Cells must integrate signals from their environment and respond accurately in order to grow and divide properly. However, the chemical reactions within single cells do not occur with deterministic certainty. Rather, they occur with a probability due, in part, to the abundance of molecular components and their rates of synthesis and degradation. Therefore, while an entire population of cells may respond appropriately to environmental cues, single cells may vary wildly in their output responses. This phenomenon is called biological noise, and increasingly has been reported to be an important determinant for population heterogeneity, fitness, and development. Although biological noise has been characterized in a variety of systems and cellular pathways, mechanisms that regulate cell-to-cell variability remain poorly understood. In this work, we investigated the role of biological noise in the transcriptional output of the mating pathway, a canonical MAP kinase pathway in S. cerevisiae. We identified a role in noise suppression for Dig1, a negative regulator of the transcription factor Ste12. The removal of Dig1 causes an increase in intrinsic and extrinsic noise in the expression of Ste12 target genes. In conjunction, Dig1 inhibits long-range interactions between Ste12 target genes in vivo. Finally, we demonstrate a link between fitness defects and the increased gene expression noise in cells lacking Dig1. These studies suggest that gene expression noise is an evolvable trait and that, when necessary, mechanisms can arise to modulate cell-to-cell variability.

The protein YbiV from Escherichia coli K12 MG1655 is a hypothetical protein with sequence homology to the haloacid dehalogenase (HAD) superfamily of proteins. Although numerous members of this family have been identified, the functions of few are known. Using the crystal structure, sequence analysis, and biochemical assays, we have characterized ybiV as a HAD phosphatase. The crystal structure of YbiV reveals a two domain protein, one with the characteristic HAD hydrolase fold, the other an inserted a/b fold. In an effort to understand the mechanism we also solved and report the structures of YbiV in complex with beryllofluoride (BeF3-) and aluminum trifluoride (AlF3) which have been shown to mimic the phosphorylated intermediate and transition state for hydrolysis, respectively, in analogy to other HAD phosphatases. Analysis of the structures reveals the substrate binding cavity, which is hydrophilic in nature. Both structure and sequence homology indicate ybiV may be a sugar phosphatase, which is supported by biochemical assays which measured the release of free phosphate on a number of sugar-like substrates. We also investigated available genomic and functional data in an effort to determine the physiological substrate.