Species-specific circular RNA circDS-1 enhances adaptive evolution in Talaromyces marneffei through regulation of dimorphic transition and virulence
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Thermal adaptability is a crucial characteristic for mammalian pathogenic fungi that originally inhabit natural ecosystems. Thermally dimorphic fungi have evolved a unique ability to respond to host body temperature by shifting from mycelium to yeast. The high similarity of protein-coding genes between these fungi and their relatives suggests the indispensable but often overlooked roles of non-coding elements in fungal thermal adaptation. Here, we systematically delineated the landscape of full-length circRNAs in both mycelial and yeast conditions of Talaromyces marneffei , a typical thermally dimorphic fungus causing fatal Talaromycosis, by optimizing an integrative pipeline for circRNA detection utilizing next- and third-generation sequencing. We found T. marneffei circRNA demonstrated features such as shorter length, lower abundance, and circularization-biased splicing. We then identified and validated that circDS-1, independent of its parental gene, promotes the hyphae-to-yeast transition, maintains yeast morphology, and is involved in virulence regulation. Further analysis and experiments among Talaromyces confirmed that the generation of circDS-1 is driven by a T. marneffei -specific region in the flanking intron of circDS-1. Together, our findings not only provide fresh insights into the role of circRNA in fungal thermal adaptation but also reveal a novel molecular mechanism for the adaptive evolution of functional circRNAs derived from intronic mutations.
Author Summary
It is an essential characteristic for human pathogens to survive under human body temperature, which is obviously higher than environmental temperature. The morphology transformation between mycelia and yeasts of thermally dimorphic fungi are tightly associated with temperature. The limited divergences of protein-coding genes among their closest relatives are not able to explain these fungi thermal dimorphism. CircRNAs are non-coding RNAs that distribute ubiquitously across eukaryotes. However, lower eukaryotes have been relatively neglected in circRNA research, either from the biological function level or from the evolutionary level. Our study focused on the typical thermally dimorphic fungus, Talaromyces marneffei . We combined next-generation and third-generation sequencing technologies to map the full-length circRNA profile in both the saprophytic mycelial and pathogenic yeast forms of T. marneffei to identify functional circRNAs. Gene manipulation experiments were performed to evaluate the functional impact of the target circRNA circDS-1. We uncovered unique characteristics of T. marneffei circRNAs, such as shorter lengths, reduced abundance, and a preference for circularization-biased splicing events. CircDS-1, which functions independently from its host gene to promote the transition from hyphae to yeast form, maintain yeast morphology, and modulate virulence. Our study not only offers fresh perspectives on the role of circRNAs in fungal thermal adaptation, but also enhances our understanding of the adaptive evolution of pathogenic fungi as they transform from environmental to host environments.
