Structure of the transcriptional network controlling white‐opaque switching in Candida albicans

Abstract

Summary The human fungal pathogen Candida albicans can switch between two phenotypic cell types, termed “white” and “opaque.” Both cell types are heritable for many generations, and the switch between the two types occurs epigenetically, that is, without a change in the primary DNA sequence of the genome. Previous work identified six key transcriptional regulators important for white-opaque switching: Wor1, Wor2, Wor3, Czf1, Efg1, and Ahr1. In this work, we describe the structure of the transcriptional network that specifies the white and opaque cell types and governs the ability to switch between them. In particular, we use a combination of genome-wide chromatin immunoprecipitation, gene expression profiling, and microfluidics-based DNA binding experiments to determine the direct and indirect regulatory interactions that form the switch network. The six regulators are arranged together in a complex, interlocking network with many seemingly redundant and overlapping connections. We propose that the structure (or topology) of this network is responsible for the epigenetic maintenance of the white and opaque states, the switching between them, and the specialized properties of each state.

Budding off: bringing functional genomics toCandida albicans

“…As the number of data sets increases and the complexity of the systems multiply, new programs must weigh the ability of these models to accurately depict transcriptional effects [128][129][130]. Progressively, integration of previously published expression data sets is informing our understanding of C. albicans transcriptional networks to create more robust and dynamic models of regulation [75,125].…”

“…Transcriptional profiles have now been defined under a wide variety of conditions both in vitro and in vivo [99][100][101][102][103]. Profiling of unique phenotypic states, including white, opaque, gray and GUT (gastrointestinally induced transition), has been used to define the transcriptional networks regulating these states, and has revealed that these networks resemble those controlling cell fate in metazoans [34,75,98,104].…”

“…In the case of the white-opaque switch, a network of at least six transcription factors (AHR1, CZF1, EFG1, WOR1, WOR2 and WOR3) controls expression of 748 target genes [30, [75][76][77][78]. A detailed analysis of this circuit included ChIP-chip, global transcriptome analysis and mechanically induced trapping of molecular interactions (MITOMI) [75]. The latter technique involves testing the binding of an in vitro translated protein to all possible 8-mer DNA sequences to determine DNA-binding specificity [79,80].…”

Crystal structure of the WOPR-DNA complex and implications for Wor1 function in white-opaque switching of Candida albicans

“…White-opaque switching is controlled through expression of a master regulator, Wor1 (whiteopaque switching regulator 1), which is highly upregulated in opaque cells and is required for both the transition to and maintenance of the opaque cell type [10][11][12][13]. Wor1 can genetically interact with the other five key regulators, forming a network of positive and negative feedback loops to control white-opaque switching [14,15]. Recently, Wor1 is also found to regulate a phenotypic switch that promotes commensalism when passing through the mammalian gut in MTLa/α cell types [2].…”

Structure of a new DNA-binding domain which regulates pathogenesis in a wide variety of fungi

“…Recently, a series of in vitro and in vivo experiments demonstrated that the WOPR domain of Wor1 binds DNA in a sequence-specific fashion and defined the DNA sequence recognized by it (Fig. 1B) (11,12). Muc1 expressed independent of TEC1 1 (Mit1) from Saccharomyces cerevisiae, a fourth WOPR-domain protein, and Ryp1 from H. capsulatum have since been shown to recognize this same DNA sequence, representing conservation of the WOPR domain-DNA sequence interactions over a period of 600 million to 1.2 billion years (13).…”