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The COMPASS subunit Bre2 targets CRF Arp9 to regulate the bio-synthesis of secondary metabolite AFB1 and virulence in Aspergillus flavus

ABSTRACT: Aspergillus flavus, along with its notorious secondary metabolite aflatoxin B1 (AFB1), serious endangers human health. We previous revealed that histone methyltransferase complex COMPASS plays a crucial role in regulating various biological processes of A. flavus, but underlying mechanism is unclear. Here, through genetic assay and invading experiments, we found that Bre2, key subunit of COMPASS, regulates AFB1 bio-synthesis, fungal morphogenesis and virulence to crop and animal through H3K4 methylation. ChIP-seq and biochemistry analysis revealed that chromatin remolding factor (CRF) Arp9 is directly targeted by Bre2, and Arp9 implements bio-function through interacting with CRFs: RSC8, Arp7 and Sth1. ATAC analysis revealed that Arp9 deeply participates in fungal pathogenicity through regulating a serial secondary metabolism, morphogenesis and virulence associated regulators by modulating the chromatin conformation. The study revealed an epigenetic signaling pathway from COMPASS to Arp9 mediating chromatin remolding, which provides potential strategy for prevention and control of pathogenic fungi and mycotoxins.

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ORGANISM(S): Aspergillus Flavus (strain Atcc 200026 / Fgsc A1120 / Nrrl 3357 / Jcm 12722 / Srrc 167)

TISSUE(S): Mycelium

SUBMITTER: Minghui Sun

LAB HEAD: Zhenhong Zhuang

PROVIDER: PXD060646 | Pride | 2026-02-08

REPOSITORIES: Pride

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Project description:Aspergillus flavus is a common saprophyte and opportunistic pathogen producing aflatoxin (AF) and many other secondary metabolites. 5-Azacytidine (5-AC), a derivative of nucleoside cytidine, is widely used for studies in epigenetics and cancer biology as an inactivator of DNA methyltransferase and is also used for studying secondary metabolism in fungi. Our previous studies showed that 5-AC affects development and inhibits AF production in A. flavus, and that A. flavus lacks DNA methylation. How this common DNA methyltransferase inhibitor affects development and AF production is not clear. In this study, we applied an RNA-Seq approach to elucidate the mechanism of 5-ACM-bM-^@M-^Ys effect on A. flavus. In our current study, we identified 240 significantly differently expressed (Q-value<0.05) genes after 5-AC treatment, including two backbone genes in secondary metabolite clusters #27 and #35, which are involved in development or survival of sclerotia. With 5-AC treatment, about three quarters of the genes in the AF biosynthetic gene cluster in A. flavus were down-regulated to a certain degree. Strikingly, at least two genes aflI and aflLa, were completely inhibited. Interestingly, several genes involved in fungal development were down-regulated, especially veA, which is a gene that encodes protein bridges VelB and LaeA. This result supports the hypothesis that 5-AC affects development and AF production through weakening or even interrupting the connection between VelB and LaeA and then causing dysregulation of the expression pattern of genes involved in development and secondary metabolism. Our results improved the A. flavus genome annotation, provided a comprehensive view of the transcriptome of A. flavus responding to 5-AC and confirmed that fungal development and secondary metabolism are co-regulated. In additon, the RNA-Seq data of another sample treated with gallic acid was used to improve A. flavus genome annotation. mRNA of Aspergillus flavus cultured in three different culture media PDB, PDB+5-AC(5-Azacytidine),and PDB+GA(gallic acid) was subjected to sequence independently.

Project description:Diverse expression patterns for secondary metabolism gene clusters from Aspergillus flavus under different environmental conditions and in genetic mutants: Insights into regulation of cyclopiazonic acid along with aflatoxin Species of Aspergillus produce a diverse array of secondary metabolites, and recent genomic analysis predicts that these species have the capacity to synthesize many more compounds. It has been possible to infer the presence of 55 gene clusters associated with secondary metabolism in A. flavus. Presumably, secondary metabolites play important roles in the ecology of the producing species, but functions for most secondary metabolites remain unknown. Only three metabolic pathways have been associated with the predicted clusters in A. flavus. These include aflatoxin, cyclopiazonic acid (CPA), and aflatrem. To gain insight into the regulation of, and infer ecological significance for the 55 secondary metabolite gene clusters predicted in A. flavus, we examined their expression over 28 diverse conditions. Variables included culture media and temperature, fungal development, colonization of developing maize seeds, and misexpression of laeA, the global regulator of secondary metabolism. Hierarchical clustering analysis of expression profiles allowed us to categorize the gene clusters into four distinct clades. Gene clusters for the production of aflatoxins, CPA, and seven other unknown compound(s) were identified as belonging to one clade. To further explore the relationships found by gene expression analysis, aflatoxin and CPA production were quantified under five different cell culture environments known to be conducive or non-conducive for aflatoxin biosynthesis and during colonization of developing maize seeds. Results from these studies showed that secondary metabolism gene clusters have distinctive gene expression profiles. Aflatoxin and CPA were found to have unique regulation but similar enough that they would be expected to co-occur in commodities colonized with A. flavus.

Project description:Morphogenetic transitions are prevalent in the fungal kingdom. For a leading human fungal pathogen, Candida albicans, the capacity to transition between yeast and filaments is key for virulence. For the model yeast Saccharomyces cerevisiae, filamentation enables nutrient acquisition. A recent functional genomic screen in S. cerevisiae identified Mfg1 as a regulator of morphogenesis that acts in complex with Flo8 and Mss11 to mediate transcriptional responses crucial for filamentation. In C. albicans, Mfg1 also interacts physically with Flo8 and Mss11 and is critical for filamentation in response to diverse cues, but the mechanisms through which it regulates morphogenesis remained elusive. Here, we explored the consequences of perturbation of Mfg1, Flo8, and Mss11 on C. albicans morphogenesis, and identified functional divergence of complex members. We observed that C. albicans Mss11 was dispensable for filamentation, and that overexpression of FLO8 caused constitutive filamentation even in the absence of Mfg1. Harnessing transcriptional profiling and chromatin immunoprecipitation coupled to microarray analysis, we identified divergence between transcriptional targets of Flo8 and Mfg1 in C. albicans. We also established that Flo8 and Mfg1 cooperatively bind to promoters of key regulators of filamentation, including TEC1, for which overexpression was sufficient to restore filamentation in the absence of Flo8 or Mfg1. To further explore the circuitry through which Mfg1 regulates morphogenesis, we employed a novel strategy to select for mutations that restore filamentation in the absence of Mfg1. Whole genome sequencing of filamentation-competent mutants revealed chromosome 6 amplification as a conserved adaptive mechanism. A key determinant of the chromosome 6 amplification is FLO8, as deletion of one allele blocked morphogenesis, and chromosome 6 was not amplified in evolved lineages for which FLO8 was re-located to a different chromosome. Thus, this work highlights rewiring of key morphogenetic regulators over evolutionary time and aneuploidy as an adaptive mechanism driving fungal morphogenesis.

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	YAS202304230001_1_WT.raw	Raw
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The COMPASS subunit Bre2 targets CRF Arp9 to regulate the bio-synthesis of secondary metabolite AFB1 and virulence in Aspergillus flavus

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