{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T03:39:45Z","timestamp":1774928385170,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009745","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000}}],"reference-count":62,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM128797"],"award-info":[{"award-number":["R35GM128797"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Gene networks typically involve the regulatory control of multiple genes with related function. This connectivity enables correlated control of the levels and timing of gene expression. Here we study how gene expression timing in the single-input module motif can be encoded in the regulatory DNA of a gene. Using stochastic simulations, we examine the role of binding affinity, TF regulatory function and network size in controlling the mean first-passage time to reach a fixed fraction of steady-state expression for both an auto-regulated TF gene and a target gene. We also examine how the variability in first-passage time depends on these factors. We find that both network size and binding affinity can dramatically speed up or slow down the response time of network genes, in some cases predicting more than a 100-fold change compared to that for a constitutive gene. Furthermore, these factors can also significantly impact the fidelity of this response. Importantly, these effects do not occur at \u201cextremes\u201d of network size or binding affinity, but rather in an intermediate window of either quantity.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009745","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T15:12:27Z","timestamp":1642518747000},"page":"e1009745","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Controlling gene expression timing through gene regulatory architecture"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7054-0059","authenticated-orcid":true,"given":"Md Zulfikar","family":"Ali","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7656-4086","authenticated-orcid":true,"given":"Robert C.","family":"Brewster","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"key":"pcbi.1009745.ref001","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S0022-2836(61)80072-7","article-title":"Genetic regulatory mechanisms in the synthesis of proteins","volume":"3","author":"F Jacob","year":"1961","journal-title":"J Mol Biol"},{"key":"pcbi.1009745.ref002","volume-title":"A genetic switch: phage lambda revisited","author":"M Ptashne","year":"2004","edition":"3"},{"issue":"4916","key":"pcbi.1009745.ref003","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1126\/science.2667136","article-title":"Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins","volume":"245","author":"PJ Mitchell","year":"1989","journal-title":"Science"},{"issue":"D1","key":"pcbi.1009745.ref004","doi-asserted-by":"crossref","first-page":"D212","DOI":"10.1093\/nar\/gky1077","article-title":"RegulonDB v 10.5: tackling challenges to unify classic and high throughput knowledge of gene regulation in E. coli K-12","volume":"47","author":"A Santos-Zavaleta","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pcbi.1009745.ref005","article-title":"The EcoCyc Database","volume":"8","author":"PD Karp","year":"2018","journal-title":"EcoSal Plus"},{"issue":"12","key":"pcbi.1009745.ref006","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1371\/journal.pcbi.0020164","article-title":"Transcriptional regulation by competing transcription factor modules","volume":"2","author":"R Hermsen","year":"2006","journal-title":"PLoS Comput Biol"},{"issue":"4","key":"pcbi.1009745.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pbio.1001528","article-title":"Promoter Sequence Determines the Relationship between Expression Level and Noise","volume":"11","author":"LB Carey","year":"2013","journal-title":"PLOS Biology"},{"issue":"34","key":"pcbi.1009745.ref008","doi-asserted-by":"crossref","first-page":"14024","DOI":"10.1073\/pnas.1301301110","article-title":"Composability of regulatory sequences controlling transcription and translation in Escherichia coli","volume":"110","author":"S Kosuri","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"issue":"6","key":"pcbi.1009745.ref009","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/nbt.2205","article-title":"Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters","volume":"30","author":"E Sharon","year":"2012","journal-title":"Nat Biotechnol"},{"issue":"5861","key":"pcbi.1009745.ref010","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1126\/science.1144331","article-title":"Effects of molecular memory and bursting on fluctuations in gene expression","volume":"319","author":"JM Pedraza","year":"2008","journal-title":"Science"},{"key":"pcbi.1009745.ref011","article-title":"Properties of cell signaling pathways and gene expression systems operating far from steady-state","volume":"8","author":"JP Di-Bella","year":"2018","journal-title":"Scientific Reports"},{"key":"pcbi.1009745.ref012","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1016\/j.cell.2018.10.042","article-title":"Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains","volume":"175","author":"A Boija","year":"2018","journal-title":"Cell"},{"key":"pcbi.1009745.ref013","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.molcel.2014.01.026","article-title":"Fold change of nuclear NF-B determines TNF-induced transcription in single cells","volume":"53","author":"REC Lee","year":"2014","journal-title":"Mol Cell"},{"key":"pcbi.1009745.ref014","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/s41556-020-0485-0","article-title":"Phase separation of TAZ compartmentalizes the transcription machinery to promote gene expression","volume":"22","author":"Y Lu","year":"2020","journal-title":"Nature Cell Biology"},{"issue":"1","key":"pcbi.1009745.ref015","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/ng881","article-title":"Network motifs in the transcriptional regulation network of Escherichia coli","volume":"31","author":"SS Shen-Orr","year":"2002","journal-title":"Nat Genet"},{"issue":"5594","key":"pcbi.1009745.ref016","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1126\/science.1075090","article-title":"Transcriptional regulatory networks in Saccharomyces cerevisiae","volume":"298","author":"TI Lee","year":"2002","journal-title":"Science"},{"issue":"5","key":"pcbi.1009745.ref017","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/ng1348","article-title":"Just-in-time transcription program in metabolic pathways","volume":"36","author":"A Zaslaver","year":"2004","journal-title":"Nat Genet"},{"issue":"7","key":"pcbi.1009745.ref018","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1371\/journal.pbio.0030238","article-title":"Precise temporal modulation in the response of the SOS DNA repair network in individual bacteria","volume":"3","author":"N Friedman","year":"2005","journal-title":"PLoS Biol"},{"issue":"16","key":"pcbi.1009745.ref019","doi-asserted-by":"crossref","first-page":"10555","DOI":"10.1073\/pnas.152046799","article-title":"Assigning numbers to the arrows: parameterizing a gene regulation network by using accurate expression kinetics","volume":"99","author":"M Ronen","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pcbi.1009745.ref020","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/ng0402-348","article-title":"Bringing Order to Organogenesis","volume":"30","author":"MI Arnone","year":"2002","journal-title":"Nature Genetics"},{"key":"pcbi.1009745.ref021","volume-title":"Chapman & Hall\/CRC mathematical and computational biology series","author":"U Alon","year":"2007"},{"key":"pcbi.1009745.ref022","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1093\/bfgp\/els057","article-title":"Event timing at the single-cell level","volume":"12","author":"E Yurkovsky","year":"2013","journal-title":"Brief Funct Genomics"},{"key":"pcbi.1009745.ref023","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.cell.2007.09.044","article-title":"Dissecting timing variability in yeast meiosis","volume":"131","author":"I Nachman","year":"2007","journal-title":"Cell"},{"key":"pcbi.1009745.ref024","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1101\/gad.1335705","article-title":"Evidence that entry into sporulation in Bacillus subtilis is governed by a gradual increase in the level and activity of the master regulator Spo0A","volume":"19","author":"M Fujita","year":"2005","journal-title":"Genes dev"},{"key":"pcbi.1009745.ref025","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature08012","article-title":"Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis","volume":"459","author":"SL Spencer","year":"2009","journal-title":"Nature"},{"issue":"3","key":"pcbi.1009745.ref026","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.cels.2019.07.008","article-title":"The Design Principles of Biochemical Timers: Circuits that Discriminate between Transient and Sustained Stimulation","volume":"9","author":"J Gerardin","year":"2019","journal-title":"Cell systems"},{"issue":"6440","key":"pcbi.1009745.ref027","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1126\/science.aau8287","article-title":"Complex signal processing in synthetic gene circuits using cooperative regulatory assemblies","volume":"364","author":"CJ Bashor","year":"2019","journal-title":"Science"},{"issue":"7312","key":"pcbi.1009745.ref028","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nature09326","article-title":"Functional roles for noise in genetic circuits","volume":"467","author":"A Eldar","year":"2010","journal-title":"Nature"},{"issue":"3","key":"pcbi.1009745.ref029","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1093\/nar\/gkw1235","article-title":"Stochastic timing in gene expression for simple regulatory strategies","volume":"45","author":"AD Co","year":"2017","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pcbi.1009745.ref030","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S0022-2836(02)00994-4","article-title":"Negative autoregulation speeds the response times of transcription networks","volume":"323","author":"N Rosenfeld","year":"2002","journal-title":"J Mol Biol"},{"issue":"6","key":"pcbi.1009745.ref031","doi-asserted-by":"crossref","first-page":"e1007405","DOI":"10.1371\/journal.pgen.1007405","article-title":"Non-equilibrium repressor binding kinetics link DNA damage dose to transcriptional timing within the SOS gene network","volume":"14","author":"MJ Culyba","year":"2018","journal-title":"PLoS Genet"},{"issue":"5524","key":"pcbi.1009745.ref032","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1126\/science.1058758","article-title":"Ordering genes in a flagella pathway by analysis of expression kinetics from living bacteria","volume":"292","author":"S Kalir","year":"2001","journal-title":"Science"},{"issue":"5556","key":"pcbi.1009745.ref033","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1126\/science.1065175","article-title":"Regulation of organogenesis by the Caenorhabditis elegans FoxA protein PHA-4","volume":"295","author":"J Gaudet","year":"2002","journal-title":"Science"},{"issue":"6","key":"pcbi.1009745.ref034","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.cell.2011.02.015","article-title":"Impulse control: temporal dynamics in gene transcription","volume":"144","author":"N Yosef","year":"2011","journal-title":"Cell"},{"issue":"3","key":"pcbi.1009745.ref035","first-page":"e00686","article-title":"Temporal hierarchy of gene expression mediated by transcription factor binding affinity and activation dynamics","volume":"6","author":"R Gao","year":"2015","journal-title":"mBio"},{"key":"pcbi.1009745.ref036","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/msb.2011.88","article-title":"Temporal competition between differentiation programs determines cell fate choice","volume":"7","author":"A Kuchina","year":"2011","journal-title":"Mol Syst Biol"},{"issue":"9","key":"pcbi.1009745.ref037","doi-asserted-by":"crossref","first-page":"4016","DOI":"10.1073\/pnas.0915138107","article-title":"Abduction and asylum in the lives of transcription factors","volume":"107","author":"A Burger","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"issue":"6","key":"pcbi.1009745.ref038","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.cell.2014.02.022","article-title":"The transcription factor titration effect dictates level of gene expression","volume":"156","author":"RC Brewster","year":"2014","journal-title":"Cell"},{"issue":"3","key":"pcbi.1009745.ref039","doi-asserted-by":"crossref","first-page":"e0120555","DOI":"10.1371\/journal.pone.0120555","article-title":"Protein copy number distributions for a self-regulating gene in the presence of decoy binding sites","volume":"10","author":"P Bokes","year":"2015","journal-title":"PloS one"},{"key":"pcbi.1009745.ref040","article-title":"Inherent regulatory asymmetry emanating from network architecture in a prevalent autoregulatory motif","volume":"9","author":"MZ Ali","year":"2020","journal-title":"Elife"},{"issue":"5","key":"pcbi.1009745.ref041","doi-asserted-by":"crossref","first-page":"052410","DOI":"10.1103\/PhysRevE.102.052410","article-title":"Tunability enhancement of gene regulatory motifs through competitionfor regulatory protein resources","volume":"102","author":"S Das","year":"2020","journal-title":"Phys Rev E"},{"key":"pcbi.1009745.ref042","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/msb.2012.7","article-title":"A regulatory role for repeated decoy transcription factor binding sites in target gene expression","volume":"8","author":"TH Lee","year":"2012","journal-title":"Mol Syst Biol"},{"issue":"4","key":"pcbi.1009745.ref043","doi-asserted-by":"crossref","first-page":"e1005491","DOI":"10.1371\/journal.pcbi.1005491","article-title":"Effect of transcription factor resource sharing on gene expression noise","volume":"13","author":"D Das","year":"2017","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1009745.ref044","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1021\/j100540a008","article-title":"Exact stochastic simulation of coupled chemical reactions","volume":"81","author":"DT Gillespie","year":"1977","journal-title":"Journal of Physical Chemistry"},{"issue":"4","key":"pcbi.1009745.ref045","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1073\/pnas.1609012114","article-title":"First-passage time approach to controlling noise in the timing of intracellular events","volume":"114","author":"KR Ghusinga","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009745.ref046","volume-title":"Stochastic Processes in Physics and Chemistry","author":"N Van Kampen","year":"2007"},{"key":"pcbi.1009745.ref047","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511606014","volume-title":"A Guide to First-Passage Processes","author":"S Redner","year":"2001"},{"key":"pcbi.1009745.ref048","doi-asserted-by":"crossref","DOI":"10.1002\/9781119165156.ch5","volume-title":"First Passage Processes in Cellular Biology","author":"S Iyer-Biswas","year":"2016"},{"key":"pcbi.1009745.ref049","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/252546a0","article-title":"Comparison of classical and autogenous systems of regulation in inducible operons","volume":"252","author":"MA Savageau","year":"1974","journal-title":"Nature"},{"issue":"6786","key":"pcbi.1009745.ref050","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/35014651","article-title":"Engineering stability in gene networks by autoregulation","volume":"405","author":"A Becskei","year":"2000","journal-title":"Nature"},{"issue":"5828","key":"pcbi.1009745.ref051","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1126\/science.1141967","article-title":"Probing transcription factor dynamics at the single-molecule level in a living cell","volume":"316","author":"J Elf","year":"2007","journal-title":"Science"},{"issue":"3","key":"pcbi.1009745.ref052","doi-asserted-by":"crossref","first-page":"e1001100","DOI":"10.1371\/journal.pcbi.1001100","article-title":"Effect of Promoter Architecture on the Cell-to-Cell Variability in Gene Expression","volume":"7","author":"A Sanchez","year":"2011","journal-title":"PLoS Computational Biology"},{"key":"pcbi.1009745.ref053","volume-title":"Physical biology of the cell","author":"R Phillips","year":"2013","edition":"2"},{"issue":"D1","key":"pcbi.1009745.ref054","doi-asserted-by":"crossref","first-page":"D212","DOI":"10.1093\/nar\/gky1077","article-title":"RegulonDB v 10.5: tackling challenges to unify classic and high throughput knowledge of gene regulation in E. coli K-12","volume":"47","author":"A Santos-Zavaleta","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pcbi.1009745.ref055","doi-asserted-by":"crossref","first-page":"036004","DOI":"10.1088\/1478-3975\/13\/3\/036004","article-title":"Estimation of mean first passage time for bursty gene expression","volume":"13","author":"M Shreshtha","year":"2016","journal-title":"Phys Biol"},{"issue":"4 Pt 1","key":"pcbi.1009745.ref056","doi-asserted-by":"crossref","first-page":"041920","DOI":"10.1103\/PhysRevE.86.041920","article-title":"Influence of decoys on the noise and dynamics of gene expression","volume":"86","author":"A Burger","year":"2012","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys"},{"issue":"11","key":"pcbi.1009745.ref057","doi-asserted-by":"crossref","first-page":"e1002265","DOI":"10.1371\/journal.pcbi.1002265","article-title":"Speed, Sensitivity, and Bistability in Auto-activating Signaling Circuits","volume":"7","author":"R Hermsen","year":"2011","journal-title":"PLoS Comput Biol"},{"issue":"5","key":"pcbi.1009745.ref058","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1080\/00107510500052444","article-title":"Power laws, Pareto distributions and Zipf\u2019s law","volume":"46","author":"M Newman","year":"2005","journal-title":"Contemporary Physics"},{"issue":"5767","key":"pcbi.1009745.ref059","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1126\/science.1119623","article-title":"Probing gene expression in live cells, one protein molecule at a time","volume":"311","author":"J Yu","year":"2006","journal-title":"Science"},{"issue":"1","key":"pcbi.1009745.ref060","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0022-2836(77)90279-0","article-title":"Transcription and translation initiation frequencies of the Escherichia coli lac operon","volume":"114","author":"D Kennell","year":"1977","journal-title":"J Mol Biol"},{"key":"pcbi.1009745.ref061","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1126\/science.1188308","article-title":"Quantifying E. coli Proteome and Transcriptome with Single-Molecule Sensitivity in Single Cells","volume":"329","author":"Y Taniguchi","year":"2010","journal-title":"Science"},{"key":"pcbi.1009745.ref062","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/msb.2012.42","article-title":"Gene location and DNA density determine transcription factor distributions in Escherichia coli","volume":"8","author":"TE Kuhlman","year":"2012","journal-title":"Mol Syst Biol"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009745","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009745","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T13:41:55Z","timestamp":1643377315000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009745"}},"subtitle":[],"editor":[{"given":"Alexandre V.","family":"Morozov","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,1,18]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,18]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009745","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.04.09.439163","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,18]]}}}