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

Antti Honkela, Jaakko Peltonen, Hande Topa, Iryna Charapitsa, Filomena Matarese, Korbinian Grote, Hendrik G. Stunnenberg, George Reid, Neil D. Lawrence, Magnus Rattray

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13115-13120
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number42
DOIs
Publication statusPublished - 20 Oct 2015
Externally publishedYes

Keywords

  • Gaussian process inference
  • Gene expression
  • Gene transcription
  • RNA processing
  • RNA splicing

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