Talaromycosis is an invasive mycosis endemic in tropical and subtropical Asia and is caused by the pathogenic fungus Talaromyces marneffei . Approximately 17,300 cases of T. marneffei infection are diagnosed annually, and the reported mortality rate is extremely high (~1/3).

Chromatin complexes control a vast number of epigenetic developmental processes. Filamentous fungi present an important clade of microbes with poor understanding of underlying epigenetic mechanisms. Here, we describe a chromatin binding complex in the fungus Aspergillus nidulans composing of a H3K4 histone demethylase KdmB, a cohesin acetyltransferase (EcoA), a histone deacetylase (RpdA) and a histone reader/E3 ligase protein (SntB). In vitro and in vivo evidence demonstrate that this KERS complex is assembled from the EcoA-KdmB and SntB-RpdA heterodimers. KdmB and SntB play opposing roles in regulating the cellular levels and stability of EcoA, as KdmB prevents SntB-mediated degradation of EcoA. The KERS complex is recruited to transcription initiation start sites at active core promoters exerting promoter-specific transcriptional effects. Interestingly, deletion of any one of the KERS subunits results in a common negative effect on morphogenesis and production of secondary metabolites, molecules important for niche securement in filamentous fungi. Consequently, the entire mycotoxin sterigmatocystin gene cluster is downregulated and asexual development is reduced in the four KERS mutants. The elucidation of the recruitment of epigenetic regulators to chromatin via the KERS complex provides the first mechanistic, chromatin-based understanding of how development is connected with small molecule synthesis in fungi.

The ability to scavenge and use a wide range of nutrients for growth is crucial for microorganisms’ survival in the wild. Carbon catabolite repression (CCR) is a transcriptional regulatory phenomenon of both bacteria and fungi to coordinate the expression of genes required for preferential utilization of carbon sources.

Invasive Pulmonary Aspergillosis, which is caused by the filamentous fungusAspergillus 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 firstA.fumigatusglobal chromatin profiling of two histone modifications, H3K4me3 and H3K9me3, focusing on the two most investigatedA.fumigatusclinical 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 onA.fumigatusfitness, but also caution about unnoticed chromosomal variations among common laboratory strains.

The bacterial DNA phosphorothioate (PT) modification system is orchestrated by the DndCDE enzymatic complex. This system collaborates with restriction components DndF, DndG, and DndH to establish a widespread prokaryotic anti-phage defense network. In the evolutionary arms race, phages such as JSS1 have evolved counter strategies, including the expression of the JSS1_004 protein, to subvert PT-mediated host immunity. Although the N-terminal kinase domain of JSS1_004 is known to inhibit DndFGH through phosphorylation-dependent inactivation, the functional role of its C-terminal shutoff domain remained enigmatic. Here, we demonstrate that both domains are indispensable for full antagonistic activity against the DndBCDE-FGH system. Genetic dissection revealed that the absence of either domain substantially compromises suppression efficacy. Notably, JSS1_004 exhibits pleiotropic effects on host physiology, including repressing the dndBCDE-FGH operon confirmed by transcriptome. ChIP-seq analysis further revealed that JSS1_004 binding to promoter regions and coding sequences of genes associated with protein synthesis machinery, including tRNA, rRNA, and ribosomal subunit genes (SSU/LSU), thereby hijacking the host’s translational apparatus. Although the potent inhibitory efficacy and broad-spectrum antagonistic properties make JSS1_004 a promising functional element for engineered phage applications, the severe cytotoxicity of JSS1_004 constrains its biotechnological applicability. To overcome this limitation, we engineered attenuated JSS1_004 variants. These modified constructs maintained robust antagonism against the DndBCDE-FGH system while significantly reducing host toxicity, enabling cross-protection of heterologous phages against PT-based restriction and expanding the potential of phage therapy. Our findings advance the understanding of phage-host interactions and provide a framework for optimizing phage therapeutics to circumvent bacterial defense barriers. IMPORTANCE: Our recent investigation elucidated the molecular mechanism by which bacteriophage JSS1 counteracted the bacterial DndBCDE-FGH anti-phage defense system. Upon host invasion, the early gene transcriptional fragment of JSS1 facilitated the rapid expression of JSS1_004, with a N-terminal kinase domain that mediated phosphorylation of serine, threonine, and tyrosine residues within the DndFGH defense complex. This post-translational modification induced conformational changes in the complex, effectively neutralizing its restriction activity against phage propagation. However, the role of the C-terminal shutoff domain remains to be elucidated. In this study, we revealed that both the kinase and shutoff domains were crucial for the antagonistic function of JSS1_004. Moreover, transcriptomic and ChIP-seq analyses revealed JSS1_004’s broad expressional regulation of host gene expression, thus establishing a cellular environment conducive to bacteriophage replication. Furthermore, we successfully developed and integrated attenuated-cytotoxicity variants of JSS1_004 into the genome of M13 phages, conferring robust resistance against the DndBCDE-FGH defense system. These findings provide critical insights into the molecular arms race between phages and prokaryotic hosts while expanding the toolkit for developing phage-based biotechnological applications.