Set202 is a histone lysine methyltransferase that enables <i>Cryptococcus neoformans</i> to adapt to the host environment

ABSTRACT All pathogens rely on dynamic gene expression for host adaptation and disease causation. This is especially important for pathogens that normally are found in the environment, like Cryptococcus neoformans, given that environmental and host conditions are dramatically different. Epigenetic modifications, like those carried out by SET-domain histone lysine methyltransferases (HKMTs), are essential for this genome expression flexibility. While transcription factors and signaling cascades have been well-studied in C. neoformans ’s host adaptation, the role of HKMTs in this process has not been explored. Here, we characterize the gene SET202 , previously reported as a putative HKMT important for growth in host lungs. We show that set202Δ mutants have 50% less phagosomal permeabilization than the wild-type fungi, have phagosomal maturation defects, and poor intracellular survival. Additionally, they are defective in traits promoting virulence, including significantly smaller capsules, less melanin, and poor growth under host-like conditions. These phenotypes contributed to reduced virulence in a murine model of infection but, notably, this defect was host-temperature-dependent. In order to explain mechanistically how SET202 deletion could affect such a wide range of processes, we assessed and demonstrated, for the first time, that Set202 is a true histone-3-lysine 36 methyltransferase, supporting its role in epigenetically modifying the fungal genome to enable adaptation to the hostile host conditions. Consequently, our findings support the study of the biological function of Set202, as it can serve as a potential future therapeutic target for the treatment of infections caused by C. neoformans, and possibly other pathogenic fungi. IMPORTANCE Epigenetic modifications are essential for a wide variety of processes, from cancer to infectious diseases. In the fungal world, they have been associated with fungal stress response, antifungal resistance, and disease establishment. However, in the environmental opportunistic pathogen Cryptococcus neoformans , the role of histone methyltransferases (HKMTs), one of the main epigenetic regulators, has been poorly elucidated. Herein, we characterize the role of a putative HKMT, Set202, in C. neoformans’ transition from the environment to the host. This is utmost important because this fungus’s main driver of disease is its ability to adapt to host conditions. We show that Set202 regulates a variety of processes needed for disease by acting as a true HKMT. Given the inadequate treatments available for diseases caused by this fungus, and that HKMTs are conserved in other fungal pathogens, characterizing Set202 function will provide crucial information to develop new treatments for this and other fungal diseases.