The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks

S. Mangan, A. Zaslaver, U. Alon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

428 Scopus citations

Abstract

Recent analysis of the structure of transcription regulation networks revealed several "network motifs": regulatory circuit patterns that occur much more frequently than in randomized networks. It is important to understand whether these network motifs have specific functions. One of the most significant network motifs is the coherent feedforward loop, in which transcription factor X regulates transcription factor Y, and both jointly regulate gene Z. On the basis of mathematical modeling and simulations, it was suggested that the coherent feedforward loop could serve as a sign-sensitive delay element: a circuit that responds rapidly to step-like stimuli in one direction (e.g. ON to OFF), and at a delay to steps in the opposite direction (OFF to ON). Is this function actually carried out by feedforward loops in living cells? Here, we address this experimentally, using a system with feedforward loop connectivity, the L-arabinose utilization system of Escherichiacoli. We measured responses to step-like cAMP stimuli at high temporal resolution and accuracy by means of green fluorescent protein reporters. We show that the arabinose system displays sign-sensitive delay kinetics. This type of kinetics is important for making decisions based on noisy inputs by filtering out fluctuations in input stimuli, yet allowing rapid response. This information-processing function may be performed by the feedforward loop regulation modules that are found in diverse systems from bacteria to humans.

Original languageAmerican English
Pages (from-to)197-204
Number of pages8
JournalJournal of Molecular Biology
Volume334
Issue number2
DOIs
StatePublished - 21 Nov 2003
Externally publishedYes

Bibliographical note

Funding Information:
We thank C. Bargmann, D. Ginsberg, O. Hobert, S. Leibler, M. Magnasco, S. Quake, R. Schleif, E. Sontag, and all members of our laboratory for discussions. This work was supported by the Israel Science Foundation, a Minerva Junior Research Group, and the Human Frontiers Science project.

Keywords

  • Computational biology
  • Design principles
  • Network motifs
  • Systems biology

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