Mechanisms of transcriptional regulation underlying temporal integration of signals

Nucleic Acids Res. 2006;34(18):5175-83. doi: 10.1093/nar/gkl654. Epub 2006 Sep 22.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Regulatory Networks*
  • Genes, Immediate-Early
  • Glucose / pharmacology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Kinetics
  • Models, Genetic*
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic*

Substances

  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Transcription Factor AP-1
  • Glucose