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

PLoS Genet. 2020 Nov 5;16(11):e1009071. doi: 10.1371/journal.pgen.1009071. eCollection 2020 Nov.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Candida albicans / genetics*
  • Candida albicans / metabolism
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly / genetics*
  • Chromatin Assembly and Disassembly / physiology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Fungal Proteins / genetics
  • Gene Expression Regulation, Fungal / genetics
  • Proteomics / methods
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Virulence / genetics

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Fungal Proteins
  • RSC complex, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors

Grants and funding

This work was financially supported by CSIR, Govt. of India (38(1457)/18/EMR-II), IITB-Monash Research Academy, Mumbai, India (IMURA0477), the Office of the Vice-Provost for Research and Research Infrastructure at Monash University, and a project grant from the Australian National Health and Medical Research Council (NHMRC) (APP1138812, to AT and JV). VKB was supported by fellowship from the IITB-Monash Research Academy, Mumbai, India (IMURA0477). AT is a Future Fellow of the Australian Research Council (FT190100733). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.