title: Promoter sequence determines the relationship between expression level and noise.
abstract: 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.
authors.affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Lucas B
authors.initials: LB
authors.lastname: Carey
authors.forename: David
authors.initials: D
authors.lastname: van Dijk
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Sloot
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Kaandorp
authors.forename: Eran
authors.initials: E
authors.lastname: Segal
mesh_terms: D000426:Alcohol Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D027682:Cation Transport Proteins / Q000235:genetics; D004790:Enzyme Induction; D015870:Gene Expression; D015966:Gene Expression Regulation, Fungal; D015723:Gene Library; D017930:Genes, Reporter; D007700:Kinetics; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D027682:Cation Transport Proteins; D008164:Luminescent Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C103264:ZAP1 protein, S cerevisiae; C098750:ZRT1 protein, S cerevisiae; C101759:ZRT2 protein, S cerevisiae; C054562:yellow fluorescent protein, Bacteria; C516801:ADH1 protein, S cerevisiae; C516802:ADH3 protein, S cerevisiae; D000426:Alcohol Dehydrogenase
references.citation: EMBO J. 2004 Mar 10;23(5):1123-32
references.pmid: 14976557
references.citation: Nat Struct Mol Biol. 2008 Dec;15(12):1263-71
references.pmid: 19011635
references.citation: Nature. 2002 Sep 19;419(6904):304-8
references.pmid: 12239569
references.citation: BMC Genomics. 2008 Aug 01;9:370
references.pmid: 18673560
references.citation: EMBO J. 2006 Dec 13;25(24):5726-34
references.pmid: 17139254
references.citation: Science. 2011 Apr 22;332(6028):472-4
references.pmid: 21415320
references.citation: Nature. 2003 Apr 10;422(6932):633-7
references.pmid: 12687005
references.citation: Science. 2010 Feb 26;327(5969):1142-5
references.pmid: 20185727
references.citation: Transcription. 2011 Jan-Feb;2(1):9-14
references.pmid: 21326903
references.citation: PLoS Comput Biol. 2011 Mar;7(3):e1001100
references.pmid: 21390269
references.citation: PLoS Biol. 2006 Oct;4(10):e309
references.pmid: 17048983
references.citation: Biophys J. 2001 Dec;81(6):3116-36
references.pmid: 11720979
references.citation: Mol Syst Biol. 2009;5:300
references.pmid: 19690569
references.citation: Genes Dev. 2011 Jan 1;25(1):29-40
references.pmid: 21156811
references.citation: Nature. 1997 Jun 26;387(6636):913-7
references.pmid: 9202124
references.citation: Nucleic Acids Res. 2008 Jun;36(11):3570-8
references.pmid: 18453629
references.citation: Mol Syst Biol. 2010 Apr 13;6:358
references.pmid: 20393578
references.citation: Phys Rev Lett. 2006 Oct 20;97(16):168302
references.pmid: 17155441
references.citation: Nat Genet. 2002 May;31(1):69-73
references.pmid: 11967532
references.citation: PLoS Genet. 2009 Oct;5(10):e1000673
references.pmid: 19798446
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5081-6
references.pmid: 18353986
references.citation: Biochim Biophys Acta. 1953 Jul;11(3):383-95
references.pmid: 13093744
references.citation: Methods Mol Biol. 2006;313:171-92
references.pmid: 16118434
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):E67-76
references.pmid: 21464323
references.citation: Science. 2010 Jul 30;329(5991):533-8
references.pmid: 20671182
references.citation: Nat Struct Mol Biol. 2004 May;11(5):394-403
references.pmid: 15114340
references.citation: Annu Rev Biophys Biomol Struct. 2007;36:413-34
references.pmid: 17477840
references.citation: Science. 2004 Jun 18;304(5678):1811-4
references.pmid: 15166317
references.citation: Science. 2005 Mar 25;307(5717):1965-9
references.pmid: 15790857
references.citation: Science. 2011 Apr 22;332(6028):475-8
references.pmid: 21512033
references.citation: Nature. 2006 Mar 16;440(7082):358-62
references.pmid: 16541077
references.citation: Nat Genet. 2011 Jun;43(6):554-60
references.pmid: 21532574
references.citation: Mol Cell. 2011 Feb 18;41(4):480-92
references.pmid: 21329885
references.citation: J Theor Biol. 2008 Sep 7;254(1):178-96
references.pmid: 18572196
references.citation: Nat Genet. 2006 Jun;38(6):610-1
references.pmid: 16736013
references.citation: Genome Res. 2011 Dec;21(12):2114-28
references.pmid: 22009988
references.citation: Nat Genet. 2006 Jun;38(6):636-43
references.pmid: 16715097
references.citation: Dev Cell. 2010 Apr 20;18(4):544-55
references.pmid: 20412770
references.citation: Nucleic Acids Res. 2010 May;38(8):2712-26
references.pmid: 20211838
references.citation: Science. 2007 Jul 27;317(5837):526-9
references.pmid: 17569828
references.citation: Nature. 2005 Sep 29;437(7059):699-706
references.pmid: 16170311
references.citation: Mol Microbiol. 1996 Mar;19(6):1225-39
references.pmid: 8730865
references.citation: Nature. 2006 Jun 15;441(7095):840-6
references.pmid: 16699522