Identification of high-confidence RNA regulatory elements by combinatorial classification of RNA\u2013protein binding sites

Yang Eric Li,Dong Wang,Binbin Shi,Fei Wang,Zhi John Lu,Marco Marcia,Yu-Cheng T Yang,Mu Xiao

doi:10.1186/s13059-017-1298-8

Abstract

Crosslinking immunoprecipitation sequencing (CLIP-seq) technologies have enabled researchers to characterize transcriptome-wide binding sites of RNA-binding protein (RBP) with high resolution. We apply a soft-clustering method, RBPgroup, to various CLIP-seq datasets to group together RBPs that specifically bind the same RNA sites. Such combinatorial clustering of RBPs helps interpret CLIP-seq data and suggests functional RNA regulatory elements. Furthermore, we validate two RBP–RBP interactions in cell lines. Our approach links proteins and RNA motifs known to possess similar biochemical and cellular properties and can, when used in conjunction with additional experimental data, identify high-confidence RBP groups and their associated RNA regulatory elements.

Highlights

RNA-binding proteins (RBPs) are essential to sustain fundamental cellular functions, such as splicing, polyadenylation, transport, translation, and degradation of RNA transcripts [1, 2]
The binding peaks of PAR-CLIP data were defined by Piranha [21] and PARalyzer [22]; the binding peaks of HITS-CLIP data were defined by Piranha and crosslinking-induced mutation site (CIMS) [23]
We can see that different RBPs display a very different number of binding peaks, ranging broadly from several thousands, i.e. for HNRNPU and TNRC6A, to tens of thousands, i.e. for CPSF6 and MOV10 (Fig. 1a, Additional file 1: Figure S1a)

Summary

Introduction

RNA-binding proteins (RBPs) are essential to sustain fundamental cellular functions, such as splicing, polyadenylation, transport, translation, and degradation of RNA transcripts [1, 2]. One study estimated that more than 1500 different RBPs exist in human [3]. These RBPs cooperate or compete with each other in binding their RNA targets [4,5,6]. Many RBPs are capable of binding different RNA targets, partially by associating with different co-factors [7,8,9]. Some consensus RNA sequence motifs are recognized by homologous RBPs or homologous domains [10]. Proteins and RNAs appear to interact in a combinatorial manner [11]

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Discussion

Conclusion