Title: Double-negative feedback loops as a common design motif in the transcriptional networks regulating cell fate

Authors: Sudin Bhattacharya, Qiang Zhang, Melvin E. Andersen

Addresses: Program in Chemical Safety Sciences, Division of Computational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA. ' Program in Chemical Safety Sciences, Division of Computational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA. ' Program in Chemical Safety Sciences, Division of Computational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA

Abstract: The gene networks that regulate the choice of cell fate in living organisms contain a set of ubiquitous design motifs. We discuss the role of one such motif, the double-negative feedback loop, in producing discrete and stable steady states during the development of mammalian cell lineages. Several examples of this motif are described from the literature. Thereafter, we use an ordinary differential equation-based computational model of the double-negative feedback loop motif to illustrate the mechanism by which it generates stable cellular states. Stochastic simulations show how this motif ensures robustness of cell states to stochastic fluctuations in gene expression.

Keywords: design in nature; double-negative feedback loops; DNFLs; design motifs; transcriptional networks; stochastic simulation; gene networks; cell fate; mammalian cell lineages; ordinary differential equations; computational modelling; gene expression.

DOI: 10.1504/IJDE.2011.041408

International Journal of Design Engineering, 2011 Vol.4 No.1, pp.41 - 57

Published online: 30 Sep 2014 *

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