Abstract
Phenotypic plasticity is common in development. For Candida albicans, the most common cause of invasive fungal infections in humans, morphological plasticity is its defining feature and is critical for its pathogenesis. Unlike other fungal pathogens that exist primarily in either yeast or hyphal forms, C. albicans is able to switch reversibly between yeast and hyphal growth forms in response to environmental cues. Although many regulators have been found involved in hyphal development, the mechanisms of regulating hyphal development and plasticity of dimorphism remain unclear. Here we show that hyphal development involves two sequential regulations of the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal morphogenesis via activation of the cAMP-PKA pathway. Maintenance requires promoter recruitment of Hda1 histone deacetylase under reduced Tor1 (target of rapamycin) signaling. Hda1 deacetylates a subunit of the NuA4 histone acetyltransferase module, leading to eviction of the NuA4 acetyltransferase module and blockage of Nrg1 access to promoters of hypha-specific genes. Promoter recruitment of Hda1 for hyphal maintenance happens only during the period when Nrg1 is gone. The sequential regulation of hyphal development by the activation of the cAMP-PKA pathway and reduced Tor1 signaling provides a molecular mechanism for plasticity of dimorphism and how C. albicans adapts to the varied host environments in pathogenesis. Such temporally linked regulation of promoter chromatin by different signaling pathways provides a unique mechanism for integrating multiple signals during development and cell fate specification.
Highlights
Many organisms or cells are able to alter their phenotype or developmental fate in response to changes in their environment, a phenomenon referred to as plasticity
The significance of Nrg1 is underscored by recent phenotypic profiling of 143 transcriptional regulator knockout mutants, where only nrg1 and tup1 mutants are filamentous under all conditions examined [52]
By chromatin immunoprecipitation (ChIP) of C-terminal Myc-tagged Nrg1, we found that Nrg1 was at the promoters of hypha-specific genes HWP1, ALS3, and ECE1 during yeast growth (Figure 1)
Summary
Many organisms or cells are able to alter their phenotype or developmental fate in response to changes in their environment, a phenomenon referred to as plasticity. The dynamic process of cell fate specification is determined by a network of regulatory genes. Understanding temporal dynamic regulation of gene expression in response to extracellular signals is critical for our comprehension of cell fate specification and plasticity. Unlike many other pathogenic fungi that exist primarily in either yeast or hyphal forms and infect a specific organ, C. albicans is able to undergo reversible morphological changes between yeast, pseudohyphal, and hyphal forms of growth in response to environmental cues and can successfully infect many different anatomical sites of the human host. Several of the genes that are expressed in hyphae encode virulence factors. HWP1, ALS3, and RBT5 encode cell wall proteins that are important for adhesion to host cells and iron acquisition from the host [3,4,5,6]
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