An incoherent feed-forward loop (FFL) is one of the most-frequently observed motifs in biomolecular regulatory networks. It has been thought that the incoherent FFL is designed simply to induce a transient response shaped by a 'fast activation and delayed inhibition'. We find that the dynamics of various incoherent FFLs can be further classified into two types: time-dependent biphasic responses and dose-dependent biphasic responses. Why do the structurally identical incoherent FFLs play such different dynamical roles? Through computational studies, we show that the dynamics of the two types of incoherent FFLs are mutually exclusive. Following from further computational results and experimental observations, we hypothesize that incoherent FFLs have been optimally designed to achieve distinct biological function arising from different cellular contexts. Additional Supporting Information may be found in the online version of the article.

Cellular circuits have positive and negative feedback loops that allow them to respond properly to noisy external stimuli. It is intriguing that such feedback loops exist in many cases in a particular form of coupled positive and negative feedback loops with different time delays. As a result of our mathematical simulations and investigations into various experimental evidences, we found that such coupled feedback circuits can rapidly turn on a reaction to a proper stimulus, robustly maintain its status, and immediately turn off the reaction when the stimulus disappears. In other words, coupled feedback loops enable cellular systems to produce perfect responses to noisy stimuli with respect to signal duration and amplitude. This suggests that coupled positive and negative feedback loops form essential signal transduction motifs in cellular signaling systems.

BackgroundNetwork motifs provided a “conceptual tool” for understanding the functional principles of biological networks, but such motifs have primarily been used to consider static network structures. Static networks, however, cannot be used to reveal time- and region-specific traits of biological systems. To overcome this limitation, we proposed the concept of a “spatiotemporal network motif,” a spatiotemporal sequence of network motifs of sub-networks which are active only at specific time points and body parts.ResultsOn the basis of this concept, we analyzed the developmental gene regulatory network of the Drosophila melanogaster embryo. We identified spatiotemporal network motifs and investigated their distribution pattern in time and space. As a result, we found how key developmental processes are temporally and spatially regulated by the gene network. In particular, we found that nested feedback loops appeared frequently throughout the entire developmental process. From mathematical simulations, we found that mutual inhibition in the nested feedback loops contributes to the formation of spatial expression patterns.ConclusionsTaken together, the proposed concept and the simulations can be used to unravel the design principle of developmental gene regulatory networks.

Most biological processes have been considered to be irreversible for a long time, but some recent studies have shown the possibility of their reversion at a cellular level. How can we then understand the reversion of such biological processes? We introduce a unified conceptual framework based on the attractor landscape, a molecular phase portrait describing the dynamics of a molecular regulatory network, and the phenotype landscape, a map of phenotypes determined by the steady states of particular output molecules in the attractor landscape. In this framework, irreversible processes involve reshaping of the phenotype landscape, and the landscape reshaping causes the irreversibility of processes. We suggest reverse control by network rewiring which changes network dynamics with constant perturbation, resulting in the restoration of the original phenotype landscape. The proposed framework provides a conceptual basis for the reverse control of irreversible biological processes through network rewiring. WIREs Syst Biol Med 2016, 8:366–377. doi: 10.1002/wsbm.1346For further resources related to this article, please visit the WIREs website.

The NF-kappaB signaling pathway can perform multiple functional roles depending on specific cellular environments and cell types. Even in the same cell clones, the pathway can show different kinetic and phenotypic properties. It is believed that the complex networks controlling the NF-kappaB signaling pathway can generate these diverse and sometimes ambiguous phenomena. We noted, however, that the dynamics of NF-kappaB signaling pathway is highly stochastic and that the NF-kappaB signaling pathway contains multiple negative feedback circuits formed by IkappaB isoform proteins, IkappaBalpha and IkappaBepsilon in particular. Considering the topological similarity, their functional roles seem to be redundant, raising the question why different types of IkappaB isoforms need to exist. From extensive stochastic simulations of the NF-kappaB signaling pathway, we found that each IkappaB isoform actually conducts a different regulatory role through its own negative feedback. Specifically, our data suggest that IkappaBalpha controls the dynamic patterns of nuclear NF-kappaB, while IkappaBepsilon induces cellular heterogeneity of the NF-kappaB activities. These results may provide an answer to the question of how a single NF-kappaB signaling pathway can perform multiple biological functions even in the same clonal populations.