Topology, tinkering and evolution of the human transcription factor network

Patterns of protein interactions are organized around complex heterogeneous networks. Their architecture has been suggested to be of relevance in understanding the interactome and its functional organization, which pervades cellular robustness. Transcription factors are particularly relevant in this context, given their central role in gene regulation. Here we present the first topological study of the human protein-protein interacting transcription factor network built using the TRANSFAC database. We show that the network exhibits scale-free and small-world properties with a hierarchical and modular structure, which is built around a small number of key proteins. Most of these proteins are associated with proliferative diseases and are typically not linked to each other, thus reducing the propagation of failures through compartmentalization. Network modularity is consistent with common structural and functional features and the features are generated by two distinct evolutionary strategies: amplification and shuffling of interacting domains through tinkering and acquisition of specific interacting regions. The function of the regulatory complexes may have played an active role in choosing one of them.