{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,1,29]],"date-time":"2023-01-29T05:22:29Z","timestamp":1674969749826},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2016,10,2]],"date-time":"2016-10-02T00:00:00Z","timestamp":1475366400000},"content-version":"vor","delay-in-days":1237,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: \u00a0cis-regulatory DNA sequence elements, such as enhancers and silencers, function to control the spatial and temporal expression of their target genes. Although the overall levels of gene expression in large cell populations seem to be precisely controlled, transcription of individual genes in single cells is extremely variable in real time. It is, therefore, important to understand how these cis-regulatory elements function to dynamically control transcription at single-cell resolution. Recently, statistical methods have been proposed to back calculate the rates involved in mRNA transcription using parameter estimation of a mathematical model of transcription and translation. However, a major complication in these approaches is that some of the parameters, particularly those corresponding to the gene copy number and transcription rate, cannot be distinguished; therefore, these methods cannot be used when the copy number is unknown.<\/jats:p>\n               <jats:p>Results: Here, we develop a hierarchical Bayesian model to estimate biokinetic parameters from live cell enhancer\u2013promoter reporter measurements performed on a population of single cells. This allows us to investigate transcriptional dynamics when the copy number is variable across the population. We validate our method using synthetic data and then apply it to quantify the function of two known developmental enhancers in real time and in single cells.<\/jats:p>\n               <jats:p>Availability: Supporting information is submitted with the article.<\/jats:p>\n               <jats:p>Contact: \u00a0d.j.woodcock@warwick.ac.uk<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btt201","type":"journal-article","created":{"date-parts":[[2013,5,16]],"date-time":"2013-05-16T01:00:44Z","timestamp":1368666044000},"page":"1519-1525","source":"Crossref","is-referenced-by-count":5,"title":["A hierarchical model of transcriptional dynamics allows robust estimation of transcription rates in populations of single cells with variable gene copy number"],"prefix":"10.1093","volume":"29","author":[{"given":"Dan J.","family":"Woodcock","sequence":"first","affiliation":[{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"}]},{"given":"Keith W.","family":"Vance","sequence":"additional","affiliation":[{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"},{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"},{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"}]},{"given":"Micha\u0142","family":"Komorowski","sequence":"additional","affiliation":[{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"},{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"},{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"}]},{"given":"Georgy","family":"Koentges","sequence":"additional","affiliation":[{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"}]},{"given":"B\u00e4rbel","family":"Finkenst\u00e4dt","sequence":"additional","affiliation":[{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"}]},{"given":"David A.","family":"Rand","sequence":"additional","affiliation":[{"name":"1 Warwick Systems Biology Centre and 2Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, 3MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3PT, 4Department of Statistics, University of Warwick, Coventry, CV4 7AL, UK and 5Institute of Fundamental Technological Research, Polish Academy of Sciences, Pawi\u0144skiego 5B, 02-106 Warszawa, Poland"}]}],"member":"286","published-online":{"date-parts":[[2013,5,14]]},"reference":[{"key":"2023012810443556200_btt201-B1","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1126\/science.1164860","article-title":"Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription","volume":"324","author":"Ashall","year":"2009","journal-title":"Science"},{"key":"2023012810443556200_btt201-B2","doi-asserted-by":"crossref","first-page":"275","DOI":"10.2307\/3001863","article-title":"The truncated Poisson","volume":"8","author":"David","year":"1952","journal-title":"Biometrics"},{"key":"2023012810443556200_btt201-B3","doi-asserted-by":"crossref","first-page":"e27886","DOI":"10.1371\/journal.pone.0027886","article-title":"Extracting fluorescent reporter time courses of cell lineages from high-throughput microscopy at low temporal resolution","volume":"6","author":"Downey","year":"2011","journal-title":"PLoS One"},{"key":"2023012810443556200_btt201-B4","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1101\/gr.1196503","article-title":"Fast evaluation of fluctuations in biochemical networks with the linear noise approximation","volume":"13","author":"Elf","year":"2003","journal-title":"Genome Res."},{"key":"2023012810443556200_btt201-B5","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1126\/science.1070919","article-title":"Stochastic gene expression in a single cell","volume":"297","author":"Elowitz","year":"2002","journal-title":"Science"},{"key":"2023012810443556200_btt201-B6","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.1093\/bioinformatics\/btn562","article-title":"Reconstruction of transcriptional dynamics from gene reporter data using differential equations","volume":"24","author":"Finkenst\u00e4dt","year":"2008","journal-title":"Bioinformatics"},{"key":"2023012810443556200_btt201-B7","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":"2023012810443556200_btt201-B8","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1093\/bioinformatics\/btm367","article-title":"Bayesian inference for dynamic transcriptional regulation; the hes1 system as a case study","volume":"23","author":"Heron","year":"2007","journal-title":"Bioinformatics"},{"key":"2023012810443556200_btt201-B9","doi-asserted-by":"crossref","first-page":"e1000192","DOI":"10.1371\/journal.pcbi.1000192","article-title":"Nonidentifiability of the source of intrinsic noise in gene expression from single-burst data","volume":"4","author":"Ingram","year":"2008","journal-title":"PLoS Comp. Biol."},{"key":"2023012810443556200_btt201-B10","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.semcdb.2009.07.007","article-title":"A systems biology approach to understanding cis-regulatory module function","volume":"20","author":"Jeziorska","year":"2009","journal-title":"Semin. Cell Dev. Biol."},{"key":"2023012810443556200_btt201-B11","doi-asserted-by":"crossref","first-page":"5687","DOI":"10.1074\/jbc.M111.286484","article-title":"Novel cis-regulatory modules control expression of the Hairy and Enhancer of Split-1 (HES1) transcription factor in myoblasts","volume":"287","author":"Jeziorska","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2023012810443556200_btt201-B12","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1186\/1471-2105-10-343","article-title":"Bayesian inference of biochemical kinetic parameters using a linear noise approximation","volume":"10","author":"Komorowski","year":"2009","journal-title":"BMC Bioinformatics"},{"key":"2023012810443556200_btt201-B13","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0925-4773(96)00646-6","article-title":"Two enhancer domains control early aspects of the complex expression pattern of Msx1","volume":"62","author":"MacKenzie","year":"1997","journal-title":"Mech. Dev."},{"issue":"Part 2","key":"2023012810443556200_btt201-B14","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/0898-1221(86)90242-7","article-title":"The incomplete \u0393 function as a continuous Poisson distribution","volume":"12","author":"Marsaglia","year":"1986","journal-title":"Comput. Math. Appl."},{"key":"2023012810443556200_btt201-B15","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/nbt.2137","article-title":"Systematic dissection and optimization of inducible enhancers in human cells using a massively parallel reporter assay","volume":"30","author":"Melnikov","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"2023012810443556200_btt201-B16","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/S0092-8674(00)00212-9","article-title":"Dedifferentiation of mammalian myotubes induced by msx1","volume":"103","author":"Odelberg","year":"2000","journal-title":"Cell"},{"key":"2023012810443556200_btt201-B17","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nbt.2136","article-title":"Massively parallel functional dissection of mammalian enhancers in vivo","volume":"30","author":"Patwardhan","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"2023012810443556200_btt201-B18","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature02257","article-title":"Summing up the noise in gene networks","volume":"427","author":"Paulsson","year":"2004","journal-title":"Nature"},{"key":"2023012810443556200_btt201-B19","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.plrev.2005.03.003","article-title":"Models of gene expression","volume":"2","author":"Paulsson","year":"2005","journal-title":"Phys. Life Rev."},{"key":"2023012810443556200_btt201-B20","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":"Sharon","year":"2012","journal-title":"Nat. Biotechnol."},{"key":"2023012810443556200_btt201-B21","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"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/29\/12\/1519\/48886231\/bioinformatics_29_12_1519.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/29\/12\/1519\/48886231\/bioinformatics_29_12_1519.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T12:27:59Z","timestamp":1674908879000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/29\/12\/1519\/293165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,5,14]]},"references-count":21,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2013,6,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btt201","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2013,6,15]]},"published":{"date-parts":[[2013,5,14]]}}}