Abstract
Invasive Pulmonary Aspergillosis, which is caused by the filamentous fungus Aspergillus fumigatus, is a life-threatening infection for immunosuppressed patients. Chromatin structure regulation is important for genome stability maintenance and has the potential to drive genome rearrangements and affect virulence and pathogenesis of pathogens. Here, we performed the first A. fumigatus global chromatin profiling of two histone modifications, H3K4me3 and H3K9me3, focusing on the two most investigated A. fumigatus clinical isolates, Af293 and CEA17. In eukaryotes, H3K4me3 is associated with active transcription, while H3K9me3 often marks silent genes, DNA repeats, and transposons. We found that H3K4me3 deposition is similar between the two isolates, while H3K9me3 is more variable and does not always represent transcriptional silencing. Our work uncovered striking differences in the number, locations, and expression of transposable elements between Af293 and CEA17, and the differences are correlated with H3K9me3 modifications and higher genomic variations among strains of Af293 background. Moreover, we further showed that the Af293 strains from different laboratories actually differ in their genome contents and found a frequently lost region in chromosome VIII. For one such Af293 variant, we identified the chromosomal changes and demonstrated their impacts on its secondary metabolites production, growth and virulence. Overall, our findings not only emphasize the influence of genome heterogeneity on A. fumigatus fitness, but also caution about unnoticed chromosomal variations among common laboratory strains.
Highlights
Invasive Pulmonary Aspergillosis (IPA) is a life-threatening infection in immunosuppressed patients [1,2] caused mainly by the filamentous fungus Aspergillus fumigatus, a ubiquitous soil inhabitant that can utilize a wide variety of organic substrates and grow under a broad range of environmental conditions [3]
Characterization of one of the Af293 variant strains, which has undergone chromosomal loss and amplification of two separate regions in chromosome VIII (Chr VIII), showed significant improvements in secondary metabolites production, growth and virulence compared to the original Af293 isolate
In order to compare chromatin activities of the two A. fumigatus reference strains Af293 and CEA17, we performed Chromatin Immunoprecipitation coupled to high throughput sequencing (ChIP-seq) to map genome wide nucleosome occupancy and histone H3 K4 trimethylation (H3K4me3) that associates with active transcription
Summary
Invasive Pulmonary Aspergillosis (IPA) is a life-threatening infection in immunosuppressed patients [1,2] caused mainly by the filamentous fungus Aspergillus fumigatus, a ubiquitous soil inhabitant that can utilize a wide variety of organic substrates and grow under a broad range of environmental conditions [3]. A. fumigatus produces asexual conidia that readily become airborne and can survive diverse environmental conditions [4]. Several A. fumigatus strains can infect immunosuppressed patients [2]. If the invader succeeds in establishing an infection in a host who is subjected to an antifungal treatment, A. fumigatus hyphae must survive the fungicidal and/or fungistatic effects of the antifungal drug(s) to persist inside the host [8]. It is essential that A. fumigatus can adapt its physiology to the changing conditions during the course of infection to thrive as a pathogen [9]
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