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Precision measurements using a host of different techniques including fluorescence and sequencing readouts have raised the bar for what it means to quantitatively understand transcriptional regulation. In particular our understanding of the simplest genetic circuit is sufficiently refined both experimentally and theoretically that it has become possible to carefully discriminate between different conceptual pictures of how this regulatory system works. This regulatory motif, originally posited by Jacob and Monod in the 1960s, consists of a single transcriptional repressor binding to a promoter site and inhibiting transcription. In this paper, we show how seven distinct models of this so-called simple-repression motif, based both on thermodynamic and kinetic thinking, can be used to derive the predicted levels of gene expression and shed light on the often surprising past success of the thermodynamic models. These different models are then invoked to confront a variety of different data on mean, variance and full gene expression distributions, illustrating the extent to which such models can and cannot be distinguished, and suggesting a two-state model with a distribution of burst sizes as the most potent of the seven for describing the simple-repression motif.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008572","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T13:45:43Z","timestamp":1611063943000},"page":"e1008572","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":31,"title":["Reconciling kinetic and thermodynamic models of bacterial transcription"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0768-7234","authenticated-orcid":true,"given":"Muir","family":"Morrison","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9510-0527","authenticated-orcid":true,"given":"Manuel","family":"Razo-Mejia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3082-2809","authenticated-orcid":true,"given":"Rob","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"issue":"12","key":"pcbi.1008572.ref001","doi-asserted-by":"crossref","first-page":"e114347","DOI":"10.1371\/journal.pone.0114347","article-title":"The Influence of Promoter Architectures and Regulatory Motifs on Gene Expression in Escherichia coli","volume":"9","author":"M Rydenfelt","year":"2014","journal-title":"PLoS One"},{"issue":"21","key":"pcbi.1008572.ref002","doi-asserted-by":"crossref","first-page":"E4796","DOI":"10.1073\/pnas.1722055115","article-title":"Systematic Approach for Dissecting the Molecular Mechanisms of Transcriptional Regulation in Bacteria","volume":"115","author":"NM Belliveau","year":"2018","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"5","key":"pcbi.1008572.ref003","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1093\/nar\/gkz030","article-title":"The y-ome Defines the 35% of Escherichia coli Genes That Lack Experimental Evidence of Function","volume":"47","author":"S Ghatak","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"pcbi.1008572.ref004","doi-asserted-by":"crossref","first-page":"212","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 Research"},{"issue":"4","key":"pcbi.1008572.ref005","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1073\/pnas.79.4.1129","article-title":"Quantitative Model for Gene Regulation by Lambda Phage Repressor","volume":"79","author":"GK Ackers","year":"1982","journal-title":"Proceedings of The National Academy Of Sciences Of The United States Of America"},{"issue":"2","key":"pcbi.1008572.ref006","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/0022-2836(85)90086-5","article-title":"The OR Control System of Bacteriophage Lambda. 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