Abstract
Candida albicans is an important opportunistic fungal pathogen of immunocompromised individuals. One critical virulence attribute is its morphogenetic plasticity. Hyphal development requires two temporally linked changes in promoter chromatin, which is sequentially regulated by temporarily clearing the transcription inhibitor Nrg1 upon activation of the cAMP/PKA pathway and promoter recruitment of the histone deacetylase Hda1 under reduced Tor1 signaling. Molecular mechanisms for the temporal connection and the link to Tor1 signaling are not clear. Here, through a forward genetic screen, we report the identification of the GATA family transcription factor Brg1 as the factor that recruits Hda1 to promoters of hypha-specific genes during hyphal elongation. BRG1 expression requires both the removal of Nrg1 and a sub-growth inhibitory level of rapamycin; therefore, it is a sensitive readout of Tor1 signaling. Interestingly, promoters of hypha-specific genes are not accessible to Brg1 in yeast cells. Furthermore, ectopic expression of Brg1 cannot induce hyphae, but can sustain hyphal development. Nucleosome mapping of a hypha-specific promoter shows that Nrg1 binding sites are in nucleosome free regions in yeast cells, whereas Brg1 binding sites are occupied by nucleosomes. Nucleosome disassembly during hyphal initiation exposes the binding sites for both regulators. During hyphal elongation, Brg1-mediated Hda1 recruitment causes nucleosome repositioning and occlusion of Nrg1 binding sites. We suggest that nucleosome repositioning is the underlying mechanism for the yeast-hyphal transition. The hypha-specific regulator Ume6 is a key downstream target of Brg1 and functions after Brg1 as a built-in positive feedback regulator of the hyphal transcriptional program to sustain hyphal development. With the levels of Nrg1 and Brg1 dynamically and sensitively controlled by the two major cellular growth pathways, temporal changes in nucleosome positioning during the yeast-to-hypha transition provide a mechanism for signal integration and cell fate specification. This mechanism is likely used broadly in development.
Highlights
Candida albicans is a major opportunistic fungal pathogen of humans [1,2]
Among the 8 mutants, we found that promoter recruitment of Hda1 in the presence of rapamycin was
We report the identification of Brg1, by a forward genetic screen, as the transcription factor that recruits Hda1 to promoters of hypha-specific genes under reduced Tor1 signaling for sustained hyphal development
Summary
Candida albicans is a major opportunistic fungal pathogen of humans [1,2]. In most healthy individuals C. albicans exists as a harmless commensal in the oral cavity and the gastrointestinal and urogenital tracts. One critical virulence attribute of C. albicans is its ability to undergo hyphal development in response to environmental cues. Mutants that are defective in hyphal formation display much reduced virulence in animal models of systemic candidiasis [3,4]. Hyphal morphogenesis is coupled with virulence as genes that control hyphal morphology are co-regulated with genes encoding virulence factors such as proteases and adhesins [4]. The transcription factor Ume, expressed during hyphal development, controls the level and duration of hypha-specific genes and is important for hyphal elongation [9,10,11]. Hyphal morphogenesis and cell chain formation are under the control of another hypha-specific gene that encodes the G1 cyclin-related protein Hgc1 [12,13,14,15,16]
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