Abstract
BackgroundPathways in biological system often cooperate with each other to function. Changes of interactions among pathways tightly associate with alterations in the properties and functions of the cell and hence alterations in the phenotype. So, the pathway interactions and especially their changes over time corresponding to specific phenotype are critical to understanding cell functions and phenotypic plasticity.MethodsWith prior-defined pathways and incorporated protein-protein interaction (PPI) data, we counted PPIs between corresponding gene sets of each pair of distinct pathways to construct a comprehensive pathway network. Then we proposed a novel concept, characteristic sub pathway network (CSPN), to realize the phenotype-specific pathway interactions. By adding gene expression data regarding a given phenotype, angiogenesis, active PPIs corresponding to stimulation of interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) on human umbilical vein endothelial cells (HUVECs) respectively were derived. Two kinds of CSPN, namely the static or the dynamic CSPN, were detected by counting active PPIs.ResultsA comprehensive pathway network containing 37 signalling pathways as nodes and 263 pathway interactions were obtained. Two phenotype-specific CSPNs for angiogenesis, corresponding to stimulation of IL-1 and TNF-α on HUVEC respectively, were addressed. From phenotype-specific CSPNs, a static CSPN involving interactions among B cell receptor, T cell receptor, Toll-like receptor, MAPK, VEGF, and ErbB signalling pathways, and a dynamic CSPN involving interactions among TGF-β, Wnt, p53 signalling pathways and cell cycle pathway, were detected for angiogenesis on HUVEC after stimulation of IL-1 and TNF-α respectively. We inferred that, in certain case, the static CSPN maintains related basic functions of the cells, whereas the dynamic CSPN manifests the cells' plastic responses to stimulus and therefore reflects the cells' phenotypic plasticity.ConclusionThe comprehensive pathway network helps us realize the cooperative behaviours among pathways. Moreover, two kinds of potential CSPNs found in this work, the static CSPN and the dynamic CSPN, are helpful to deeply understand the specific function of HUVEC and its phenotypic plasticity in regard to angiogenesis.
Highlights
Pathways in biological system often cooperate with each other to function
Two kinds of potential characteristic sub pathway network (CSPN) found in this work, the static CSPN and the dynamic CSPN, are helpful to deeply understand the specific function of human umbilical vein endothelial cells (HUVECs) and its phenotypic plasticity in regard to angiogenesis
To detect static CSPN, we firstly identify the common static sub pathway network where nodes and edges appear at each time point of each network, identify highly connected pathways in this sub pathway network
Summary
Pathways in biological system often cooperate with each other to function. Changes of interactions among pathways tightly associate with alterations in the properties and functions of the cell and alterations in the phenotype. The pathway interactions and especially their changes over time corresponding to specific phenotype are critical to understanding cell functions and phenotypic plasticity. Gene Set Enrichment Analysis [2] and other similar tools are capable to determine pathways which are enriched in the gene list of specific phenotype. These methods fail to furnish the interactions among pathways, not to mention changes of the pathway interactions. Changes of the pathway interactions are important for comprehending alterations in the properties and functions of the cell and the phenotypic plasticity, which is cell’s ability to alter phenotype in response to specific environmental stimulus [1,7,8]
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