structural discrimination of robustness in transcriptional feedforward loops for pattern formation结构鲁棒性的歧视转录前馈模式形成的循环.pdfVIP

Structural Discrimination of Robustness in Transcriptional Feedforward Loops for Pattern Formation 1 1,2 Guillermo Rodrigo *, Santiago F. Elena ´ ´ ´ 1 Instituto de Biologıa Molecular y Celular de Plantas, Consejo Superior de Investigaciones Cientıficas - Universidad Politecnica de Valencia, Valencia, Spain, 2 Santa Fe Institute, Santa Fe, New Mexico, United States of America Abstract Signaling pathways are interconnected to regulatory circuits for sensing the environment and expressing the appropriate genetic profile. In particular, gradients of diffusing molecules (morphogens) determine cell fate at a given position, dictating development and spatial organization. The feedforward loop (FFL) circuit is among the simplest genetic architectures able to generate one-stripe patterns by operating as an amplitude detection device, where high output levels are achieved at intermediate input ones. Here, using a heuristic optimization-based approach, we dissected the design space containing all possible topologies and parameter values of the FFL circuits. We explored the ability of being sensitive or adaptive to variations in the critical morphogen level where cell fate is switched. We found four different solutions for precision, corresponding to the four incoherent architectures, but remarkably only one mode for adaptiveness, the incoherent type 4 (I4-FFL). We further carried out a theoretical study to unveil the design principle for such structural discrimination, finding that the synergistic action and cooperative binding on the downstream promoter are instrumental to achieve absolute adaptive responses. Subsequently, we analyzed the robustness of these optimal c