Biology subjects

Yu, S.-R.

Publications and source records attributed to Yu, S.-R..

4 recordsLinked to original sources

bioRxiv2026

Systematic histone mutagenesis reveals nucleosome-dependent maintenance of three-dimensional chromosome architecture and virulence in Cryptococcus neoformans

BackgroundGenomic stability is maintained through the coordinated regulation of DNA repair, dNTP pool balance, and histone dynamics--the three pillars of the DNA damage response. Because histones constitute the fundamental 3D physical scaffold of the genome, their precise regulation is essential for the spatial organization that dictates environmental fitness. In the radiotolerant pathogen Cryptococcus neoformans, the Rad53-Bdr1 pathway is a central DDR mediator; however, the mechanisms linking this checkpoint to histone dynamics remain poorly understood. Because conventional one-dimensional analyses cannot capture how spatial chromatin folding shapes transcriptional reprogramming, we integrated high-throughput chromosome conformation capture (Hi-C) with transcriptomic profiling to address this gap. ResultsWe demonstrate that HTA1 and HTB1, encoding H2A and H2B, are essential for viability, whereas H3 and H4 paralogs exhibit functional redundancy. Although most core histones are regulated by Rad53, HHT1 and variant HTZ1 are expressed independently of the Rad53. Notably, loss of the H3 paralog HHT2 induces growth defects under diverse stress conditions. Integrated RNA sequencing and Hi-C analyses reveal that HHT2 deletion drives transcriptional reprogramming of stress-responsive genes, coinciding with large-scale chromatin rearrangements such as A/B compartment switching and topologically associating domain boundary shifts. Furthermore, HHT2 loss impairs virulence factor formation and attenuates virulence. ConclusionOur findings identify core histones as essential architects of the 3D genome in C. neoformans. By establishing a causal link between chromatin structural collapse and transcriptional reprogramming, this study highlights 3D genome architecture as a decisive physical switch linking nucleosome-level dynamics to global transcriptional programs required for environmental survival.

microbiology↗

bioRxiv2026

Systematic profiling of WD40 proteins reveals Wcp1, a cyclophilin linking CO2/heat tolerance to acidic pH adaptation in Cryptococcus neoformans

WD40 domains are major protein-protein interaction (PPI) scaffolds, yet their contributions to fungal pathogenicity remain poorly defined. We systematically analysed 94 canonical WD40 proteins in Cryptococcus neoformans. Conditional knockdown and sporulation identified 36 essential WD40 proteins, while in vitro and in vivo profiling of 103 signature-tagged deletion strains spanning 52 genes uncovered 31 pathogenicity-related WD40 proteins, including epigenetic and post-transcriptional regulators. We identified Wcp1, a dual-domain protein whose WD40-repeat and cyclophilin domains are required for growth at 37{degrees}C under 5% CO2. Its WD40 scaffold and PPIase domain supported CO2/heat tolerance and virulence. Notably, Wcp1 couples these functions to acidic pH adaptation: wcp1{Delta} failed to grow under elevated temperature and CO2 at acidic pH, exhibited enhanced intracellular acidification, reduced macrophage survival and attenuated virulence in Drosophila and mice. Integrated transcriptomic and proteomic analyses place Wcp1 at the centre of intracellular pH homeostasis, coordinating proton transport, metabolic adaptation and stress-buffering networks.

microbiology↗

bioRxiv2026

Systematic Profiling of Essential Fungal Transcription Factors Uncovers Ezt1 as a Central Pathobiological and Morphogenic Regulator in Cryptococcus neoformans

Cryptococcus neoformans is a global fungal pathogen that causes fatal cryptococcosis, and the limitations of current antifungals underscore the urgent need for new therapeutics. Here we systematically investigate essential transcriptional regulators in C. neoformans as potential antifungal targets, developing experimental pipelines that assess growth requirement, essentiality and function through conditional gene expression, constitutive overexpression, and meiotic spore analysis. We identify one quasi-essential (growth-required but non-essential) transcription factor, Fhl1, and 13 essential transcriptional regulators, three of which are transcription factors (Ezt1, Ezt2 and Cbf1) highly divergent from counterparts in other eukaryotes. Notably, Ezt1 modulates the expression of more than 1,200 genes, controlling growth, antifungal drug and stress responses, sexual development and virulence. Our findings define the essential transcriptional regulator landscape of C. neoformans and provide a framework for prioritising divergent essential regulators, particularly Ezt1, for antifungal target discovery.

microbiology↗

bioRxiv2025

The protein phosphatase 2C domain contributes to the pathobiological function of adenylyl cyclase in Cryptococcus neoformans

Adenylyl cyclase produces cyclic adenosine monophosphate, a signalling molecule that controls fungal development and virulence. Fungal adenylyl cyclases are distinguished by the presence of a conserved protein phosphatase 2C domain, whose function remains unknown. Here we show that the protein phosphatase 2C domain of Cac1, the adenylyl cyclase of the human pathogen Cryptococcus neoformans, has an unusual structure but functions as a metal-dependent serine/threonine phosphatase. Deletion of this domain or the adenylyl cyclase catalytic domain demonstrated that the protein phosphatase 2C domain is required for full Cac1 activity, influencing melanin and capsule synthesis, sexual differentiation, titan cell formation, and cell wall integrity. Notably, loss of the protein phosphatase 2C domain induces type 2 helper T-cell-biased immunity and extensive pulmonary damage yet does not cause mortality in mice. Integrated transcriptomic and phosphoproteomic analyses further revealed shared and domain-specific signalling outputs. Together, these findings define a pivotal role for the adenylyl cyclase-linked protein phosphatase 2C domain in C. neoformans pathobiology.

microbiology↗