ES is the incumbent of the Soretta and Henry Shapiro Career Development Chair. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by grants from the European Research Council (ERC) and The US National Institutes of Health (NIH) to ES. Received: NovemAccepted: FebruPublished: April 2, 2013Ĭopyright: © 2013 Carey et al. PLoS Biol 11(4):Īlbert Einstein College of Medicine, United States of America These results show that a single TF can regulate transcription through multiple mechanisms, resulting in similar changes in mean expression but vastly different changes in cell-to-cell variability.Ĭitation: Carey LB, van Dijk D, Sloot PMA, Kaandorp JA, Segal E (2013) Promoter Sequence Determines the Relationship between Expression Level and Noise. Using computational modeling and mutations of specific promoter elements, we show that the molecular mechanisms of regulation can be inferred by measuring how noise changes with expression. We found that different native promoters that are all targets of the same TF exhibit diverse responses to changing TF levels in terms of both gene expression level and cell-to-cell variability (noise) in expression. To examine the relationship between promoter sequence, mechanism of regulation, and response to TF activity, we measured expression of 16 target genes of a single TF in response to changes in TF concentration in single cells. The response of each target gene is determined by the interplay between TF concentration and the context in which TF binding sites occur in each target promoter. In response to environmental changes, cells regulate the activity of transcription factors (TFs), which in turn change the expression of dozens of downstream target genes by binding to their promoters. Taken together, we show that the precise amount by which noise changes with expression is specific to the regulatory mechanism of transcription and translation that acts at each gene. ![]() Our results suggest a global principle whereby at low TF concentrations, the dominant source of differences in expression between promoters stems from differences in burst frequency, whereas at high TF concentrations differences in burst size dominate. In addition, we find that further reduction in noise is achieved when a single TF both activates and represses a single target gene. Notably, we found that another mechanism of repression by Zap1, which is encoded in the promoter DNA, likely decreases the size of transcriptional bursts, producing a unique transcriptional state characterized by low expression and low noise. Kinetic modeling suggests that this is due to two distinct Zap1-mediated mechanisms that both change the frequency of transcriptional bursts. ![]() For most activated and repressed Zap1 targets, noise decreases as expression increases. ![]() Here, we measure expression and noise as a function of TF activity for 16 native targets of the transcription factor Zap1 that are regulated by it through diverse mechanisms. A change in transcription factor (TF) activity results in changes in the expression of its targets, but the way in which cell-to-cell variability in expression (noise) changes as a function of TF activity, and whether targets of the same TF behave similarly, is not known. The ability of cells to accurately control gene expression levels in response to extracellular cues is limited by the inherently stochastic nature of transcriptional regulation.
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