Dynamics of transcriptional regulation from total RNA-seq experiments

The kinetic rates of RNA synthesis, processing and degradation determine the dynamics of transcriptional regulation by governing both the abundance and the responsiveness to modulations of premature and mature RNA species. The study of RNA dynamics is largely based on the integrative analysis of total and nascent transcription, with the latter being quantified through RNA metabolic labelling. We describe here a computational method, based on mathematical modelling of intronic and exonic expression, able to derive the dynamics of transcription from steady-state or time course profiling of just total RNA, without requiring any information on nascent transcripts. Our approach closely recapitulates the kinetic rates obtained through RNA metabolic labelling, reduces the cost and complexity of the experiments, and can be adopted to study experimental conditions where nascent transcription cannot be readily profiled. We applied this method to the characterization of post-transcriptional regulation landscapes in dozens of physiological and disease conditions, and we revealed a previously unanticipated role for the kinetics of RNA processing in the modulation of RNA responsiveness.