Transcription factor binding process is the primary driver of noise in gene expression

Abstract

Noise in expression of individual genes gives rise to variations in activity of cellular pathways and generates heterogeneity in cellular phenotypes. Phenotypic heterogeneity has important implications for antibiotic persistence, mutation penetrance, cancer growth and therapy resistance. Specific molecular features such as presence of the TATA box sequence and promoter nucleosome occupancy have been associated with noise. However, the relative importance of these features in noise regulation has not yet been assessed. In addition, how well these features can predict noise also remains unclear. Here through an integrated statistical model of gene expression noise in yeast we found that the number of regulating transcription factors (TFs) was a key predictor of noise. With an increase in the number of regulatory TFs, we observed a rise in the number of TFs that bound cooperatively. In addition, increased number of TFs meant more overlaps in TF binding sites that caused competition between TFs for binding to the same region of the promoter. Through modeling of TF binding to promoter and applying stochastic simulations, we demonstrated that competition and cooperation among TFs could increase noise. Thus, our work uncovers a process of noise regulation that arises out of the dynamics of gene regulation and is not dependent on any specific transcription factor or specific promoter sequence.