Agradecimentos: This work was performed in part at the High-Performance Computing Cluster (HPCC), which is supported by the Information and Communication Technology Office (ICTO) of the University of Macau. We thank Jacky Chan for technical supports on the HPCC. We acknowledge the technical supports and services from the Genomics, Bioinformatics and Single Cell Analysis and the Proteomics, Metabolomics and Drug Development cores. We also thank Dr. Alessia Buscaino for reading the manuscript draft and the comments and suggestions. The Science and Technology Development Fund, Macao S.A.R (FDCT) (project reference number: 0106/2020/A and 0033/2021/A1) to KHW, Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 2016/07870-9 to GHG and 2018/14821-0 to ACC and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (301058/2019-9 and 404735/2018-5) to GHG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Ver menos

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 Ver menos