Acetic acid produced by remodels chromatin architecture and suppresses gene expression in .

The skin microbiome is composed of diverse microbial communities that engage in interkingdom interactions, influencing host physiology and microbial balance. Although and are codominant members of the human skin microbiome, the molecular mechanisms underlying their interactions remain poorly understood. We aimed to investigate the mechanism by which -derived acetic acid affects chromatin organization and gene expression in modulated chromatin structure and transcriptional activity in by secreting acetic acid (AcOH), a common skin-associated organic acid. Using Hi-C, we established the first three-dimensional genome architecture map of and identified putative centromeric loci based on inter-chromosomal association scores. Co-culture with or direct treatment with AcOH induced large-scale chromatin decompaction and enhanced centromeric clustering, indicating significant reorganization of the nuclear architecture. Through chromatin immunoprecipitation (ChIP)-seq analysis, we observed that AcOH exposure led to a redistribution of histone acetylation from promoter regions to gene bodies. This chromatin remodeling was further associated with extensive transcriptional repression, particularly of genes involved in translation, metabolism, and virulence, as revealed by RNA-seq analysis. Of note, these changes were specific to AcOH and were not replicated under inorganic acid stress (HCl), indicating a metabolite-specific epigenetic response. This study reveals a novel form of interkingdom communication in the skin microbiome, in which -derived AcOH acts as an epigenetic modulator in . Our findings provide key mechanistic insights into how bacterial metabolites influence fungal chromatin architecture and transcription, with implications for microbial community dynamics and skin health.IMPORTANCEThis study provides essential insights into interkingdom interactions within the human skin microbiome, highlighting how microbial metabolites influence fungal biology at the chromatin level. Specifically, we identify acetic acid (AcOH), secreted by , as a key regulator that induces significant chromatin remodeling and transcriptional changes in . By presenting the first three-dimensional genome architecture map of , our findings uncover metabolite-specific chromatin dynamics that cannot be replicated by inorganic acid stress. Additionally, the conservation of this chromatin response in other species suggests broader implications for understanding microbial adaptation mechanisms in the skin environment. This work underscores the critical role of bacterial metabolites as modulators of microbial interactions and provides new avenues for investigating microbial community balance and potential therapeutic strategies for skin health.