Academic journal article Genetics

Analysis of Cryptococcus Neoformans Sexual Development Reveals Rewiring of the Pheromone-Response Network by a Change in Transcription Factor Identity

Academic journal article Genetics

Analysis of Cryptococcus Neoformans Sexual Development Reveals Rewiring of the Pheromone-Response Network by a Change in Transcription Factor Identity

Article excerpt

ABSTRACT The fundamental mechanisms that control eukaryotic development include extensive regulation at the level of transcription. Gene regulatory networks, composed of transcription factors, their binding sites in DNA, and their target genes, are responsible for executing transcriptional programs. While divergence of these control networks drives species-specific gene expression that contributes to biological diversity, little is known about the mechanisms by which these networks evolve. To investigate how network evolution has occurred in fungi, we used a combination of microarray expression profiling, cis-element identification, and transcription-factor characterization during sexual development of the human fungal pathogen Cryptococcus neoformans. We first defined the major gene expression changes that occur over time throughout sexual development. Through subsequent bioinformatic and molecular genetic analyses, we identified and functionally characterized the C. neoformans pheromone-response element (PRE). We then discovered that transcriptional activation via the PRE requires direct binding of the high-mobility transcription factor Mat2, which we conclude functions as the elusive C. neoformans pheromone-response factor. This function of Mat2 distinguishes the mechanism of regulation through the PRE of C. neoformans from all other fungal systems studied to date and reveals species-specific adaptations of a fungal transcription factor that defies predictions on the basis of sequence alone. Overall, our findings reveal that pheromone-response network rewiring has occurred at the level of transcription factor identity, despite the strong conservation of upstream and downstream components, and serve as a model for how selection pressures act differently on signaling vs. gene regulatory components during eukaryotic evolution.

DURING eukaryotic growth, developmental transitions require the accurate sensing of environmental and cellular signals and subsequent generation of appropriate responses. The fundamental mechanisms that govern these responses include extensive regulation of gene expression. In particular, the accurate timing, location, and extent of the transcription of specific genes are required for normal eukaryotic development. These critical transcriptional regulatory events are governed by gene regulatory networks, composed of DNA-binding proteins, their associated binding sites in DNA, and cohorts of regulated target genes (Davidson EH et al. 2002; Wilczynski and Furlong 2010).

One of the most well characterized eukaryotic gene regulatory networks governs cell type determination in the model yeast Saccharomyces cerevisiae. In S. cerevisiae, two mating types (a and a) are specified by the expression of cell type-specific transcription factors (a1 in a cells and a1 and a2 in a cells) (Herskowitz 1985, 1988). Through coordinate activation and repression of specific gene cohorts, the actions of the transcriptional factors establish three cell types (a, a, and a/a) with distinct properties critical for maintaining the S. cerevisiae sexual cycle (Galgoczy et al. 2004). The more recent elucidation of cell identity circuits in related fungi and subsequent comparative studies with the S. cerevisiae paradigm have been invaluable in revealing features of regulatory network evolution (Tsong et al. 2003, 2006; Baker et al. 2011). For example, the cell identity regulatory network in the related Candida albicans includes an ancient regulator (a2) and diverged cis-regulatory features that indicate the differing mechanisms by which gene regulation evolves and contributes to biological diversity (Tsong et al. 2003, 2006). These studies demonstrate the value of evaluating transcriptional circuits in distinct fungi; such comparative studies have already elucidated nonpredicted regulatory systems governing processes as varied as environmental stress tolerance, carbon source utilization, and dimorphism (Kadosh and Johnson 2001; Martchenko et al. …

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