UCSF

Adaptive responses to environmental stimuli are integral to the survival and persistence of microbial pathogens. The thermally dimorphic human fungal pathogen Histoplasma senses temperature to transition between a mold form in soil and a pathogenic yeast in mammalian hosts. RYP transcription factors (TFs) are required to drive yeast-phase growth and the yeast transcriptome but the contributions of chromatin-modifying enzymes to the gene regulatory landscape of Histoplasma are unknown. Through chemical inhibition and genetics, we determined that the class I histone deacetylase (HDAC) RPD3 is required for normal Histoplasma yeast morphology at 37 ºC. Rpd3 regulated the expression of key morphology-specific genes, including virulence genes critical for pathogenesis and TFs that drive filamentation, was required for normal DNA-binding activity of RYP TFs, and influenced histone acetylation levels at the loci of putative pro-filamentation TFs. Furthermore, Rpd3 was required for virulence in a macrophage model of infection. Taken together, Rpd3 is a critical regulatory component that both activates the pathogenesis program and represses the filamentation program to establish thermal dimorphism in Histoplasma.