title: Synthetic incoherent feedforward circuits show adaptation to the amount of their genetic template.
abstract: 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.
authors.affiliation: Department of Bioengineering and Department of Electrical Engineering, University of Texas at Dallas, Richardson, TX, USA.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Bleris
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xie
authors.forename: David
authors.initials: D
authors.lastname: Glass
authors.forename: Asa
authors.initials: A
authors.lastname: Adadey
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sontag
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Benenson
mesh_terms: D030541:Databases, Genetic; D018628:Gene Dosage; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D010957:Plasmids; D034622:RNA Interference; D058615:Synthetic Biology; D013698:Templates, Genetic; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection / Q000379:methods
chemical_list: D035683:MicroRNAs; D014157:Transcription Factors