title: Two DNA-encoded strategies for increasing expression with opposing effects on promoter dynamics and transcriptional noise.
abstract: Individual cells from a genetically identical population exhibit substantial variation in gene expression. A significant part of this variation is due to noise in the process of transcription that is intrinsic to each gene, and is determined by factors such as the rate with which the promoter transitions between transcriptionally active and inactive states, and the number of transcripts produced during the active state. However, we have a limited understanding of how the DNA sequence affects such promoter dynamics. Here, we used single-cell time-lapse microscopy to compare the effect on transcriptional dynamics of two distinct types of sequence changes in the promoter that can each increase the mean expression of a cell population by similar amounts but through different mechanisms. We show that increasing expression by strengthening a transcription factor binding site results in slower promoter dynamics and higher noise as compared with increasing expression by adding nucleosome-disfavoring sequences. Our results suggest that when achieving the same mean expression, the strategy of using stronger binding sites results in a larger number of transcripts produced from the active state, whereas the strategy of adding nucleosome-disfavoring sequences results in a higher frequency of promoter transitions between active and inactive states. In the latter strategy, this increased sampling of the active state likely reduces the expression variability of the cell population. Our study thus demonstrates the effect of cis-regulatory elements on expression variability and points to concrete types of sequence changes that may allow partial decoupling of expression level and noise.
authors: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Maya
authors: M
authors: Dadiani
authors: David
authors: D
authors: van Dijk
authors: Barak
authors: B
authors: Segal
authors: Yair
authors: Y
authors: Field
authors: Gil
authors: G
authors: Ben-Artzi
authors: Tali
authors: T
authors: Raveh-Sadka
authors: Michal
authors: M
authors: Levo
authors: Irene
authors: I
authors: Kaplow
authors: Adina
authors: A
authors: Weinberger
authors: Eran
authors: E
authors: Segal
mesh_terms: D001665:Binding Sites; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D011063:Poly A-U; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D014157:Transcription Factors; D011063:Poly A-U
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