Coupled pre-mRNA and mRNA dynamics unveil operational strategies underlying transcriptional responses to stimuli

Abstract

• By analyzing the signals from intronic probes of exon arrays, we performed, for the first time, genome-wide measurement of pre-mRNA expression dynamics.

• We discovered a striking lack of correspondence between mRNA and pre-mRNA temporal expression profiles following stimulus, demonstrating that measurement of mRNA dynamics does not suffice to infer transcript production profiles.

• By combining simultaneous measurement of pre-mRNA and mRNA profiles with a simple new quantitative theoretical description of transcription, we are able to infer complex time dependence of both transcript production and mRNA degradation.

• The production profiles of many transcripts reveal an operational strategy we termed Production Overshoot, which is used to accelerate mRNA response. The biological relevance of our findings was substantiated by observing similar results when studying the response of three different mammalian cell types to different stimuli.

Abstract

Transcriptional responses to extracellular stimuli involve tuning the rates of transcript production and degradation. Here, we show that the time-dependent profiles of these rates can be inferred from simultaneous measurements of precursor mRNA (pre-mRNA) and mature mRNA profiles. Transcriptome-wide measurements demonstrate that genes with similar mRNA profiles often exhibit marked differences in the amplitude and onset of their production rate. The latter is characterized by a large dynamic range, with a group of genes exhibiting an unexpectedly strong transient production overshoot, thereby accelerating their induction and, when combined with time-dependent degradation, shaping transient responses with precise timing and amplitude.