title: A hierarchical model of transcriptional dynamics allows robust estimation of transcription rates in populations of single cells with variable gene copy number.
abstract: BACKGROUND
  cis-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.
  
  
  RESULTS
  Here, we develop a hierarchical Bayesian model to estimate biokinetic parameters from live cell enhancer-promoter 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.
  
  
  BACKGROUND
  Supporting information is submitted with the article.
authors.affiliation: Warwick Systems Biology Centre and Department of Life Sciences, University of Warwick, Coventry, CV4 7AL, UK. d.j.woodcock@warwick.ac.uk
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Woodcock
authors.forename: Keith W
authors.initials: KW
authors.lastname: Vance
authors.forename: Michal
authors.initials: M
authors.lastname: Komorowski
authors.forename: Georgy
authors.initials: G
authors.lastname: Koentges
authors.forename: Bärbel
authors.initials: B
authors.lastname: Finkenstädt
authors.forename: David A
authors.initials: DA
authors.lastname: Rand
mesh_terms: D000465:Algorithms; D000818:Animals; D001499:Bayes Theorem; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D018628:Gene Dosage; D051957:MSX1 Transcription Factor / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D059010:Single-Cell Analysis; D014158:Transcription, Genetic
chemical_list: D051957:MSX1 Transcription Factor