RNA splicing regulates the temporal order of TNF-induced gene expression (167.5)

When cells are induced to express inflammatory genes by treatment with TNF the mRNAs for the induced genes appear in three distinct waves, defining gene Groups I, II and III or early, intermediate and late genes. To examine the basis for these different kinetic classes, we developed a PCR-based procedure to distinguish pre-mRNA synthesis from mRNA synthesis. It showed that the three Groups initiate transcription virtually simultaneously but that delays in splicing characterize Groups II and III. We examined the elongation times and polyadenylation timing, concluding that pre-mRNA synthesis is coordinate but splicing differences directly regulate the timing of mRNA production. Coupled to previous measurements of the half-life of mRNAs, the kinetic parameters can be combined in a general mathematical model of pre-mRNA conversion to mRNA that reproduces the experimental kinetics without recourse to differences in transcription.This model could be a generally relevant description of sequential transcriptional events in response to inducers.