Noise-Based Switches and Amplifiers for Gene Expression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 5; pp. 2075 - 2080
• Main Authors: Hasty, Jeff, Pradines, Joel, Dolnik, Milos, Collins, J. J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 29.02.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Bacteriophages; Biochemistry; Biological Sciences; Biology; Design engineering; DNA-Binding Proteins; Evolutionary noise; Gene expression; Gene expression regulation; Gene Expression Regulation, Viral; Gene therapy; Genes; Low noise; Models, Genetic; Noise; Phage ^l; Physics; Promoter regions; Repressor Proteins - genetics; Steady states; Viral Proteins - genetics; Viral Regulatory and Accessory Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.040411297

The regulation of cellular function is often controlled at the level of gene transcription. Such genetic regulation usually consists of interacting networks, whereby gene products from a single network can act to control their own expression or the production of protein in another network. Engineered control of cellular function through the design and manipulation of such networks lies within the constraints of current technology. Here we develop a model describing the regulation of gene expression and elucidate the effects of noise on the formulation. We consider a single network derived from bacteriophage λ and construct a two-parameter deterministic model describing the temporal evolution of the concentration of λ repressor protein. Bistability in the steady-state protein concentration arises naturally, and we show how the bistable regime is enhanced with the addition of the first operator site in the promotor region. We then show how additive and multiplicative external noise can be used to regulate expression. In the additive case, we demonstrate the utility of such control through the construction of a protein switch, whereby protein production is turned "on" and "off" by using short noise pulses. In the multiplicative case, we show that small deviations in the transcription rate can lead to large fluctuations in the production of protein, and we describe how these fluctuations can be used to amplify protein production significantly. These results suggest that an external noise source could be used as a switch and/or amplifier for gene expression. Such a development could have important implications for gene therapy.