The architecture of the human RNA-binding protein regulatory network

Abstract RNA-binding proteins (RBPs) are key players of post-transcriptional regulation of gene expression. These proteins influence both cellular physiology and pathology by regulating processes ranging from splicing and polyadenylation to mRNA localization, stability, and translation. To fine-tune the outcome of their regulatory action, RBPs rely on an intricate web of competitive and cooperative interactions. Several studies have described individual interactions of RBPs with RBP mRNAs, suggestive of a RBP-RBP regulatory structure. Here we present the first systematic investigation of this structure, based on a network including almost fifty thousand experimentally determined interactions between RBPs and bound RBP mRNAs. Our analysis identified two features defining the structure of the RBP-RBP regulatory network. What we call “RBP clusters” are groups of densely interconnected RBPs which co-regulate their targets, suggesting a tight control of cooperative and competitive behaviors. “RBP chains”, instead, are hierarchical structures driven by evolutionarily ancient RBPs, which connect the RBP clusters and could in this way provide the flexibility to coordinate the tuning of a broad set of biological processes. The combination of these two features suggests that RBP chains may use the modulation of their RBP targets to coordinately control the different cell programs controlled by the RBP clusters. Under this island-hopping model, the regulatory signal flowing through the chains hops from one RBP cluster to another, implementing elaborate regulatory plans to impact cellular phenotypes. This work thus establishes RBP-RBP interactions as a backbone driving post-transcriptional regulation of gene expression to allow the fine-grained control of RBPs and their targets.