title: Probing the effect of promoters on noise in gene expression using thousands of designed sequences.
abstract: Genetically identical cells exhibit large variability (noise) in gene expression, with important consequences for cellular function. Although the amount of noise decreases with and is thus partly determined by the mean expression level, the extent to which different promoter sequences can deviate away from this trend is not fully known. Here, we present a high-throughput method for measuring promoter-driven noise for thousands of designed synthetic promoters in parallel. We use it to investigate how promoters encode different noise levels and find that the noise levels of promoters with similar mean expression levels can vary more than one order of magnitude, with nucleosome-disfavoring sequences resulting in lower noise and more transcription factor binding sites resulting in higher noise. We propose a kinetic model of gene expression that takes into account the nonspecific DNA binding and one-dimensional sliding along the DNA, which occurs when transcription factors search for their target sites. We show that this assumption can improve the prediction of the mean-independent component of expression noise for our designed promoter sequences, suggesting that a transcription factor target search may affect gene expression noise. Consistent with our findings in designed promoters, we find that binding-site multiplicity in native promoters is associated with higher expression noise. Overall, our results demonstrate that small changes in promoter DNA sequence can tune noise levels in a manner that is predictable and partly decoupled from effects on the mean expression levels. These insights may assist in designing promoters with desired noise levels.
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Eilon
authors.initials: E
authors.lastname: Sharon
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: David
authors.initials: D
authors.lastname: van Dijk
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Yael
authors.initials: Y
authors.lastname: Kalma
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Leeat
authors.initials: L
authors.lastname: Keren
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel;
authors.forename: Ohad
authors.initials: O
authors.lastname: Manor
authors.affiliation: Agilent Laboratories, Santa Clara, California 95051, USA; Computer Science Department, Technion, Haifa 32000, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Yakhini
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; eran.segal@weizmann.ac.il.
authors.forename: Eran
authors.initials: E
authors.lastname: Segal
mesh_terms: D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D004247:DNA / Q000378:metabolism*; D015870:Gene Expression; D005800:Genes, Fungal; D016014:Linear Models; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D004247:DNA