The RSC (Remodels the Structure of Chromatin) complex of Candida albicans shows compositional divergence with distinct roles in regulating pathogenic traits.

Regulation of gene expression programs is crucial for the survival of microbial pathogens in host environments and for their ability to cause disease. Here we investigated the epigenetic regulator RSC (Remodels the Structure of Chromatin) in the most prevalent human fungal pathogen Candida albicans. Biochemical analysis showed that CaRSC comprises 13 subunits and contains two novel non-essential members, which we named Nri1 and Nri2 (Novel RSC Interactors) that are exclusive to the CTG clade of Saccharomycotina. Genetic analysis showed distinct essentiality of C. albicans RSC subunits compared to model fungal species suggesting functional and structural divergence of RSC functions in this fungal pathogen. Transcriptomic and proteomic profiling of a conditional mutant of the essential catalytic subunit gene STH1 demonstrated global roles of RSC in C. albicans biology, with the majority of growth-related processes affected, as well as mis-regulation of genes involved in morphotype switching, host-pathogen interaction and adaptive fitness. We further assessed the functions of non-essential CaRSC subunits, showing that the novel subunit Nri1 and the bromodomain subunit Rsc4 play roles in filamentation and stress responses; and also interacted at the genetic level to regulate cell viability. Consistent with these roles, Rsc4 is required for full virulence of C. albicans in the murine model of systemic infection. Taken together, our data builds the first comprehensive study of the composition and roles of RSC in C. albicans, showing both conserved and distinct features compared to model fungal systems. The study illuminates how C. albicans uses RSC-dependent transcriptional regulation to respond to environmental signals and drive survival fitness and virulence in mammals. Author summary The nucleosomal structure of chromatin poses a natural barrier to transcription. As such, a host of factors regulate transcription by modulating the dynamic accessibility of DNA to the transcriptional machinery. One such factor, the Remodels the Structure of Chromatin (RSC) complex, disrupts histone-DNA contacts and causes DNA translocation using energy derived from ATP hydrolysis. The importance of gene expression in regulating pathogenic traits has been widely recognized in the pathogenic yeast Candida albicans, however the contributions of chromatin regulators in general, and the RSC complex in particular remain understudied. Here, we show that while the C. albicans RSC has broadly conserved counterparts in the model yeasts, it has distinct composition and functions. We identified two novel RSC subunits specific to the CTG clade of fungi, one of which is required for proper filamentation and adaptive fitness of the pathogen. Perturbation of RSC function led to the misregulation of genes controlling pathogenic attributes, and attenuated the virulence of C. albicans in a mammalian infection model. Our findings highlight the species-specific distinctions of RSC in the pathogenic landscape of C. albicans, with implications for targeting this complex for designing antifungal interventions in the future.