Unraveling the dynamic transcriptomic changes during the dimorphic transition of Talaromyces marneffei through time-course analysis

Systemic dimorphic fungi pose a significant public health challenge, causing over one million new infections annually. The dimorphic transition between saprophytic mycelia and pathogenic yeasts is strongly associated with the pathogenesis of dimorphic fungi. However, despite the dynamic nature of dimorphic transition, the current omics studies focused on dimorphic transition primarily employ static strategies, partly due to the lack of suitable dynamic analytical methods. Here, we firstly conducted time-course transcriptional profiling during the dimorphic transition of Talaromyces marneffei, a model organism for thermally dimorphic fungi. Then, we identified 5,223 dimorphic transition induced genes (DTIGs) by developing DyGAM-NS (dynamic optimized generalized additive model with natural cubic smoothing), a model that enables the capture of non-uniform and nonlinear transcriptional changes during intricate biological processes. Notably, the DyGAM-NS outperformed other commonly used models, achieving the highest F1-score in DTIGs identification. The cluster analysis of DTIGs suggests differential functional involvement of genes at distinct stages of dimorphic transition. Moreover, we observed divergent gene expression patterns between mycelium-to-yeast and yeast-to-mycelium transitions, indicating the asymmetrical nature of two transition directions. Additionally, leveraging the identified DTIGs, we constructed a regulatory network for the dimorphic transition and identified two zinc finger-containing transcription factors that potentially regulate dimorphic transition in T. marneffei. In summary, our study not only elucidates the dynamic changes in transcriptional profiles during the dimorphic transition of T. marneffei but also provides a novel perspective for unraveling the underlying mechanisms of fungal dimorphism. IMPORTANCEThe dimorphic transition, i.e., morphological switch between saprophytic mycelia and pathogenic yeasts, plays a pivotal role in the pathogenesis of dimorphic fungi. However, the underlying mechanisms of dimorphic transition remain poorly understood, partly due to the lack of dynamic analytical methods suitable for its intricate nature. In the current study, we dissected the dynamic transcriptional profiles of dimorphic transition with a model thermally dimorphic fungus, T. marneffei, by developing a novel analytical method, DyGAM-NS. We proved that DyGAM-NS was more powerful in capturing the non-uniform and nonlinear gene expression variations during the dimorphic transition. With DyGAM-NS, we identified a repertoire of genes associated with dimorphic transition, and comprehensively unraveled distinct functions and expression patterns at different transition stages of T. marneffei, which offers novel perspectives regarding the mechanistic underpinnings of fungal dimorphism.