Synthetic incoherent feedforward circuits show adaptation to the amount of their genetic template

• Main Authors: Bleris, Leonidas (Author), Xie, Zhen (Contributor), Glass, David (Author), Adadey, Asa (Author), Sontag, Eduardo (Author), Benenson, Yaakov (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2013-03-07T16:40:54Z.
• Subjects: Article
• Online Access: Get fulltext

Natural and synthetic biological networks must function reliably in the face of fluctuating stoichiometry of their molecular components. These fluctuations are caused in part by changes in relative expression efficiency and the DNA template amount of the network-coding genes. Gene product levels could potentially be decoupled from these changes via built-in adaptation mechanisms, thereby boosting network reliability. Here, we show that a mechanism based on an incoherent feedforward motif enables adaptive gene expression in mammalian cells. We modeled, synthesized, and tested transcriptional and post-transcriptional incoherent loops and found that in all cases the gene product adapts to changes in DNA template abundance. We also observed that the post-transcriptional form results in superior adaptation behavior, higher absolute expression levels, and lower intrinsic fluctuations. Our results support a previously hypothesized endogenous role in gene dosage compensation for such motifs and suggest that their incorporation in synthetic networks will improve their robustness and reliability.
National Institute of General Medical Sciences (U.S.) (Grant GM068763)
National Institutes of Health (U.S.) (Grant NIH 1R01GM086881)
United States. Air Force Office of Scientific Research (Grant FA9550-08)
National Science Foundation (U.S.) (Grant DMS-0614371)