{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T07:25:10Z","timestamp":1772695510429,"version":"3.50.1"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: Stochastic promoter switching between transcriptionally active (ON) and inactive (OFF) states is a major source of noise in gene expression. It is often implicitly assumed that transitions between promoter states are memoryless, i.e. promoters spend an exponentially distributed time interval in each of the two states. However, increasing evidence suggests that promoter ON\/OFF times can be non-exponential, hinting at more complex transcriptional regulatory architectures. Given the essential role of gene expression in all cellular functions, efficient computational techniques for characterizing promoter architectures are critically needed.<\/jats:p>\n               <jats:p>Results: We have developed a novel model reduction for promoters with arbitrary numbers of ON and OFF states, allowing us to approximate complex promoter switching behavior with Weibull-distributed ON\/OFF times. Using this model reduction, we created bursty Monte Carlo expectation-maximization with modified cross-entropy method (\u2018bursty MCEM2\u2019), an efficient parameter estimation and model selection technique for inferring the number and configuration of promoter states from single-cell gene expression data. Application of bursty MCEM2 to data from the endogenous mouse glutaminase promoter reveals nearly deterministic promoter OFF times, consistent with a multi-step activation mechanism consisting of 10 or more inactive states. Our novel approach to modeling promoter fluctuations together with bursty MCEM2 provides powerful tools for characterizing transcriptional bursting across genes under different environmental conditions.<\/jats:p>\n               <jats:p>Availability and implementation: R source code implementing bursty MCEM2 is available upon request.<\/jats:p>\n               <jats:p>Contact: \u00a0absingh@udel.edu<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btv007","type":"journal-article","created":{"date-parts":[[2015,1,9]],"date-time":"2015-01-09T02:26:44Z","timestamp":1420770404000},"page":"1428-1435","source":"Crossref","is-referenced-by-count":46,"title":["Inferring single-cell gene expression mechanisms using stochastic simulation"],"prefix":"10.1093","volume":"31","author":[{"suffix":"Jr.","given":"Bernie J.","family":"Daigle","sequence":"first","affiliation":[{"name":"1 Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA 93106, 2Department of Electrical and Computer Engineering, University of Delaware, Newark, DE 19716 and 3Department of Computer Science, University of California, Santa Barbara, CA 93106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad","family":"Soltani","sequence":"additional","affiliation":[{"name":"1 Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA 93106, 2Department of Electrical and Computer Engineering, University of Delaware, Newark, DE 19716 and 3Department of Computer Science, University of California, Santa Barbara, CA 93106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda R.","family":"Petzold","sequence":"additional","affiliation":[{"name":"1 Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA 93106, 2Department of Electrical and Computer Engineering, University of Delaware, Newark, DE 19716 and 3Department of Computer Science, University of California, Santa Barbara, CA 93106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhyudai","family":"Singh","sequence":"additional","affiliation":[{"name":"1 Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA 93106, 2Department of Electrical and Computer Engineering, University of Delaware, Newark, DE 19716 and 3Department of Computer Science, University of California, Santa Barbara, CA 93106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,1,7]]},"reference":[{"key":"2023051308511130100_btv007-B1","doi-asserted-by":"crossref","first-page":"214107","DOI":"10.1063\/1.2799998","article-title":"A modified next reaction method for simulating chemical systems with time dependent propensities and delays","volume":"127","author":"Anderson","year":"2007","journal-title":"J. Chem. Phys."},{"key":"2023051308511130100_btv007-B2","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/nature04599","article-title":"Stochastic protein expression in individual cells at the single molecule level","volume":"440","author":"Cai","year":"2006","journal-title":"Nature"},{"key":"2023051308511130100_btv007-B3","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1126\/science.1161427","article-title":"A stochastic single-molecule event triggers phenotype switching of a bacterial cell","volume":"322","author":"Choi","year":"2008","journal-title":"Science"},{"key":"2023051308511130100_btv007-B4","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/1471-2105-13-68","article-title":"Accelerated maximum likelihood parameter estimation for stochastic biochemical systems","volume":"13","author":"Daigle","year":"2012","journal-title":"BMC Bioinformatics"},{"key":"2023051308511130100_btv007-B5","doi-asserted-by":"crossref","first-page":"17454","DOI":"10.1073\/pnas.1213530109","article-title":"Transcriptional burst frequency and burst size are equally modulated across the human genome","volume":"109","author":"Dar","year":"2012","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023051308511130100_btv007-B6","volume-title":"Statistical Distributions","author":"Evans","year":"2000","edition":"3rd edn"},{"key":"2023051308511130100_btv007-B7","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1146\/annurev.physchem.58.032806.104637","article-title":"Stochastic simulation of chemical kinetics","volume":"58","author":"Gillespie","year":"2007","journal-title":"Annu. Rev. Phys. Chem."},{"key":"2023051308511130100_btv007-B8","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.cell.2005.09.031","article-title":"Real-time kinetics of gene activity in individual bacteria","volume":"123","author":"Golding","year":"2005","journal-title":"Cell"},{"key":"2023051308511130100_btv007-B9","doi-asserted-by":"crossref","first-page":"e1000607","DOI":"10.1371\/journal.pbio.1000607","article-title":"Dynamic analysis of stochastic transcription cycles","volume":"9","author":"Harper","year":"2011","journal-title":"PLoS Biol."},{"key":"2023051308511130100_btv007-B10","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/j.cell.2013.02.014","article-title":"Transcriptional regulation and its misregulation in disease","volume":"152","author":"Lee","year":"2013","journal-title":"Cell"},{"key":"2023051308511130100_btv007-B11","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1080\/15326349308807278","article-title":"Selecting and implementing phase approximations for semi-Markov models","volume":"9","author":"Malhotra","year":"1993","journal-title":"Commun. Statist.-Stochastic Models"},{"key":"2023051308511130100_btv007-B12","doi-asserted-by":"crossref","first-page":"20563","DOI":"10.1073\/pnas.1312310110","article-title":"Stimulus-induced modulation of transcriptional bursting in a single mammalian gene","volume":"110","author":"Molina","year":"2013","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2023051308511130100_btv007-B13","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/msb.2009.75","article-title":"Listening to the noise: random fluctuations reveal gene network parameters","volume":"5","author":"Munsky","year":"2009","journal-title":"Mol. Syst. Biol."},{"key":"2023051308511130100_btv007-B14","doi-asserted-by":"crossref","first-page":"e309","DOI":"10.1371\/journal.pbio.0040309","article-title":"Stochastic mRNA synthesis in mammalian cells","volume":"4","author":"Raj","year":"2006","journal-title":"PLoS Biol."},{"key":"2023051308511130100_btv007-B15","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1126\/science.1105891","article-title":"Noise in gene expression: origins, consequences, and control","volume":"309","author":"Raser","year":"2005","journal-title":"Science"},{"key":"2023051308511130100_btv007-B16","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ymeth.2013.03.026","article-title":"Stochastic models of transcription: From single molecules to single cells","volume":"62","author":"Sanchez","year":"2013","journal-title":"Methods"},{"key":"2023051308511130100_btv007-B17","doi-asserted-by":"crossref","first-page":"2214","DOI":"10.1016\/j.bpj.2014.09.017","article-title":"Transient changes in intercellular protein variability identify sources of noise in gene expression","volume":"107","author":"Singh","year":"2014","journal-title":"Biophys. J."},{"key":"2023051308511130100_btv007-B18","doi-asserted-by":"crossref","first-page":"L32","DOI":"10.1016\/j.bpj.2010.03.001","article-title":"Transcriptional bursting from the HIV-1 promoter is a significant source of stochastic noise in HIV-1 gene expression","volume":"98","author":"Singh","year":"2010","journal-title":"Biophys. J."},{"key":"2023051308511130100_btv007-B19","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/ng.821","article-title":"General properties of transcriptional time series in Escherichia coli","volume":"43","author":"So","year":"2011","journal-title":"Nat. Genet."},{"key":"2023051308511130100_btv007-B20","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1126\/science.1198817","article-title":"Mammalian genes are transcribed with widely different bursting kinetics","volume":"332","author":"Suter","year":"2011","journal-title":"Science"},{"key":"2023051308511130100_btv007-B21","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1098\/rsif.2008.0172","article-title":"Approximate Bayesian computation scheme for parameter inference and model selection in dynamical systems","volume":"6","author":"Toni","year":"2009","journal-title":"J. R. Soc. Interface"},{"key":"2023051308511130100_btv007-B22","doi-asserted-by":"crossref","DOI":"10.1201\/9781420010664","volume-title":"Stochastic Modelling for Systems Biology","author":"Wilkinson","year":"2006"},{"key":"2023051308511130100_btv007-B23","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":"Yu","year":"2006","journal-title":"Science"},{"key":"2023051308511130100_btv007-B24","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1126\/science.279.5358.1896","article-title":"Genomic cis-regulatory logic: experimental and computational analysis of a sea urchin gene","volume":"279","author":"Yuh","year":"1998","journal-title":"Science"},{"key":"2023051308511130100_btv007-B25","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1016\/j.bpj.2012.02.001","article-title":"Analytical distribution and tunability of noise in a model of promoter progress","volume":"102","author":"Zhang","year":"2012","journal-title":"Biophys. J."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/9\/1428\/50306506\/bioinformatics_31_9_1428.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/9\/1428\/50306506\/bioinformatics_31_9_1428.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T08:53:23Z","timestamp":1683968003000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/31\/9\/1428\/200727"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,7]]},"references-count":25,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2015,5,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btv007","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2015,5,1]]},"published":{"date-parts":[[2015,1,7]]}}}