Finding a Signal in the Noise: Understanding the Biological Sources and Consequences of Cell-to-Cell Heterogeneity in Gene Expression

Mammalian gene expression is a noisy process with significant variability between cells exposed to the same environmental cues. There is evidence that gene expression noise is constrained across the genome, but how activation of gene transcription occurs within these global constraints is less clear. Here we studied transcriptional noise associated with activation by the transcription factor NF-κB, which has central roles in immunity and development. We found that NF-κB target promoters display a global mean-versus-noise relationship. We further found that within a very narrow range of mean basal transcription (1-2 transcripts per cell), transcriptional activation by NF-κB causes distinct changes in transcriptional noise for different gene targets, while remaining constrained along mean-versus-noise trend lines. Strikingly, the different modes of transcriptional noise following NF-κB activation are associated with significant differences in biological processes at the promoter, which may represent one source of global constraint. We also see evidence of phenotypic consequences: HIV promoters support gene expression that maps to the interface between these two modes of NF-κB-induced transcriptional noise, affording HIV the potential for wide phenotypic heterogeneity when coupled to viral-mediated positive feedback amplification of noise, rather than noise-controlling motifs.