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Promoter Sequence Determines the Relationship between Expression Level and Noise

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. A change in transcription factor (TF) activity results in changes in the expression of its targets, but the way in which c...

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Autores principales: Carey, Lucas B., van Dijk, David, Sloot, Peter M. A., Kaandorp, Jaap A., Segal, Eran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614515/
https://www.ncbi.nlm.nih.gov/pubmed/23565060
http://dx.doi.org/10.1371/journal.pbio.1001528
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author Carey, Lucas B.
van Dijk, David
Sloot, Peter M. A.
Kaandorp, Jaap A.
Segal, Eran
author_facet Carey, Lucas B.
van Dijk, David
Sloot, Peter M. A.
Kaandorp, Jaap A.
Segal, Eran
author_sort Carey, Lucas B.
collection PubMed
description 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. 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. 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. For most activated and repressed Zap1 targets, noise decreases as expression increases. Kinetic modeling suggests that this is due to two distinct Zap1-mediated mechanisms that both change the frequency of transcriptional bursts. 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. In addition, we find that further reduction in noise is achieved when a single TF both activates and represses a single target 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. 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.
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spelling pubmed-36145152013-04-05 Promoter Sequence Determines the Relationship between Expression Level and Noise Carey, Lucas B. van Dijk, David Sloot, Peter M. A. Kaandorp, Jaap A. Segal, Eran PLoS Biol Research Article 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. 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. 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. For most activated and repressed Zap1 targets, noise decreases as expression increases. Kinetic modeling suggests that this is due to two distinct Zap1-mediated mechanisms that both change the frequency of transcriptional bursts. 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. In addition, we find that further reduction in noise is achieved when a single TF both activates and represses a single target 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. 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. Public Library of Science 2013-04-02 /pmc/articles/PMC3614515/ /pubmed/23565060 http://dx.doi.org/10.1371/journal.pbio.1001528 Text en © 2013 Carey et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Carey, Lucas B.
van Dijk, David
Sloot, Peter M. A.
Kaandorp, Jaap A.
Segal, Eran
Promoter Sequence Determines the Relationship between Expression Level and Noise
title Promoter Sequence Determines the Relationship between Expression Level and Noise
title_full Promoter Sequence Determines the Relationship between Expression Level and Noise
title_fullStr Promoter Sequence Determines the Relationship between Expression Level and Noise
title_full_unstemmed Promoter Sequence Determines the Relationship between Expression Level and Noise
title_short Promoter Sequence Determines the Relationship between Expression Level and Noise
title_sort promoter sequence determines the relationship between expression level and noise
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614515/
https://www.ncbi.nlm.nih.gov/pubmed/23565060
http://dx.doi.org/10.1371/journal.pbio.1001528
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