Mechanisms of transcriptional regulation underlying temporal integration of signals

How cells convert the duration of signals into differential adaptation of gene expression is a poorly understood issue. Signal-induced immediate-early gene (IEG) expression couples early signals to late expression of downstream genes. Here we study how kinetic features of the IEG- system allow temporal integration of stimuli in a pancreatic beta cell model of metabolic stimulation. Gene expression profiling revealed that beta cells produce drastically different transcriptional outputs in response to different stimuli durations. Noteworthy, most genes (87%) regulated by a sustained stimulation (4 h) were not regulated by a transient stimulation (1 h followed by 3 h without stimulus). We analyzed the induction kinetics of several previously identified IEGs and . IEG expression persisted as long as stimulation was maintained, but was rapidly lost upon stimuli removal, abolishing the delayed induction. The molecular mechanisms coupling the duration of stimuli to quantitative transcription were demonstrated for the AP-1 transcription factor. In conclusion, we propose that the network composed of IEGs and their dynamically functions to convert signal inputs of different durations into quantitative differences in global transcriptional adaptation. These findings provide a novel and more comprehensive view of dynamic gene regulation.