Model-based clustering reveals vitamin D dependent multi-centrality hubs in a network of vitamin-related proteins

Nutritional systems biology offers the potential for comprehensive predictions that account for all metabolic changes with the intricate biological organization and the multitudinous interactions between the cellular proteins. Protein-protein interaction (PPI) networks can be used for an integrative description of molecular processes. Although widely adopted in nutritional systems biology, these networks typically encompass a single category of functional interaction (i.e., metabolic, regulatory or signaling) or nutrient. Incorporating multiple nutrients and functional interaction categories under an integrated framework represents an informative approach for gaining system level insight on nutrient metabolism.

We constructed a multi-level PPI network starting from the interactions of 200 vitamin-related proteins. Its final size was 1,657 proteins, with 2,700 interactions. To characterize the role of the proteins we computed 6 centrality indices and applied model-based clustering. We detected a subgroup of 22 proteins that were highly central and significantly related to vitamin D. Immune system and cancer-related processes were strongly represented among these proteins. Clustering of the centralities revealed a degree of redundancy among the indices; a repeated analysis using subsets of the centralities performed well in identifying the original set of 22 most central proteins.

Hierarchical and model-based clustering revealed multi-centrality hubs in a vitamin PPI network and redundancies among the centrality indices. Vitamin D-related proteins were strongly represented among network hubs, highlighting the pervasive effects of this nutrient. Our integrated approach to network construction identified promiscuous transcription factors, cytokines and enzymes - primarily related to immune system and cancer processes - representing potential gatekeepers linking vitamin intake to disease.