungal Resistance
Perfect, J. R., & Ghannoum, M. A. (2020) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2020.05.003 · Cited by 44 · see citing works
Epigenetic Control of Phenotypic Plasticity in the Filamentous Fungus Neurospora crassa
Kronholm, I., Johannesson, H., & Ketola, T. (2016) · G3 Genes Genomes Genetics · doi:10.1534/g3.116.033860 · Cited by 46 · see citing works
Feretzaki, M., Billmyre, R. B., Clancey, S. A., Wang, X., & Heitman, J. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1005868 · Cited by 45 · see citing works
Self-citationEvolutionary Optimization Based on Biological Evolution in Plants
Gupta, N., Khosravy, M., Patel, N. V., & Sethi, I. K. (2018) · Procedia Computer Science · doi:10.1016/j.procs.2018.07.218 · Cited by 44 · see citing works
Day, T. (2016) · Molecular Ecology · doi:10.1111/mec.13603 · Cited by 44 · see citing works
RNA Interference in Fungi: Retention and Loss
Nicolás, F. E., & Garre, V. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.funk-0008-2016 · Cited by 43 · see citing works
Self-citationA non-canonical RNAi pathway controls virulence and genome stability in Mucorales
Arques, C. P., Navarro-Mendoza, M. I., Murcia, L., Navarro, E., Garre, V., & Nicolás, F. E. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008611 · Cited by 43 · see citing works
Self-citationUmbilicariaceae (lichenized Ascomycota) – Trait evolution and a new generic concept
Давыдов, E. A., Peršoh, D., & Rambold, G. (2017) · Taxon · doi:10.12705/666.2 · Cited by 42 · see citing works
Huang, J. T., Rowe, D., Subedi, P., Zhang, W., Suelter, T., Valent, B. S., & Cook, D. E. (2022) · Nature Communications · doi:10.1038/s41467-022-34736-1 · Cited by 41 · see citing works
Mendelian evolutionary theory optimization algorithm
Gupta, N., Khosravy, M., Patel, N. V., Dey, N., & Mahela, O. P. (2020) · Soft Computing · doi:10.1007/s00500-020-05239-2 · Cited by 41 · see citing works
Emerging Trends in Epigenetic Regulation of Nutrient Deficiency Response in Plants
Sirohi, G., Pandey, B. K., Deveshwar, P., & Giri, J. (2016) · Molecular Biotechnology · doi:10.1007/s12033-016-9919-0 · Cited by 40 · see citing works
Mucor circinelloides Thrives inside the Phagosome through an Atf-Mediated Germination Pathway
Arques, C. P., Navarro-Mendoza, M. I., Murcia, L., Lax, C., Martínez-García, P., Heitman, J., Nicolás, F. E., & Garre, V. (2019) · mBio · doi:10.1128/mbio.02765-18 · Cited by 40 · see citing works
Self-citationRNA-based therapeutics to treat human fungal infections
Bruch, A., Kelani, A. A., & Blango, M. G. (2022) · Trends in Microbiology · doi:10.1016/j.tim.2021.09.007 · Cited by 39 · see citing works
Mucorales and Mucormycosis: Recent Insights and Future Prospects
Tahiri, G., Lax, C., Cánovas-Márquez, J. T., Carrillo-Marín, P., Sanchis, M., Navarro, E., Garre, V., & Nicolás, F. E. (2023) · Journal of Fungi · doi:10.3390/jof9030335 · Cited by 37 · see citing works
Self-citationRNAi pathways in Mucor: A tale of proteins, small RNAs and functional diversity
Torres‐Martínez, S., & Ruiz‐Vázquez, R. M. (2015) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2015.11.006 · Cited by 37 · see citing works
Self-citationKhan, N. A., Asaf, S., Ahmad, W., Jan, R., Bilal, S., Khan, I., Khan, A. L., Kim, K., & Al‐Harrasi, A. (2023) · Journal of Fungi · doi:10.3390/jof9020254 · Cited by 35 · see citing works
Understanding Mucormycoses in the Age of “omics”
Soare, A. Y., Watkins, T. N., & Bruno, V. M. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00699 · Cited by 35 · see citing works
Lax, C., Navarro-Mendoza, M. I., Arques, C. P., Navarro, E., Nicolás, F. E., & Garre, V. (2021) · Cell Reports Methods · doi:10.1016/j.crmeth.2021.100124 · Cited by 34 · see citing works
Self-citationMadhavan, Y., Sai, K. V., Shanmugam, D. K., Aashabharathi, M., Devi, G. K., Mohanta, Y. K., Venugopal, D. C., Mohanta, T. K., Sharma, N., & Saravanan, M. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11133620 · Cited by 34 · see citing works
Epigenetic Regulation of Antifungal Drug Resistance
Patra, S., Raney, M., Pareek, A., & Kaur, R. (2022) · Journal of Fungi · doi:10.3390/jof8080875 · Cited by 33 · see citing works
Glycan Alteration Imparts Cellular Resistance to a Membrane-Lytic Anticancer Peptide
Ishikawa, K., Medina, S. H., Schneider, J. P., & Klar, A. J. S. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2016.12.009 · Cited by 32 · see citing works
The interaction of fungi with the environment orchestrated by RNAi
Villalobos‐Escobedo, J. M., Herrera‐Estrella, A., & Carreras-Villaseñor, N. (2016) · Mycologia · doi:10.3852/15-246 · Cited by 31 · see citing works
The molecular mechanism of azole resistance in Aspergillus fumigatus: from bedside to bench and back
Wei, X., Zhang, Y., & Lü, L. (2015) · The Journal of Microbiology · doi:10.1007/s12275-015-5014-7 · Cited by 31 · see citing works
Spada, M., Pugliesi, C., Fambrini, M., & Pecchia, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126798 · Cited by 30 · see citing works
Fungal biology in the post-genomic era
Scazzocchio, C. (2014) · Fungal Biology and Biotechnology · doi:10.1186/s40694-014-0007-6 · Cited by 30 · see citing works
Wilson, R., Bourgeois, M. L., Perez, M. F., & Sarkies, P. (2023) · PLoS Genetics · doi:10.1371/journal.pgen.1010647 · Cited by 29 · see citing works
Molecular mechanisms that govern infection and antifungal resistance in Mucorales
Lax, C., Nicolás, F. E., Navarro, E., & Garre, V. (2024) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00188-22 · Cited by 28 · see citing works
Self-citationLax, C., Mondo, S. J., Osorio-Concepción, M., Muszewska, A., Corrochano-Luque, M., Gutiérrez, G., Riley, R. W., Lipzen, A., Guo, J., Hundley, H. N., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50365-2 · Cited by 27 · see citing works
Self-citationIdentification of an active RNAi pathway in Candida albicans
Iracane, E., Arias‐Sardá, C., Maufrais, C., Ene, I. V., d’Enfert, C., & Buscaino, A. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2315926121 · Cited by 26 · see citing works
Genomic epidemiology describes introduction and outbreaks of antifungal drug-resistant Candida auris
Kappel, D., Gifford, H., Brackin, A. P., Abdolrasouli, A., Eyre, D. W., Jeffery, K. J., Schelenz, S., Aanensen, D. M., Brown, C. S., Borman, A. M., et al. (2024) · npj Antimicrobials and Resistance · doi:10.1038/s44259-024-00043-6 · Cited by 30 · see citing works
Ruiz‐Vázquez, R. M., Nicolás, F. E., Torres‐Martínez, S., & Garre, V. (2015) · Advances in genetics · doi:10.1016/bs.adgen.2015.07.002 · Cited by 26 · see citing works
Self-citationGarcia, A., Adedoyin, G., Heitman, J., & Lee, S. C. (2017) · G3 Genes Genomes Genetics · doi:10.1534/g3.117.041095 · Cited by 25 · see citing works
Self-citationDiscovering the hidden function in fungal genomes
Gervais, N. C., & Shapiro, R. S. (2024) · Nature Communications · doi:10.1038/s41467-024-52568-z · Cited by 23 · see citing works
Recent Advances and Future Directions in the Understanding of Mucormycosis
Garre, V. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.850581 · Cited by 22 · see citing works
Characterization of the FKBP12-Encoding Genes in Aspergillus fumigatus
Falloon, K., Juvvadi, P. R., Richards, A. D., Vargas-Muñiz, J. M., Renshaw, H., & Steinbach, W. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0137869 · Cited by 21 · see citing works
Role of Non-coding RNAs in Fungal Pathogenesis and Antifungal Drug Responses
Dhingra, S. (2020) · Current Clinical Microbiology Reports · doi:10.1007/s40588-020-00151-7 · Cited by 21 · see citing works
Navarro-Mendoza, M. I., Arques, C. P., Parker, J. E., Xu, Z., Kelly, S. L., & Heitman, J. (2024) · mBio · doi:10.1128/mbio.01661-24 · Cited by 20 · see citing works
Self-citationLópez‐Berges, M. S., Scheven, M. T., Hortschansky, P., Misslinger, M., Baldin, C., Gsaller, F., Werner, E. R., Krüger, T., Kniemeyer, O., Weber, J., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147739 · Cited by 21 · see citing works
Yaseen, I., White, S. A., Torres-Garcia, S., Spanos, C., Lafos, M., Gaberdiel, E., Yeboah, R., El Karoui, M., Rappsilber, J., Pidoux, A. L., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00801-y · Cited by 20 · see citing works
Zhang, Z., Zhai, Y., Guo, Y., Li, D., Wang, Z., Wang, J., Chen, Y., Wang, Q., & Gao, Z. (2017) · Microbial Drug Resistance · doi:10.1089/mdr.2017.0018 · Cited by 20 · see citing works
Phenotypic instability in fungi
Silar, P. (2019) · Advances in applied microbiology · doi:10.1016/bs.aambs.2019.03.002 · Cited by 18 · see citing works
Ianiri, G., Clancey, S. A., Lee, S. C., & Heitman, J. (2017) · mBio · doi:10.1128/mbio.01752-17 · Cited by 19 · see citing works
Self-citationRNAi epimutations conferring antifungal drug resistance are inheritable
Arques, C. P., Navarro-Mendoza, M. I., Xu, Z., Walther, G., & Heitman, J. (2025) · Nature Communications · doi:10.1038/s41467-025-62572-6 · Cited by 18 · see citing works
Self-citationNavarro-Mendoza, M. I., Arques, C. P., & Heitman, J. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2220475120 · Cited by 18 · see citing works
Self-citationAn old confusion: Entomophthoromycosis versus mucormycosis and their main differences
Acosta-España, J. D., & Voigt, K. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1035100 · Cited by 17 · see citing works
cyp51A gene silencing using RNA interference in azole‐resistant A spergillus fumigatus
Mousavi, B., Hedayati, M. T., Teimoori‐Toolabi, L., Guillot, J., Alizadeh, A., & Badali, H. (2015) · Mycoses · doi:10.1111/myc.12417 · Cited by 16 · see citing works
Genetic Tools for Investigating Mucorales Fungal Pathogenesis
Garcia, A., Vellanki, S., & Lee, S. C. (2018) · Current Clinical Microbiology Reports · doi:10.1007/s40588-018-0097-7 · Cited by 16 · see citing works
Self-citationCánovas-Márquez, J. T., Falk, S., Nicolás, F. E., Padmanabhan, S., Perez, R. Z., Sánchez‐Ferrer, Á., Navarro, E., & Garre, V. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab238 · Cited by 15 · see citing works
Self-citationGenetic Manipulation in Mucorales and New Developments to Study Mucormycosis
Lax, C., Cánovas-Márquez, J. T., Tahiri, G., Navarro, E., Garre, V., & Nicolás, F. E. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073454 · Cited by 15 · see citing works
Self-citationBiologia futura: combinatorial stress responses in fungi
Emri, T., Forgács, K., & Pócsi, I. (2022) · Biologia Futura · doi:10.1007/s42977-022-00121-8 · Cited by 15 · see citing works
Phenotypic Evolution With and Beyond Genome Evolution
Félix, M. (2016) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2016.04.002 · Cited by 14 · see citing works
Functional Evolution in Orthologous Cell-encoded RNA-dependent RNA Polymerases
Qian, X., Hamid, F., Sahili, A. E., Darwis, D., Wong, Y. H., Bhushan, S., Makeyev, E. V., & Lescar, J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.685933 · Cited by 13 · see citing works
Mohamed, H., Naz, T., Yang, J., Shah, A. M., Nazir, Y., & Song, Y. (2021) · Journal of Fungi · doi:10.3390/jof7121061 · Cited by 14 · see citing works
The mechanisms of target and non-target resistance to QoIs in Corynespora Cassiicola
Sun, B., Zhou, R., Zhu, G., Xie, X., Chai, A., Li, L., Fan, T., Zhang, S., Li, B., & Shi, Y. (2023) · Pesticide Biochemistry and Physiology · doi:10.1016/j.pestbp.2023.105760 · Cited by 12 · see citing works
The RNAi Mechanism Regulates a New Exonuclease Gene Involved in the Virulence of Mucorales
Arques, C. P., Navarro-Mendoza, M. I., Murcia, L., Navarro, E., Garre, V., & Nicolás, F. E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052282 · Cited by 12 · see citing works
Self-citationRNA metabolism and regulation of virulence programs in fungi
Sesma, A. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.03.019 · Cited by 12 · see citing works
Adaptive Evolution and Epigenetics
Kronholm, I. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-805388-1.00028-6 · Cited by 11 · see citing works
Barber, A. E., Riedel, J., Sae-Ong, T., Kang, K., Brabetz, W., Panagiotou, G., Deising, H. B., & Kurzai, O. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.26.116616 · Cited by 11 · see citing works
Mapping the dynamics of epigenetic adaptation in S. pombe during heterochromatin misregulation
Larkin, A., Kunze, C., Seman, M., Levashkevich, A., Curran, J., Morris-Evans, D., Lemieux, S., Khalil, A. S., & Ragunathan, K. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.07.006 · Cited by 10 · see citing works
Genetic and epigenetic engines of diversity in pathogenic microbes
Billmyre, R. B., & Heitman, J. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006468 · Cited by 10 · see citing works
Self-citation
- Authors
- Calo, S., Shertz-Wall, C., Lee, S. C., Bastidas, R. J., Nicolás, F. E., Granek, J. A., Mieczkowski, P., Torres-Martínez, S., Ruiz-Vázquez, R. M., Cardenas, M. E., & Heitman, J.
- Affiliations
- Duke Medical Center (US)
- Universidad de Murcia (ES)
- Duke University (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Heitman, Joseph
- ORCID
- Venue
- Nature
- Published
- 2014-07-27
- Volume
- 513
- Issue
- 7519
- Pages
- 555-558
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4177005
- OpenAlex
- W2007345431
- Cited by
- 175
- References
- 44
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 22 · 2023: 16 · 2022: 21 · 2021: 16 · 2020: 20 · 2019: 10 · 2018: 5 · 2017: 15 · 2016: 13 · 2015: 9 · 2014: 4
- FWCI
- 9.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Ministerio de Ciencia e Innovación
- National Institutes of Health (5r01ca154499-05)
- National Cancer Institute (R01-CA154499, R01 CA154499-04)
- National Institute of Allergy and Infectious Diseases (R37AI039115, R37 AI 39115-17, R01 AI50438-10, R01AI050438, R01AI039115)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Mucor circinelloides, antifungal resistance, tacrolimus, FK506, RNA interference, epimutations, epigenetic silencing, FKBP12, calcineurin, yeast growth, opportunistic fungal pathogens
- MeSH terms
- Humans, Molecular Sequence Data, Mucor, Mucormycosis, Mutation, Phenotype, Tacrolimus, Calcineurin, Tacrolimus Binding Protein 1A, Drug Resistance, Fungal, Hyphae, RNA Interference, Epigenesis, Genetic, Calcineurin Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
