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 < target > genes. Here we study how kinetic features of the IEG-< target > 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 < targets >. IEG expression persisted as long as stimulation was maintained, but was rapidly lost upon stimuli removal, abolishing the delayed < target > induction. The molecular mechanisms coupling the duration of stimuli to quantitative < target > transcription were demonstrated for the AP-1 transcription factor. In conclusion, we propose that the network composed of IEGs and their < targets > 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.