Tracing the molecular basis of transcriptional dynamics in noisy data by using an experiment-based mathematical model.

Katja N Rybakova, Aleksandra Tomaszewska, Simon van Mourik, Joke Blom, Hans V Westerhoff, Carsten Carlberg, Frank J Bruggeman

Index: Nucleic Acids Res. 43(1) , 153-61, (2015)

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Abstract

Changes in transcription factor levels, epigenetic status, splicing kinetics and mRNA degradation can each contribute to changes in the mRNA dynamics of a gene. We present a novel method to identify which of these processes is changed in cells in response to external signals or as a result of a diseased state. The method employs a mathematical model, for which the kinetics of gene regulation, splicing, elongation and mRNA degradation were estimated from experimental data of transcriptional dynamics. The time-dependent dynamics of several species of adipose differentiation-related protein (ADRP) mRNA were measured in response to ligand activation of the transcription factor peroxisome proliferator-activated receptor δ (PPARδ). We validated the method by monitoring the mRNA dynamics upon gene activation in the presence of a splicing inhibitor. Our mathematical model correctly identifies splicing as the inhibitor target, despite the noise in the data. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.