Zinc proteome interaction network as a model to identify nutrient-affected pathways in human pathologies

Abstract

Zinc is an essential micronutrient playing fundamental roles in cellular metabolism. It acts mostly through binding a wide range of proteins, thus affecting a broad spectrum of biological processes, which include cell division, growth and differentiation. Full annotation of zinc-binding proteins showed them to represent about 10 % of the human proteome, with over 300 enzymes containing zinc ions within their catalytic domains. Also, hundreds of key regulatory proteins, including transcription factors, require zinc for their activity. In this study, the whole set of zinc-binding proteins together with their direct interactors was listed and defined as the zinc proteome (ZNP). We interrogated pathway analysis tools to identify the cellular processes that are predicted to be affected by zinc availability. Network and functional enrichment analyses highlighted biological processes potentially affected by deregulated zinc homeostasis. This computational approach was also tested on a real case study: The possible involvement of ZNP network proteins in Crohn's disease pathogenesis was assessed on genes transcriptionally regulated in the intestine of patients affected by this condition. The analysis produced a network of pathways likely to be influenced by zinc and associated with Crohn's disease. These results highlight a central role for zinc in the tissue remodeling process which occurs upon gut inflammation, pointing at novel disease pathways whose effect could be worsened by zinc dyshomeostasis and impaired zinc fluxes in specific damaged areas. Overall, our computational approach could provide novel insights into pathological conditions and could therefore be used to drive mechanistic research in under-investigated fields of research. An interactive version of the determined ZNP network is available at URL http://93.63.165.11/ZNnetwork/ .

Fig. 1

Cluster analysis of ZNBPs. The three parameters employed to characterize topological properties of ZNBPs are represented along the three major axes. Colored dots indicate different clusters of ZNBPs. Members of cluster 1 that play a central role in network topology with lower number of BPs are shown in black, cluster 2 characterized by few interactors at the edge of the network is shown in red and cluster 3 characterized by many interactors and present in a high number of BPs is shown in green

Fig. 2

Network of ZNP interactions extracted from the microarray experiments of Noble et al. (2010). Genes are represented by nodes and interactions by edges. Green-colored nodes indicate down-regulated genes, red color variations refer to up-regulated genes. Border colors indicate genes modulated in CD versus control tissues. Fill colors correspond to genes modulated in inflamed versus non-inflamed CD tissues. Arrows point at pairs of ZNP network proteins whose direct interaction is annotated in public databases

Fig. 3

Overrepresented ZNP BPs within the expression profiles of inflamed versus non-inflamed CD tissues. Red and green nodes indicate up-regulated and down-regulated ZNP network genes, respectively. Nodes are connected through edges to the corresponding BPs