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. 2020 Jan 3;11(1):54.
doi: 10.3390/genes11010054.

Large-Scale Profiling of RBP-circRNA Interactions from Public CLIP-Seq Datasets

Minzhe Zhang  1 , Tao Wang  1   2   3 , Guanghua Xiao  1   2   4 , Yang Xie  1   2   4
Affiliations

Large-Scale Profiling of RBP-circRNA Interactions from Public CLIP-Seq Datasets

Minzhe Zhang et al. Genes (Basel). .

Abstract

Circular RNAs are a special type of RNA that has recently attracted a lot of research interest in studying its formation and function. RNA binding proteins (RBPs) that bind circRNAs are important in these processes, but have been relatively less studied. CLIP-Seq technology has been invented and applied to profile RBP-RNA interactions on the genome-wide scale. While mRNAs are usually the focus of CLIP-Seq experiments, RBP-circRNA interactions could also be identified through specialized analysis of CLIP-Seq datasets. However, many technical difficulties are involved in this process, such as the usually short read length of CLIP-Seq reads. In this study, we created a pipeline called Clirc specialized for profiling circRNAs in CLIP-Seq data and analyzing the characteristics of RBP-circRNA interactions. In conclusion, to our knowledge, this is one of the first studies to investigate circRNAs and their binding partners through repurposing CLIP-Seq datasets, and we hope our work will become a valuable resource for future studies into the biogenesis and function of circRNAs.

Keywords: CLIP-Seq; Circ-RNA; RBP.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cartoon of the Clirc pipeline to identify circRNAs bound by RBP from CLIP-Seq data. (a) Build combined library from linearized circRNA sequences and linear transcripts, (b) Competitive alignment of CLIP-Seq reads to combined library, (c) Identification of circRNAs through Clirc pipeline.
Figure 2
Figure 2
Overview of circRNAs bound by RBPs. (a) Exemplary circRNA bound by mouse RBP SRSF1. (b) Summary statistics of circRNAs bound by RBPs in all analyzed RBPs.
Figure 3
Figure 3
HOMER motif search results for EIF4A3, Tra2b, and Pol II. The left panel shows the protein and cell line/tissue information, the middle panel shows top circRNA motif and the right panel shows the p-values and percentages of sequences containing each motif. RBP, RNA binding proteins.
Figure 4
Figure 4
Proportion of circRNA reads in the same strand of the parental genes (x) vs. proportion of CLIP-Seq reads mapped to linear transcripts in sense strand (y). Dot size represents number of circRNA sequences in a study. The CLIP-Seq reads whose circRNA sequences are more than 500 and whose absolute (x-y) difference is more than 20% are labeled at the bottom right corner.
Figure 5
Figure 5
Functional implications of RBP-circRNA interactions. (a) Hierarchical clustering plot of RPBs based on the similarity of their circRNA binding profile. This analysis is only conducted for the human RBPs. Red marks RBPs that are mainly cytoplasmic, yellow marks RBPs that abundantly exist in both cytoplasm and nucleus, and blue marks RBPs that are mainly nuclear. (b) Enriched gene ontology (GO) terms for each RBP. Log-transformed p-value is calculated as p-value from a hypergeometric test of each set of parental genes of circRNAs bound by an RBP vs. genes in each gene ontology term, subtracted by averaged random p-value from hypergeometric tests of 10 randomizations. The significance level is controlled at 0.05, adjusted by the Bonferroni method. Significantly enriched GO terms are labeled according to the colors of the RBPs. (c) Log-transformed GO terms enrichment p-values of binding sites in circRNA parental genes vs. in linear transcripts for the YBX1 protein. The adjustment method is the same.
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