Molecular interactions are studied as independent networks in systems biology. However, molecular networks do not exist independently of each other. In a network of networks approach (called multiplex), we study the joint organization of transcriptional regulatory network (TRN) and protein–protein interaction (PPI) network. We find that TRN and PPI are non-randomly coupled across five different eukaryotic species. Gene degrees in TRN (number of downstream genes) are positively correlated with protein degrees in PPI (number of interacting protein partners). Gene–gene and protein–protein interactions in TRN and PPI, respectively, also non-randomly overlap. These design principles are conserved across the five eukaryotic species. Robustness of the TRN–PPI multiplex is dependent on this coupling. Functionally important genes and proteins, such as essential, disease-related and those interacting with pathogen proteins, are preferentially situated in important parts of the human multiplex with highly overlapping interactions. We unveil the multiplex architecture of TRN and PPI. Multiplex architecture may thus define a general framework for studying molecular networks. This approach may uncover the building blocks of the hierarchical organization of molecular interactions.
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