UCSF

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.