Partner: Dan Woodcock

University of Warwick (GB)

Recent publications
1.Woodcock D.J., Vance K.W., Komorowski M., Koentges G., Finkenstädt B., Rand D.A., A hierarchical model of transcriptional dynamics allows robust estimation of transcription rates in populations of single cells with variable gene copy number, BIOINFORMATICS, ISSN: 1367-4803, DOI: 10.1093/bioinformatics/btt201, Vol.29, pp.1519-1525, 2013
Abstract:

Motivation: 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.

Affiliations:
Woodcock D.J.-University of Warwick (GB)
Vance K.W.-University of Warwick (GB)
Komorowski M.-IPPT PAN
Koentges G.-University of Warwick (GB)
Finkenstädt B.-University of Warwick (GB)
Rand D.A.-University of Warwick (GB)
2.Finkenstädt B., Woodcock D.J., Komorowski M., Harper C.V., Davis J.R.E., White M.R.H., Rand D.A., Quantifying intrinsic and extrinsic noise in gene transcription using the linear noise approximation: An application to single cell data, Annals of Applied Statistics, ISSN: 1932-6157, DOI: 10.1214/13-AOAS669, Vol.7, No.4, pp.1960-1982, 2013
Abstract:

A central challenge in computational modeling of dynamic biological systems is parameter inference from experimental time course measurements. However, one would not only like to infer kinetic parameters but also study their variability from cell to cell. Here we focus on the case where single-cell fluorescent protein imaging time series data are available for a population of cells. Based on van Kampen’s linear noise approximation, we derive a dynamic state space model for molecular populations which is then extended to a hierarchical model. This model has potential to address the sources of variability relevant to single-cell data, namely, intrinsic noise due to the stochastic nature of the birth and death processes involved in reactions and extrinsic noise arising from the cell-to-cell variation of kinetic parameters. In order to infer such a model from experimental data, one must also quantify the measurement process where one has to allow for nonmeasurable molecular species as well as measurement noise of unknown level and variance. The availability of multiple single-cell time series data here provides a unique testbed to fit such a model and quantify these different sources of variation from experimental data.

Keywords:

Linear noise approximation, kinetic parameter estimation, intrinsic and extrinsic noise, state space model and Kalman filter, Bayesian hierarchical modeling

Affiliations:
Finkenstädt B.-University of Warwick (GB)
Woodcock D.J.-University of Warwick (GB)
Komorowski M.-IPPT PAN
Harper C.V.-University of Manchester (GB)
Davis J.R.E.-University of Manchester (GB)
White M.R.H.-University of Manchester (GB)
Rand D.A.-University of Warwick (GB)