Abstract

BackgroundRNA-binding proteins (RBPs) are crucial in modulating RNA metabolism in eukaryotes thereby controlling an extensive network of RBP-RNA interactions. Although previous studies on the conservation of RBP targets have been carried out in lower eukaryotes such as yeast, relatively little is known about the extent of conservation of the binding sites of RBPs across mammalian species.ResultsIn this study, we employ CLIP-seq datasets for 60 human RBPs and demonstrate that most binding sites for a third of these RBPs are conserved in at least 50% of the studied vertebrate species. Across the studied RBPs, binding sites were found to exhibit a median conservation of 58%, ~ 20% higher than random genomic locations, suggesting a significantly higher preservation of RBP-RNA interaction networks across vertebrates. RBP binding sites were highly conserved across primates with weak conservation profiles in birds and fishes. We also note that phylogenetic relationship between members of an RBP family does not explain the extent of conservation of their binding sites across species. Multivariate analysis to uncover features contributing to differences in the extents of conservation of binding sites across RBPs revealed RBP expression level and number of post-transcriptional targets to be the most prominent factors. Examination of the location of binding sites at the gene level confirmed that binding sites occurring on the 3′ region of a gene are highly conserved across species with 90% of the RBPs exhibiting a significantly higher conservation of binding sites in 3′ regions of a gene than those occurring in the 5′. Gene set enrichment analysis on the extent of conservation of binding sites to identify significantly associated human phenotypes revealed an enrichment for multiple developmental abnormalities.ConclusionsOur results suggest that binding sites of human RBPs are highly conserved across primates with weak conservation profiles in lower vertebrates and evolutionary relationship between members of an RBP family does not explain the extent of conservation of their binding sites. Expression level and number of targets of an RBP are important factors contributing to the differences in the extent of conservation of binding sites. RBP binding sites on 3′ ends of a gene are the most conserved across species. Phenotypic analysis on the extent of conservation of binding sites revealed the importance of lineage-specific developmental events in post-transcriptional regulatory network evolution.

Highlights

  • RNA-binding proteins (RBPs) are crucial in modulating RNA metabolism in eukaryotes thereby controlling an extensive network of RNAbinding protein (RBP)-RNA interactions

  • Once all binding sites of an RBP were mapped to corresponding Multiple Alignment Format (MAF) blocks, the percentage of species that each binding site was conserved in was calculated by counting the number of species in each mapped MAF block

  • This procedure was repeated for binding sites of all RBPs, which revealed a considerable difference in the extent of conservation of binding sites between RBPs (Fig. 2)

Read more

Summary

Introduction

RNA-binding proteins (RBPs) are crucial in modulating RNA metabolism in eukaryotes thereby controlling an extensive network of RBP-RNA interactions. Previous studies on the conservation of RBP targets have been carried out in lower eukaryotes such as yeast, relatively little is known about the extent of conservation of the binding sites of RBPs across mammalian species. Protein coding sequences conserved across multiple species are of great significance since they encode for proteins that are part of indispensable biological functions. Certain highly conserved protein coding sequences have shown a significant functional enrichment for RNA binding activity and splicing regulation [9], and several existing studies reveal that RNA-binding proteins (RBPs) are highly conserved across species [12,13,14,15,16]. RNA binding proteins (RBPs) associate with specific mRNA sequences [17, 18], and play a key role in splicing, polyadenylation, transportation and localization of mRNA within the cells [12]. Post-transcriptional networks governed by RNA-binding proteins are vital in maintaining cellular homeostasis

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call