Functional integrative levels in the human interactome recapitulate organ organization.
Bottom Line: Overall, the functional organization of the human interactome reflects several integrative levels of functions with housekeeping and regulatory tissue-specific functions at the center and physiological tissue-specific functions at the periphery.This gradient of functions recapitulates the organization of organs, from cells to organs.Given that several gradients have already been identified across interactomes, we propose that gradients may represent a general principle of protein-protein interaction network organization.
Affiliation: INSERM, U928, TAGC, Marseille, France.
Interactome networks represent sets of possible physical interactions between proteins. They lack spatio-temporal information by construction. However, the specialized functions of the differentiated cell types which are assembled into tissues or organs depend on the combinatorial arrangements of proteins and their physical interactions. Is tissue-specificity, therefore, encoded within the interactome? In order to address this question, we combined protein-protein interactions, expression data, functional annotations and interactome topology. We first identified a subnetwork formed exclusively of proteins whose interactions were observed in all tested tissues. These are mainly involved in housekeeping functions and are located at the topological center of the interactome. This 'Largest Common Interactome Network' represents a 'functional interactome core'. Interestingly, two types of tissue-specific interactions are distinguished when considering function and network topology: tissue-specific interactions involved in regulatory and developmental functions are central whereas tissue-specific interactions involved in organ physiological functions are peripheral. Overall, the functional organization of the human interactome reflects several integrative levels of functions with housekeeping and regulatory tissue-specific functions at the center and physiological tissue-specific functions at the periphery. This gradient of functions recapitulates the organization of organs, from cells to organs. Given that several gradients have already been identified across interactomes, we propose that gradients may represent a general principle of protein-protein interaction network organization.
Related in: MedlinePlus
Mentions: Intuitively, as the LCIN forms the core cellular machinery common to all tissues, it is tempting to speculate that it should be buried in the innermost part of the interactome, leaving the topological periphery of the interactome to more tissue-specific functions. To verify this hypothesis, we used the k-core decomposition of the graph to define the topological layers of the interactome . Essentially, this means progressively pruning the graph vertices (proteins) according to the number of edges (interactions) linking them to the connected component . Proteins of high k-core are topologically central in the network whereas proteins of low k-core are peripheral. In the studied interactome, proteins of the highest k-core (k-core 9) are almost double what would be expected by chance in the LCIN (p-val = 3,78×10−14), indicating a correlation between the centrality of a protein and its involvement in common interactions. By extension, proteins of the highest k-core should be involved in housekeeping functions. Building on this idea, we addressed the possible relationship between the IU, network topology and function. As before, we calculated over- and under-representation of Gene Ontology terms annotating the proteins in each k-core category. The resulting data, for each of the clusters previously defined according to the IU categories, are shown as heatmaps and graphs in Figure 5 and Figures S4, S5, S6.