Dataset Information

The histone deacetylase genes HDA1 and RPD3 play distinct roles in regulation of high-frequency phenotypic switching in Candida albicans.

ABSTRACT: Five histone deacetylase genes (HDA1, RPD3, HOS1, HOS2, and HOS3) have been cloned from Candida albicans and characterized. Sequence analysis and comparison with 17 additional deacetylases resulted in a phylogenetic tree composed of three major groups. Transcription of the deacetylases HDA1 and RPD3 is down-regulated in the opaque phase of the white-opaque transition in strain WO-1. HOS3 is selectively transcribed as a 2.5-kb transcript in the white phase and as a less-abundant 2.3-kb transcript in the opaque phase. HDA1 and RPD3 were independently deleted in strain WO-1, and both switching between the white and opaque phases and the downstream regulation of phase-specific genes were analyzed. Deletion of HDA1 resulted in an increase in the frequency of switching from the white phase to the opaque phase, but had no effect on the frequency of switching from the opaque phase to the white phase. Deletion of RPD3 resulted in an increase in the frequency of switching in both directions. Deletion of HDA1 resulted in reduced white-phase-specific expression of the EFG1 3.2-kb transcript, but had no significant effect on white-phase-specific expression of WH11 or opaque-phase-specific expression of OP4, SAP1, and SAP3. Deletion of RPD3 resulted in reduced opaque-phase-specific expression of OP4, SAP1, and SAP3 and a slight reduction of white-phase-specific expression of WH11 and 3.2-kb EFG1. Deletion of neither HDA1 nor RPD3 affected the high level of white-phase expression and the low level of opaque-phase expression of the MADS box protein gene MCM1, which has been implicated in the regulation of opaque-phase-specific gene expression. In addition, there was no effect on the phase-regulated levels of expression of the other deacetylase genes. These results demonstrate that the two deacetylase genes HDA1 and RPD3 play distinct roles in the suppression of switching, that the two play distinct and selective roles in the regulation of phase-specific genes, and that the deacetylases are in turn regulated by switching.

SUBMITTER: Srikantha T

PROVIDER: S-EPMC95357 | biostudies-literature | 2001 Aug

REPOSITORIES: biostudies-literature

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The histone deacetylase genes HDA1 and RPD3 play distinct roles in regulation of high-frequency phenotypic switching in Candida albicans.

Srikantha T T Tsai L L Daniels K K Klar A J AJ Soll D R DR

Journal of bacteriology 20010801 15

Five histone deacetylase genes (HDA1, RPD3, HOS1, HOS2, and HOS3) have been cloned from Candida albicans and characterized. Sequence analysis and comparison with 17 additional deacetylases resulted in a phylogenetic tree composed of three major groups. Transcription of the deacetylases HDA1 and RPD3 is down-regulated in the opaque phase of the white-opaque transition in strain WO-1. HOS3 is selectively transcribed as a 2.5-kb transcript in the white phase and as a less-abundant 2.3-kb transcript ...[more]

PMID: 11443097

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Project description:Chromatin modifications affect gene regulation in response to environmental stimuli in numerous biological processes. For example, N-acetyl-glucosamine and CO2 induce a morphogenetic conversion between white (W) and opaque (O) cells in MTL (mating-type locus) homozygous and heterozygous ( A: /α) strains of the human fungal pathogen Candida albicans Here, we identify 8 histone-modifying enzymes playing distinct roles in the regulation of W/O switching in MTL homozygous and heterozygous strains. Most strikingly, genetic removal of the paralogous genes RPD3 and RPD31, both of which encode almost identical orthologues of the yeast histone deacetylase (HDAC) Rpd3, reveals opposing roles in W/O switching of MTL A: /α strains. We show that Rpd3 and Rpd31 functions depend on MTL genotypes. Strikingly, we demonstrate that Rpd3 and Rpd31, which are almost identical except for a divergent C-terminal extension present in Rpd31, exert their functions in distinct regulatory complexes referred to as CaRpd3L and CaRpd31S complexes. Moreover, we identify the Candida orf19.7185 product Ume1, the orthologue of yeast Ume1, as a shared core subunit of CaRpd3L and CaRpd31S. Mechanistically, we show that the opposing roles of Rpd3 and Rpd31 require their deacetylase activities. Importantly, CaRpd3L interacts with the heterodimeric transcriptional repressor A: 1/α2, thus controlling expression of WOR1 encoding the master regulator of W/O switching. Thus, our work provides novel insight about regulation mechanisms of W/O switching in MTL A: /α strains. This is the first example of two highly conserved HDACs exerting opposing regulatory functions in the same process in a eukaryotic cell. RPD3-like histone deacetylases (also called class I HDACs) are conserved from unicellular eukaryotes to mammals. Specifically, the genome of the human fungal pathogen Candida albicans, the most frequent cause of invasive fungal infections of high morbidity and mortality, harbors two almost identical paralogous HDACs, Rpd3 and Rpd31. We show here for the first time that Rpd3 and Rpd31 acquired functional divergence related to a distinct C-terminal domain. Rpd3 and Rpd31 associate with different complexes in the control regions of the master regulator gene WOR1, which is required for white-opaque (W/O) morphogenesis, respectively. The ability to switch is important for fungal pathogenesis, since it enables distinct host niche colonization. This work is to the best of our knowledge the first description of two paralogous HDACs playing opposing functional roles in the same developmental process. Our work adds a new angle concerning the molecular understanding of HDACs in the regulation of cell fate decisions.

Project description:UnlabelledBiofilms are resilient, surface-associated communities of cells with specialized properties (e.g., resistance to drugs and mechanical forces) that are distinct from those of suspension (planktonic) cultures. Biofilm formation by the opportunistic human fungal pathogen Candida albicans is medically relevant because C. albicans infections are highly correlated with implanted medical devices, which provide efficient substrates for biofilm formation; moreover, biofilms are inherently resistant to antifungal drugs. Biofilms are also important for C. albicans to colonize diverse niches of the human host. Here, we describe four core members of a conserved histone deacetylase complex in C. albicans (Set3, Hos2, Snt1, and Sif2) and explore the effects of their mutation on biofilm formation. We find that these histone deacetylase complex members are needed for proper biofilm formation, including dispersal of cells from biofilms and multifactorial drug resistance. Our results underscore the importance of the physical properties of biofilms in contributing to drug resistance and dispersal and lay a foundation for new strategies to target biofilm dispersal as a potential antifungal intervention.ImportanceThrough the formation of biofilms--surface-associated communities of cells--microorganisms can establish infections, become drug resistant, and evade the host immune system. Here we investigate how four core members of a conserved histone deacetylase complex mediate biofilm formation by Candida albicans, the major fungal pathogen of humans. We show that this histone deacetylase complex is required for biofilm dispersal, a process through which cells leave the biofilm to establish new infections. We also show that the deacetylase complex mediates biofilm drug resistance. This work provides new insight into how the physical properties of biofilms affect dispersal and drug resistance and suggests new potential antifungal strategies that could be effective against biofilms.

Dataset Information

The histone deacetylase genes HDA1 and RPD3 play distinct roles in regulation of high-frequency phenotypic switching in Candida albicans.

Publications

The histone deacetylase genes HDA1 and RPD3 play distinct roles in regulation of high-frequency phenotypic switching in Candida albicans.

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