Clusters of mammalian conserved RNA structures in UTRs associate with RBP binding sites

Abstract

RNA secondary structures play essential roles in the formation of the tertiary structure and function of a transcript. Recent genome-wide studies highlight significant potential for RNA structures in the mammalian genome. However, a major challenge is assigning functional roles to these structured RNAs. In this study, we conduct a guilt-by-association analysis of clusters of computationally predicted conserved RNA structure (CRSs) in human untranslated regions (UTRs) to associate them with gene functions. We filtered a broad pool of ∼500 000 human CRSs for UTR overlap, resulting in 4734 and 24 754 CRSs from the 5′ and 3′ UTR of protein-coding genes, respectively. We separately clustered these CRSs for both sets using RNAscClust, obtaining 793 and 2403 clusters, each containing an average of five CRSs per cluster. We identified overrepresented binding sites for 60 and 43 RNA-binding proteins co-localizing with the clustered CRSs. Furthermore, 104 and 441 clusters from the 5′ and 3′ UTRs, respectively, showed enrichment for various Gene Ontologies, including biological processes such as ‘signal transduction’, ‘nervous system development’, molecular functions like ‘transferase activity’ and the cellular components such as ‘synapse’ among others. Our study shows that significant functional insights can be gained by clustering RNA structures based on their structural characteristics.