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Synthetic Bistability and Differentiation in Yeast.

ABSTRACT: Engineered systems that control cellular differentiation and pattern formation are essential for applications like tissue engineering, biomaterial fabrication, and synthetic ecosystems. Synthetic circuits that can take on multiple states have been made to engineer multicellular systems. However, how to use these states to drive interesting cellular behavior remains challenging. Here, we present a cellular differentiation program involving a novel synthetic bistable switch coupled to an antibiotic resistance gene that affects growth in yeast ( S. cerevisiae). The switch is composed of a positive feedback loop involving a novel transcription factor and can be switched ON and OFF via two different transient inducer inputs. By further coupling the bistable switch with an antibiotic resistance gene, we obtained a growth differentiation circuit, where yeast cells can be switched to stable HIGH or LOW growth rate states via transient inducer inputs. This work demonstrates a rationally designed and experimentally validated cellular differentiation behavior in yeast.

SUBMITTER: Yang Y

PROVIDER: S-EPMC6948009 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Synthetic Bistability and Differentiation in Yeast.

Yang Yaoyu Y Nemhauser Jennifer L JL Klavins Eric E

ACS synthetic biology 20190501 5

Engineered systems that control cellular differentiation and pattern formation are essential for applications like tissue engineering, biomaterial fabrication, and synthetic ecosystems. Synthetic circuits that can take on multiple states have been made to engineer multicellular systems. However, how to use these states to drive interesting cellular behavior remains challenging. Here, we present a cellular differentiation program involving a novel synthetic bistable switch coupled to an antibioti ...[more]

PMID: 31021593

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Project description:BackgroundThe field of synthetic biology has greatly evolved and numerous functions can now be implemented by artificially engineered cells carrying the appropriate genetic information. However, in order for the cells to robustly perform complex or multiple tasks, co-operation between them may be necessary. Therefore, various synthetic biological systems whose functionality requires cell-cell communication are being designed. These systems, microbial consortia, are composed of engineered cells and exhibit a wide range of behaviors. These include yeast cells whose growth is dependent on one another, or bacteria that kill or rescue each other, synchronize, behave as predator-prey ecosystems or invade cancer cells.ResultsIn this paper, we study a synthetic ecosystem comprising of bacteria and yeast that communicate with and benefit from each other using small diffusible molecules. We explore the behavior of this heterogeneous microbial consortium, composed of Saccharomyces cerevisiae and Escherichia coli cells, using stochastic modeling. The stochastic model captures the relevant intra-cellular and inter-cellular interactions taking place in and between the eukaryotic and prokaryotic cells. Integration of well-characterized molecular regulatory elements into these two microbes allows for communication through quorum sensing. A gene controlling growth in yeast is induced by bacteria via chemical signals and vice versa. Interesting dynamics that are common in natural ecosystems, such as obligatory and facultative mutualism, extinction, commensalism and predator-prey like dynamics are observed. We investigate and report on the conditions under which the two species can successfully communicate and rescue each other.ConclusionsThis study explores the various behaviors exhibited by the cohabitation of engineered yeast and bacterial cells. The way that the model is built allows for studying the dynamics of any system consisting of two species communicating with one another via chemical signals. Therefore, key information acquired by our model may potentially drive the experimental design of various synthetic heterogeneous ecosystems.

Project description:BackgroundBistability and hysteresis are increasingly recognized as major properties of regulatory networks governing numerous biological phenomena, such as differentiation and cell cycle progression. The full scope of the underlying molecular mechanisms leading to bistability and hysteresis remains elusive. Nectria haemaotcocca, a saprophytic or pathogenic fungus with sexual reproduction, exhibits a bistable morphological modification characterized by a reduced growth rate and an intense pigmentation. Bistability is triggered by the presence or absence of sigma, a cytoplasmic determinant. This determinant spreads in an infectious manner in the hyphae of the growing margin, insuring hysteresis of the differentiation.ResultsSeven mutants specifically affected in the generation of sigma were selected through two different screening strategies. The s1 and s2 mutations completely abolish the generation of sigma and of its morphological expression, the Secteur. The remaining five mutations promote its constitutive generation, which determines an intense pigmentation but not growth alteration. The seven mutations map at the same locus, Ses (for 'Secteur-specific'). The s2 mutant was obtained by an insertional mutagenesis strategy, which permitted the cloning of the Ses locus. Sequence and transcription analysis reveals that Ses is composed of two closely linked genes, SesA, mutated in the s1 and s2 mutant strains, and SesB, mutated in the s* mutant strains. SesB shares sequence similarity with animal and fungal putative proteins, with potential esterase/lipase/thioesterase activity, whereas SesA is similar to proteins of unknown function present only in the filamentous fungi Fusarium graminearum and Podospora anserina.ConclusionsThe cloning of Ses provides evidence that a system encoded by two linked genes directs a bistable and hysteretic switch in a eukaryote. Atypical regulatory relations between the two proteins may account for the hysteresis of Secteur differentiation.

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Synthetic Bistability and Differentiation in Yeast.

Publications

Synthetic Bistability and Differentiation in Yeast.

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