title: Genome-wide modeling of transcription kinetics reveals patterns of RNA production delays.
abstract: Genes with similar transcriptional activation kinetics can display very different temporal mRNA profiles because of differences in transcription 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.
authors.affiliation: Department of Computer Science, Helsinki Institute for Information Technology HIIT, University of Helsinki, 00014 Helsinki, Finland; antti.honkela@hiit.fi magnus.rattray@manchester.ac.uk.
authors.forename: Antti
authors.initials: A
authors.lastname: Honkela
authors.affiliation: Department of Computer Science, Helsinki Institute for Information Technology HIIT, Aalto University, 00076 Espoo, Finland; School of Information Sciences, University of Tampere, 33014 Tampere, Finland;
authors.forename: Jaakko
authors.initials: J
authors.lastname: Peltonen
authors.affiliation: Department of Computer Science, Helsinki Institute for Information Technology HIIT, Aalto University, 00076 Espoo, Finland;
authors.forename: Hande
authors.initials: H
authors.lastname: Topa
authors.affiliation: Institute for Molecular Biology, 55128 Mainz, Germany;
authors.forename: Iryna
authors.initials: I
authors.lastname: Charapitsa
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Sciences and Faculty of Medicine, Nijmegen 6500 HB, The Netherlands;
authors.forename: Filomena
authors.initials: F
authors.lastname: Matarese
authors.affiliation: Genomatix Software GmbH, 80335 Munich, Germany;
authors.forename: Korbinian
authors.initials: K
authors.lastname: Grote
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Sciences and Faculty of Medicine, Nijmegen 6500 HB, The Netherlands;
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Institute for Molecular Biology, 55128 Mainz, Germany;
authors.forename: George
authors.initials: G
authors.lastname: Reid
authors.affiliation: Department of Computer Science, University of Sheffield, Sheffield S1 4DP, United Kingdom;
authors.forename: Neil D
authors.initials: ND
authors.lastname: Lawrence
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom antti.honkela@hiit.fi magnus.rattray@manchester.ac.uk.
authors.forename: Magnus
authors.initials: M
authors.lastname: Rattray
mesh_terms: D047628:Estrogen Receptor alpha / Q000378:metabolism; D015894:Genome, Human; D006801:Humans; D007700:Kinetics; D061986:MCF-7 Cells; D008957:Models, Genetic; D012313:RNA / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D047628:Estrogen Receptor alpha; D012313:RNA
keywords: Gaussian process inference; RNA processing; RNA splicing; gene expression; gene transcription