Dynamics of the interlocked positive feedback loops explaining the robust epigenetic switching in Candida albicans

Sriram, K.; Soliman, Sylvain; Fages, François

doi:10.1016/j.jtbi.2009.01.008

Cited by 28 publications

(32 citation statements)

References 51 publications

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“…A recent study indicated that an additional transcription factor, Wor3, plays a role in controlling this loop (64). Mediator is known to directly impact transcription, and modeling studies suggested that changes in the steady-state levels of the key regulators of the white-opaque switch are a straightforward way to explain changes in switching frequencies (65). Hence, we tested the steady-state mRNA levels of WOR1, EFG1, WOR2, and CZF1 by RT-qPCR in both white and opaque cells of the WT, med5⌬/⌬, med16⌬/⌬, med9⌬/⌬, med20⌬/⌬, and med12⌬/⌬ strains and in white cells of the med3⌬/⌬ strain since we could not obtain opaque cells of this mutant.…”

Section: Resultsmentioning

confidence: 99%

Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

2013

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The multisubunit eukaryotic Mediator complex integrates diverse positive and negative gene regulatory signals and transmits them to the core transcription machinery. Mutations in individual subunits within the complex can lead to decreased or increased transcription of certain subsets of genes, which are highly specific to the mutated subunit. Recent studies suggest a role for Mediator in epigenetic silencing. Using white-opaque morphological switching in Candida albicans as a model, we have shown that Mediator is required for the stability of both the epigenetic silenced (white) and active (opaque) states of the bistable transcription circuit driven by the master regulator Wor1. Individual deletions of eight C. albicans Mediator subunits have shown that different Mediator subunits have dramatically diverse effects on the directionality, frequency, and environmental induction of epigenetic switching. Among the Mediator deletion mutants analyzed, only Med12 has a steady-state transcriptional effect on the components of the Wor1 circuit that clearly corresponds to its effect on switching. The MED16 and MED9 genes have been found to be among a small subset of genes that are required for the stability of both the white and opaque states. Deletion of the Med3 subunit completely destabilizes the opaque state, even though the Wor1 transcription circuit is intact and can be driven by ectopic expression of Wor1. The highly impaired ability of the med3 deletion mutant to mate, even when Wor1 expression is ectopically induced, reveals that the activation of the Wor1 circuit can be decoupled from the opaque state and one of its primary biological consequences.

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Section: Resultsmentioning

confidence: 99%

Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

2013

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“…The AR circuit corresponds to two positive feedback loops, where the internalized metabolite increases its own abundance by speeding up its import and slowing down its consumption. Interlinked positive feedback loops are known to improve the bistability properties in a number of natural networks [32][33][34] and there is evidence rsif.royalsocietypublishing.org J. R. Soc. Interface 12: 20150618 that nature favours bistability through interlinked regulation [2].…”

Section: Shape and Size Of The Promoter Design Spacementioning

confidence: 99%

Design of a bistable switch to control cellular uptake

Oyarzún

Chaves

2015

J. R. Soc. Interface.

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Bistable switches are widely used in synthetic biology to trigger cellular functions in response to environmental signals. All bistable switches developed so far, however, control the expression of target genes without access to other layers of the cellular machinery. Here, we propose a bistable switch to control the rate at which cells take up a metabolite from the environment. An uptake switch provides a new interface to command metabolic activity from the extracellular space and has great potential as a building block in more complex circuits that coordinate pathway activity across cell cultures, allocate metabolic tasks among different strains or require cell-to-cell communication with metabolic signals. Inspired by uptake systems found in nature, we propose to couple metabolite import and utilization with a genetic circuit under feedback regulation. Using mathematical models and analysis, we determined the circuit architectures that produce bistability and obtained their design space for bistability in terms of experimentally tuneable parameters. We found an activation-repression architecture to be the most robust switch because it displays bistability for the largest range of design parameters and requires little fine-tuning of the promoters' response curves. Our analytic results are based on on -off approximations of promoter activity and are in excellent qualitative agreement with simulations of more realistic models. With further analysis and simulation, we established conditions to maximize the parameter design space and to produce bimodal phenotypes via hysteresis and cell-to-cell variability. Our results highlight how mathematical analysis can drive the discovery of new circuits for synthetic biology, as the proposed circuit has all the hallmarks of a toggle switch and stands as a promising design to control metabolic phenotypes across cell cultures.

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“…Together, these transcriptional regulators act as part of two mutually exclusive, self-perpetuating positive transcriptional feedback loops. It has been proposed that these feedback loops form the basis for the two cell types and the stability of each cell type through many cell divisions Sriram et al 2009). In addition to these eight regulators, recent studies have identified several additional regulators with more subtle effects on switching (i.e., Flo8, Lys143, and Ofi1); however, their relationship to the core regulatory circuits is not fully understood (Du et al 2012(Du et al , 2015Pérez et al 2014).…”

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confidence: 99%

Systematic Genetic Screen for Transcriptional Regulators of the Candida albicans White-Opaque Switch

et al. 2016

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The human fungal pathogen Candida albicans can reversibly switch between two cell types named "white" and "opaque," each of which is stable through many cell divisions. These two cell types differ in their ability to mate, their metabolic preferences and their interactions with the mammalian innate immune system. A highly interconnected network of eight transcriptional regulators has been shown to control switching between these two cell types. To identify additional regulators of the switch, we systematically and quantitatively measured white-opaque switching rates of 196 strains, each deleted for a specific transcriptional regulator. We identified 19 new regulators with at least a 10-fold effect on switching rates and an additional 14 new regulators with more subtle effects. To investigate how these regulators affect switching rates, we examined several criteria, including the binding of the eight known regulators of switching to the control region of each new regulatory gene, differential expression of the newly found genes between cell types, and the growth rate of each mutant strain. This study highlights the complexity of the transcriptional network that regulates the white-opaque switch and the extent to which switching is linked to a variety of metabolic processes, including respiration and carbon utilization. In addition to revealing specific insights, the information reported here provides a foundation to understand the highly complex coupling of white-opaque switching to cellular physiology.KEYWORDS white-opaque switching; transcriptional regulation; transcription networks; transcriptional circuits; Candida albicans T HE fungal species Candida albicans is normally a harmless component of the human microbiome, but it can also cause life threatening bloodstream infections, particularly in immunocompromised patients. C. albicans has the unusual ability to switch between two cell types, named "white" and "opaque," each with distinct cellular and colony morphologies ( Figure 1, A and B) (Slutsky et al. 1987;Soll et al. 1993;Johnson 2003;Lohse and Johnson 2009;Soll 2009;Morschhäuser 2010). Each cell type is heritable for many cell divisions, and switching from one form to the other occurs without any change in the primary DNA sequence of the genome. Under standard laboratory conditions, switching between the two cell types occurs stochastically with approximately one switching event every 10 4 cell divisions, although certain environmental cues, such as elevated temperatures, can cause mass switching from one cell type to the other (Rikkerink et al. 1988;Huang et al. 2009Huang et al. , 2010. Expression of 20% of the genes in C. albicans is differentially regulated between the two cell types (Lan et al. 2002;) and, as a result, the white and opaque forms differ in their ability to mate (Miller and Johnson 2002), their metabolic preferences (Lan et al. 2002), and their interactions with the innate immune system (Kvaal et al. 1997(Kvaal et al. , 1999Geiger et al. 2004;Lohse and Johnson 2008;Sasse et a...

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Dynamics of the interlocked positive feedback loops explaining the robust epigenetic switching in Candida albicans

Cited by 28 publications

References 51 publications

Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

Differential Regulation of White-Opaque Switching by Individual Subunits of Candida albicans Mediator

Design of a bistable switch to control cellular uptake

Systematic Genetic Screen for Transcriptional Regulators of the Candida albicans White-Opaque Switch

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