Epigenetic regulation of virulence and the transcription of ribosomal protein genes involves a YEATS family protein in Cryptococcus deneoformans

Epigenetic marks or post-translational modifications on histones have important regulatory roles in gene expression in eukaryotic organisms. The epigenetic regulation of gene expression in the pathogenic yeast Cryptococcus deneoformans remains largely undetermined. The YEATS domain proteins are readers of crotonylated lysine residues in histones. Here, we reported the identification of a single-copy gene putatively coding for a YEATS domain protein (Yst1) in C. deneoformans. To define its function, we created a mutant strain, yst1 Delta, using CRISPR-Cas9 editing. yst1 Delta exhibited defects in phenotype, for instance, it was hypersensitive to osmotic stress in the presence of 1.3 M NaCl or KCl. Furthermore, it was hypersensitive to 1% Congo red, suggesting defects in the cell wall. Interestingly, RNA-seq data revealed that Yst1p was critical for the expression of genes encoding the ribosomal proteins, that is, most were expressed with significantly lower levels of mRNA in yst1 Delta than in the wild-type strain. The mutant strain was hypersensitive to low temperature and anti-ribosomal drugs, which we putatively attribute to the impairment in ribosomal function. In addition, the yst1 Delta strain was less virulent to Galleria mellonella. These results generally suggest that Yst1, as a histone modification reader, might be a key coordinator of the transcriptome of this human pathogen. Yst1 could be a potential target for novel antifungal drugs, which might lead to significant developments in the clinical treatment of cryptococcosis.

Automated summary

The newly discovered gene Yst1 in Cryptococcus deneoformans plays an important role in gene expression as a reader of histone modifications. Deletion of Yst1 leads to decreased stress resistance, cell wall defects, impaired ribosomal function, increased sensitivity to antibiotics, and reduced virulence to the host. Yst1 could be a potential target for novel antifungal drugs, highlighting its potential importance in clinical treatment of cryptococcosis.