Genome-wide modeling of transcription kinetics reveals patterns of RNA production delays

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Antti Honkela, University of Helsinki
Jaakko Peltonen, Aalto University
Hande Topa
Iryna Charapitsa
Filomena Matarese
Korbinian Grote
Hendrik G. Stunnenberg
George Reid
Neil D. Lawrence, University of Sheffield
Magnus Rattray, University of Manchester
Proc. Natl. Acad. Sci. USA 112, pp 13115-13120

Abstract

Genes with similar transcriptional activation kinetics can display very different temporal mRNA profiles because of differences in transcrip tion time, degradation rate, and RNA-processing kinetics. Recent studies have shown that a splicing-associated RNA production delay can be significant. To investigate this issue more generally, it is useful to develop methods applicable to genome-wide datasets. We introduce a joint model of transcriptional activation and mRNA accumulation that can be used for inference of transcription rate, RNA production delay, and degradation rate given data from high-throughput sequencing time course experiments. We combine a mechanistic differential equation model with a nonparametric statistical modeling approach allowing us to capture a broad range of activation kinetics, and we use Bayesian parameter estimation to quantify the uncertainty in estimates of the kinetic parameters. We apply the model to data from estrogen receptor α activation in the MCF-7 breast cancer cell line. We use RNA polymerase II ChIP-Seq time course data to characterize transcriptional activation and mRNA-Seq time course data to quantify mature transcripts. We find that 11% of genes with a good signal in the data display a delay of more than 20 min between completing transcription and mature mRNA production. The genes displaying these long delays are significantly more likely to be short. We also find a statistical association between high delay and late intron retention in pre-mRNA data, indicating significant splicing-associated production delays in many genes.