Diverse RNA-Binding Proteins Interact with Functionally Related Sets of RNAs, Suggesting an Extensive Regulatory System

TLDR

RNA‑binding proteins regulate many post‑transcriptional steps, yet only a few have been systematically studied. The authors searched for RNA targets of 40 yeast proteins, including a selective sample of ~600 annotated or predicted RBPs and several non‑annotated proteins. They mapped RNA targets of these proteins and identified enriched sequence or predicted structural motifs in 16 RBPs’ target mRNAs across 3′‑UTRs, 5′‑UTRs, coding sequences, and other regions. The study showed that 33 of 40 proteins, including three previously unannotated RBPs, bound specific RNA sets, many targeting mRNAs encoding functionally related proteins; 70 % of the transcriptome was associated with at least one RBP, averaging three RBPs per mRNA, indicating a pervasive combinatorial regulatory network.

Abstract

RNA-binding proteins (RBPs) have roles in the regulation of many post-transcriptional steps in gene expression, but relatively few RBPs have been systematically studied. We searched for the RNA targets of 40 proteins in the yeast Saccharomyces cerevisiae: a selective sample of the approximately 600 annotated and predicted RBPs, as well as several proteins not annotated as RBPs. At least 33 of these 40 proteins, including three of the four proteins that were not previously known or predicted to be RBPs, were reproducibly associated with specific sets of a few to several hundred RNAs. Remarkably, many of the RBPs we studied bound mRNAs whose protein products share identifiable functional or cytotopic features. We identified specific sequences or predicted structures significantly enriched in target mRNAs of 16 RBPs. These potential RNA-recognition elements were diverse in sequence, structure, and location: some were found predominantly in 3′-untranslated regions, others in 5′-untranslated regions, some in coding sequences, and many in two or more of these features. Although this study only examined a small fraction of the universe of yeast RBPs, 70% of the mRNA transcriptome had significant associations with at least one of these RBPs, and on average, each distinct yeast mRNA interacted with three of the RBPs, suggesting the potential for a rich, multidimensional network of regulation. These results strongly suggest that combinatorial binding of RBPs to specific recognition elements in mRNAs is a pervasive mechanism for multi-dimensional regulation of their post-transcriptional fate.