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Review
. 2020 Aug 17:2020:6798590.
doi: 10.1155/2020/6798590. eCollection 2020.

Disease-Associated Circular RNAs: From Biology to Computational Identification

Affiliations
Review

Disease-Associated Circular RNAs: From Biology to Computational Identification

Min Tang et al. Biomed Res Int. .

Abstract

Circular RNAs (circRNAs) are endogenous RNAs with a covalently closed continuous loop, generated through various backsplicing events of pre-mRNA. An accumulating number of studies have shown that circRNAs are potential biomarkers for major human diseases such as cancer and Alzheimer's disease. Thus, identification and prediction of human disease-associated circRNAs are of significant importance. To this end, a computational analysis-assisted strategy is indispensable to detect, verify, and quantify circRNAs for downstream applications. In this review, we briefly introduce the biology of circRNAs, including the biogenesis, characteristics, and biological functions. In addition, we outline about 30 recent bioinformatic analysis tools that are publicly available for circRNA study. Principles for applying these computational strategies and considerations will be briefly discussed. Lastly, we give a complete survey on more than 20 key computational databases that are frequently used. To our knowledge, this is the most complete and updated summary on publicly available circRNA resources. In conclusion, this review summarizes key aspects of circRNA biology and outlines key computational strategies that will facilitate the genome-wide identification and prediction of circRNAs.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Translation of circRNAs. (a) circRNAs can serve as a miRNA sponge, containing multiple binding sites for miRNAs (blue) or RBPs (in red), thus affecting gene regulation. (b and c) Illustrations show the role of circRNAs as miRNAs in healthy and tumor tissues. Tumor-suppressor circRNA sponges contain binding sites for tumor-suppressor miRNAs (light purple), while oncogenic circRNA sponges contain binding sites for oncogenic miRNAs (red). Tumor-suppressor circRNAs upregulate tumor-suppressor genes (yellow) in healthy tissues but downregulate these genes in tumor tissues, whereas oncogenic circRNAs suppress oncogene (green) expression in healthy tissues but upregulate these genes in tumor tissues. AGO: Argonaute; RBP: RNA-binding protein. Illustration is inspired by and modified from [164]. (d) New studies suggest that circRNAs generated by backsplicing are able to be translated into proteins. Illustration is modified from [38, 39]. Illustrations were generated using BioRender.
Figure 2
Figure 2
Biogenesis of circRNAs. Pre-mRNAs go through two splicing pathways to generate a linear RNA via highly efficient canonical splicing (top) or to produce circRNAs and an alternatively spliced linear RNA via poorly efficient backsplicing. As a result, different types of circRNAs can be produced (see discussion in text). Illustration was generated using BioRender.
Figure 3
Figure 3
circRNAs and human diseases. circRNAs are abundantly expressed in various tissues and are implicated in a number of human diseases, including cancer and brain disorders. Illustration was generated using BioRender.
Figure 4
Figure 4
Key steps in studying circRNAs using publicly available pipelines. For read data, the library preparation is similar to traditional mRNA extraction. For stimulated data, several tools such as KNIFE and CIRI-simulator can be used. Alignment methods for linear RNAs, such as STAR and TopHat, are also commonly used for circRNAs, Therefore, a number of professional pipelines shown in Table 1 can be applied for circRNA detection, such as DCC and CIRI. For downstream analysis, other optional pipelines can be employed for different purposes. Finally, several pipelines can be used to check the association of circRNAs and diseases. The authors apologize for omitting any key pipelines or key steps. Illustration was generated using BioRender.
Figure 5
Figure 5
Searching circRNAs with circBase table browser. This illustration gives a brief introduction on how to search circBase using the table browser option. (a) circBase table browser interface. (b) An output from the result page after submitting queries.

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