Set1-mediated H3K4 methylation is required for <i>Candida albicans</i> virulence by regulating intracellular level of reactive oxygen species

<i>Candida albicans</i> is an opportunistic human fungal pathogen that exists in normal flora but can cause infection in immunocompromised individuals. The transition to pathogenic <i>C. albicans</i> requires a change of various gene expressions. Because histone-modifying enzymes can regulate gene expression, they are thought to control the virulence of <i>C. albicans</i>. Indeed, the absence of H3 lysine 4 (H3K4) methyltransferase Set1 has been shown to reduce the virulence of <i>C. albicans</i>; however, Set1-regulated genes responsible for this attenuated virulence phenotype remain unknown. Here, we demonstrated that Set1 positively regulates the expression of mitochondrial protein genes by methylating H3K4. In particular, levels of cellular mitochondrial reactive oxygen species (ROS) were higher in <i>Δset1</i> than in the wild-type due to the defect of those genes’ expression. Set1 deletion also increases H₂O₂ sensitivity and prevents proper colony formation when interacting with macrophage <i>in vitro</i>, consistent with its attenuated virulence <i>in vivo</i>. Together, these findings suggest that Set1 is required to regulate proper cellular ROS production by positively regulating the expression of mitochondrial protein genes and subsequently sustaining mitochondrial membrane integrity. Consequently, <i>C. albicans</i> maintains proper ROS levels via Set1-mediated transcriptional regulation, thus establishing a rapid defense against external ROS generated by the host.