DNA methylation is associated with phenotypic divergence between the dermatophytes Trichophyton rubrum and...

The evolutionary closely related dermatophytes Trichophyton rubrum and T. violaceum exhibit distinct pathobiology despite high genomic similarity, suggesting the involvement of epigenetic regulation beyond genetic determinants.

This study aimed to delineate the genome-wide DNA methylation landscapes of T. rubrum and T. violaceum and to elucidate the associations between epigenetic divergence, transcriptional programs, and pathogenic disparities.

We performed an integrated multi-omics analysis combining whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) on clinical isolates of both species. Systematic bioinformatic analyses were performed to identify differentially methylated regions (DMRs), differentially expressed genes (DEGs), and to explore their potential functional associations.

T. rubrum exhibited a significantly elevated global DNA methylation level (mean ± SD: 3.21% ± 1.52%) compared to T. violaceum (0.68% ± 0.35%; p < 0.01, Student's t-test), with a predominance of non-CG (CHH) context methylation. We identified 681 DMRs, predominantly enriched in promoter regions, and 1,050 DEGs between the two species. Furthermore, integrative analysis identified 11 key genes that showed a strong inverse correlation between promoter methylation and expression (Pearson r = - 0.78 to - 0.92, all P < 0.01). These genes are putatively involved in critical pathways such as virulence regulation (e.g., C6 transcription factor), multidrug transport (e.g., MFS transporter) and nutrient metabolism (e.g., amino acid permease).

This study provides the first genome-wide DNA methylation landscape of dermatophytes, revealing that DNA methylation is significantly associated with pathogenic divergence in T. rubrum and T. violaceum. Their distinct methylomes are associated with transcriptional regulation, linked to strain-specific drug response, metabolism, and host interaction, and uncover candidate epigenetic targets for antifungal therapy.