title: Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion.
abstract: Feedback is a ubiquitous control mechanism of gene networks. Here, we have used positive feedback to construct a synthetic eukaryotic gene switch in Saccharomyces cerevisiae. Within this system, a continuous gradient of constitutively expressed transcriptional activator is translated into a cell phenotype switch when the activator is expressed autocatalytically. This finding is consistent with a mathematical model whose analysis shows that continuous input parameters are converted into a bimodal probability distribution by positive feedback, and that this resembles analog-digital conversion. The autocatalytic switch is a robust property in eukaryotic gene expression. Although the behavior of individual cells within a population is random, the proportion of the cell population displaying either low or high expression states can be regulated. These results have implications for understanding the graded and probabilistic mechanisms of enhancer action and cell differentiation.
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69012 Heidelberg, Germany. becskei@embl-heidelberg.de
authors.forename: A
authors.initials: A
authors.lastname: Becskei
authors.forename: B
authors.initials: B
authors.lastname: Séraphin
authors.forename: L
authors.initials: L
authors.lastname: Serrano
mesh_terms: D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D005057:Eukaryotic Cells; D005246:Feedback; D005656:Fungal Proteins / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D013752:Tetracycline; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D013752:Tetracycline