Nonspecific transcription factor binding reduces variability in transcription factor and target protein expression

摘要

Transcription factors (TFs) interact with a multitude of binding sites on DNAand partner proteins inside cells. We investigate how nonspecificbinding/unbinding to such decoy binding sites affects the magnitude andtime-scale of random fluctuations in TF copy numbers arising from stochasticgene expression. A stochastic model of TF gene expression, together with decoysite interactions is formulated. Distributions for the total (bound andunbound) and free (unbound) TF levels are derived by analytically solving thechemical master equation under physiologically relevant assumptions. Ourresults show that increasing the number of decoy binding sides considerablyreduces stochasticity in free TF copy numbers. The TF autocorrelation functionreveals that decoy sites can either enhance or shorten the time-scale of TFfluctuations depending on model parameters. To understand how noise in TFabundances propagates downstream, a TF target gene is included in the model.Intriguingly, we find that noise in the expression of the target gene decreaseswith increasing decoy sites for linear TF-target protein dose-responses, evenin regimes where decoy sites enhance TF autocorrelation times. Moreover,counterintuitive noise transmissions arise for nonlinear dose-responses. Insummary, our study highlights the critical role of molecular sequestration bydecoy binding sites in regulating the stochastic dynamics of TFs and targetproteins at the single-cell level.