Identification of the Proliferation/Differentiation Switch in the Cellular Network of Multicellular Organisms

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Abstract
The protein–protein interaction networks, or interactome networks, have been shown to have dynamic modular structures, yet the functional connections between and among the modules are less well understood. Here, using a new pipeline to integrate the interactome and the transcriptome, we identified a pair of transcriptionally anticorrelated modules, each consisting of hundreds of genes in multicellular interactome networks across different individuals and populations. The two modules are associated with cellular proliferation and differentiation, respectively. The proliferation module is conserved among eukaryotic organisms, whereas the differentiation module is specific to multicellular organisms. Upon differentiation of various tissues and cell lines from different organisms, the expression of the proliferation module is more uniformly suppressed, while the differentiation module is upregulated in a tissue- and species-specific manner. Our results indicate that even at the tissue and organism levels, proliferation and differentiation modules may correspond to two alternative states of the molecular network and may reflect a universal symbiotic relationship in a multicellular organism. Our analyses further predict that the proteins mediating the interactions between these modules may serve as modulators at the proliferation/differentiation switch. Coordination of proliferation and differentiation is a fundamental process of multicellular organisms. Although at the cellular level proliferation and differentiation seem to correspond to different cellular states that can sometimes be seen separated by the proliferation/differentiation temporal switch, it is unclear whether such switch-like property exists at the tissue or organism level or whether it exists in postmitotic tissues in adult animals. Through integrating protein–protein interaction networks with gene expression profiles, Xia, Xue, Dong, Zhu, and colleagues found that a switch temporally separating proliferation- and differentiation-associated modules can also be detected in the adult human brain and the adult whole fruit fly. The expressions of the two modules are well coordinated at the system level. The evolutionary origins of the proliferation and differentiation modules further implicate a symbiotic relationship between the two modules. Network topologies and gene annotations support a regulatory role of the protein–protein interaction interface between the two modules.