Plasticity of the cis-regulatory input function of a gene

• Published in: PLoS biology Vol. 4; no. 4; p. e45
• Main Authors: Mayo, Avraham E, Setty, Yaakov, Shavit, Seagull, Zaslaver, Alon, Alon, Uri
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-04-2006; Public Library of Science (PLoS)
• Subjects: Base Sequence; Binding sites; Bioengineering; Bioinformatics/Computational Biology; Databases, Genetic; E coli; Escherichia coli; Escherichia coli - genetics; Eubacteria; Evolution; Experiments; Gene Expression Regulation, Bacterial; Genetic Variation - genetics; Genetics; Genetics/Genomics/Gene Therapy; Lac Operon - genetics; Mathematical models; Molecular Sequence Data; Mutation; Mutation - genetics; Phenotype; Promoter Regions, Genetic - genetics; Proteins; Regulatory Elements, Transcriptional - genetics; RNA polymerase; Systems Biology; Genetic Variation; Promoter Regions, Genetic; Phenotype; Regulatory Elements, Transcriptional; Base Sequence; Escherichia coli; Databases, Genetic; Molecular Sequence Data; Mutation; Gene Expression Regulation, Bacterial; Lac Operon
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.0040045

The transcription rate of a gene is often controlled by several regulators that bind specific sites in the gene's cis-regulatory region. The combined effect of these regulators is described by a cis-regulatory input function. What determines the form of an input function, and how variable is it with respect to mutations? To address this, we employ the well-characterized lac operon of Escherichia coli, which has an elaborate input function, intermediate between Boolean AND-gate and OR-gate logic. We mapped in detail the input function of 12 variants of the lac promoter, each with different point mutations in the regulator binding sites, by means of accurate expression measurements from living cells. We find that even a few mutations can significantly change the input function, resulting in functions that resemble Pure AND gates, OR gates, or single-input switches. Other types of gates were not found. The variant input functions can be described in a unified manner by a mathematical model. The model also lets us predict which functions cannot be reached by point mutations. The input function that we studied thus appears to be plastic, in the sense that many of the mutations do not ruin the regulation completely but rather result in new ways to integrate the inputs.