Transcriptional regulatory cascades in development: Initial rates, not steady state, determine network kinetics

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Abstract
A model was built to examine the kinetics of regulatory cascades such as occur in developmental gene networks. The model relates occupancy of cis-regulatory target sites to transcriptional initiation rate, and thence to RNA and protein output. The model was used to simulate regulatory cascades in which genes encoding transcription factors are successively activated. Using realistic parameter ranges based on extensive earlier measurements in sea urchin embryos, we find that transitions of regulatory states occur sharply in these simulations, with respect to time or changing transcription factor concentrations. As is often observed in developing systems, the simulated regulatory cascades display a succession of gene activations separated by delays of some hours. The most important causes of this behavior are cooperativity in the assembly of cis-regulatory complexes and the high specificity of transcription factors for their target sites. Successive transitions in state occur long in advance of the approach to steady-state levels of the molecules that drive the process. The kinetics of such developmental systems thus depend mainly on the initial output rates of genes activated in response to the advent of new transcription factors.