|
| Status |
Public on Feb 20, 2024 |
| Title |
Mod5 mediates a molecular trade-off between transcriptional and translational regulation and antifungal resistance. |
| Organism |
Aspergillus fumigatus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Increasing antifungal drug resistance is a major concern associated with human fungal infections. Genetic mutation and epimutation mechanisms are clearly linked to resistance in some fungi, but few studies have investigated RNA modifications (the epitranscriptome) as a mediator of resistance. Here, deletion of the Aspergillus fumigatus tRNA-modifying isopentenyl transferase ortholog, Mod5, led to altered growth and stress response, but also unexpected resistance against the antifungal drug 5-fluorocytosine (5-FC). Simultaneous profiling of the transcriptome and proteome of 5-FC-stressed wild-type and ∆mod5 strains revealed a similar general adaptation to stress; however, the knockout displayed elevated expression of cross-pathway control (CPC) genes. Quantification of CPC transcription factor cpcA and client gene argB showed premature CPC activation in ∆mod5, which was further increased upon treatment with 5-FC. By associating codon usage patterns with proteomics abundances, we observed the number of tRNATyrGΨA-decoded codons to negatively correlate with protein abundance in the knockout, indicative of modification-tunable transcripts. Overexpression of tRNATyrGΨA in the ∆mod5 strain rescued select phenotypes but, surprisingly, failed to reverse 5-FC resistance. Investigation of the purported tRNA gene-mediated silencing function of Mod5 uncovered a negative correlation between tRNA proximity and gene induction under normal growth, suggesting that tRNA gene-mediated silencing is active in A. fumigatus. In conclusion, 5-FC resistance in the absence of bifunctional Mod5 likely originates from multifaceted transcriptional and translational changes that skew the fungus towards starvation responses over optimal growth, potentially offering a mechanism reliant on RNA modification and tRNA gene-mediated silencing capable of facilitating transient antifungal resistance.
|
| |
|
| Overall design |
Comparative gene expression profiling analysis of poly(A) RNA-seq data for 𝚫mod5 knockouts of Aspergillus fumigatus mycelium left unstressed for 24 hours in Aspergillus minimal media or grown for 16 hours unstressed followed by 8 hours stressed with 5-fluorocytosine.
|
| Web link |
https://www.biorxiv.org/content/10.1101/2024.02.19.578369v1
|
| |
|
| Contributor(s) |
Blango MG, Bruch A, Lazarova V |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Dec 20, 2023 |
| Last update date |
Feb 20, 2024 |
| Contact name |
Matthew George Blango |
| Organization name |
Leibniz Institute for Natural Product Research and Infection Biology
|
| Department |
Junior Resaerch Group RNA Biology of Fungal Infections
|
| Street address |
Adolf-Reichwein-Str. 23
|
| City |
Jena |
| ZIP/Postal code |
07745 |
| Country |
Germany |
| |
|
| Platforms (1) |
| GPL33056 |
Illumina NovaSeq 6000 (Aspergillus fumigatus) |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA1055020 |
Less...
More...