Chromatin profiling reveals heterogeneity in clinical isolates of the human pathogen Aspergillus fumigatus

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.

The KdmB-EcoA-RpdA-SntB chromatin complex binds regulatory genes and coordinates fungal development with mycotoxin synthesis

“…Unexpectedly, the majority of these promoter bindings appear as point source peaks at promoter regions similar to those observed for transcription factor bindings, with only a small percentage of coding regions showing broad occupancy by the complex (Figure 3C , D ). The result was unexpected because KdmB is a H3K4me3 demethylase and therefore, expected to co-localize (at least partially) with H3K4me3 modification, which was shown to be enriched over a broad region near the 5′ end of active genes in A. nidulans and A. fumigatus ( 53 , 54 ). This prompted us to compare KERS genomic occupancy with H3K4me3 modifications (mapped by ChIPseq) in WT A. nidulans .…”

The pan-genome of Aspergillus fumigatus provides a high-resolution view of its population structure revealing high levels of lineage-specific diversity driven by recombination

“…Method validation for our pipeline for de novo assembly and pan-genomic clustering identified 10,167 genes (in 10,005 gene families) in the re-sequenced reference strain AF293, 38 more than are currently predicted in the curated Af293 reference strain. The small discrepancy between the number of genes identified in the pan-genomic analysis over those currently annotated in the reference highlights the high fidelity of the methods used here, where the additional genes identified for AF293 may represent either low levels of error in gene calling, or genuine variation between the reference Af293 isolate and the re-sequenced “AF293” isolate [ 126 ].…”

Combined Pan-, Population-, and Phylo-Genomic Analysis of Aspergillus fumigatus Reveals Population Structure and Lineage-Specific Diversity

“…Method validation for our pipeline of de novo assembly and pan-genomic clustering, identified 10,167 genes (in 10,005 gene families) in the re-sequenced reference strain AF293, 38 more than are currently predicted in the curated Af293 reference strain. The small discrepancy between the number of genes identified in the pan-genomic analysis over those currently annotated in the reference highlights the high fidelity of the methods used here, where the additional genes identified for AF293 may represent either low levels of error in gene calling, or genuine variation between the reference Af293 isolate and the re-sequenced “AF293” isolate (Colabardini et al ., 2022).…”