Abstract
Regeneration is an essential characteristic of biological organisms. The ability to regenerate injured sites is varied across organs, individuals, and species. No systematic theory explains the differences of regenerative capacity at different organizational levels. In this study, we analyzed the regenerative and nonregenerative systems in a unified framework based on a dynamic regulatory model. With the gene expression levels of the regenerative and nonregenerative systems and the multi-database-derived candidate regulations of the genes, system identification techniques are used to identify the dynamic structure of the regenerative and nonregenerative systems. That is, we exploited the regulatory abilities in the dynamic regulatory model to delineate the dynamic regulatory networks of the regenerative and nonregenerative systems. The functional analysis of the nodes in the constructed networks reveals that an excess cell communication in the nonregenerative systems may hinder the regeneration of the injured brain. The hubs and their network neighbors reflect the regulatory hot zone in the regenerative and nonregenerative networks. Next, a subgraph consisting of three connected nodes, called a triad, was considered for further systematic analysis of regenerative and nonregenerative networks. The topological structure of the triads explains the difference between the triad significance profiles of the regenerative and nonregenerative networks. In line with the previous results of the functional analysis, we focused on the functional networks consisting of the 20 common enriched functional modules in the regenerative and nonregenerative systems. The strength in the connectivity of the 20 modules reveals the different regulations of the regenerative and nonregenerative systems at the functional level. Further, the distributions of in-degree, out-degree, and clustering coefficient could implicate the evolutionary difference between the regenerative and nonregenerative systems. The advantage of the dynamic regulatory model to interpret the regenerative and nonregenerative networks motivated us to propose a quantity, called transduction ability, to evaluate the dynamical systematic property of the subsystems in the regenerative and nonregenerative systems. Against to the triad enrichment, the transduction ability of triads provides another dimension for discriminating the regenerative biological systems from nonregenerative ones. A three-level functional organization is proposed to explain the different regulatory mechanisms at the functional level based on the transduction ability and connectivity of the modules. Moreover, based on the regeneration mechanisms by comparing transduction abilities between regenerative and nonregenerative networks, we devised a drug design method to improve their transduction abilities of modules in the nonregenerative systems. The design paradigm based on the transduction ability will provide a wider choice of drug targets, reduce the effect of individual heterogeneity on drug efficacy, and shed light on the future of regenerative medicine from the systems biology perspective.