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circRNA Research

Why study circular RNAs?

 

Introduction

Circular RNA (circRNA) is a novel type of RNA that, unlike linear RNA, forms a covalently closed continuous loop, and is highly represented in the eukaryotic transcriptome. Most of these circRNAs are generated from exonic sequences, are conserved across species, and often show tissue/developmental-stage-specific expression. Circular RNAs are more stable than linear RNAs owing to their higher nuclease stability, which constitutes an enormous advantage from a clinical point of view as a novel class of biomarkers. Recently, circRNAs have been shown to function as natural miRNA sponge transcripts, the so-called competing endogenous RNAs (ceRNAs) in diverse species. Their interaction with disease associated miRNAs indicates that circular RNAs are important for disease regulation.

Characteristics of circRNAs

circRNAs "have no tail"

In circular RNA, the 3' and 5' ends normally present in an RNA molecule have been joined together to form a covalently closed continuous loop (Fig. 1). (Salzman J. , 2016) Typical detection methods isolate only those RNA molecules with characteristic molecular 'tails'. With their ends joined together, circular RNAs lack those tails, so have generally been overlooked. (Ledford, 2013)

1

circRNAs are untranslated

Though many of these circular RNAs arise from otherwise protein coding genes,[1] circular RNAs produced in the cell have not been shown to code for proteins. They have therefore been categorized as a novel class of noncoding RNA.

Location

Large numbers of circular RNAs accumulate in the cytoplasm of cells, sometimes exceeding the abundance of the associated linear mRNA by a factor of 10. This is likely because circular RNAs are resistant to degradation by many cellular RNA decay machineries, which recognize the ends of linear RNAs.(Wilusz and Sharp, 2013)

circRNAs funciton as competing endogenous RNAs (ceRNAs)

The enrichment of circRNAs in cytoplasm coupled with the extensive complementarity of circRNAs to their linear mRNA counterparts has raised the possibility that these RNA circles might exert their functional roles through an effect on microRNA binding. Recently, a circRNA called CDR1as (also known as ciRS-7) was identified. This highly stable circRNA contains more than 60 conserved binding sites for miR-7 and hence acts as an effective miR-7 sponge that affects miR-7 target gene activity. In zebrafish, its expression impaired midbrain development in a manner analogous to miR-7 knockdown. However, this is not an isolated example of circRNAs with ceRNA activity, Sry has also been validated as a miR-138 sponge. Recent bioinformatic and experimental analyses have identified thousands of circRNAs in the mammalian transcriptome, suggesting that circRNAs may in fact represent a new class of RNA regulators. Importantly, owing to their high expression levels and increased stability, circRNAs with ceRNAs activity may be exceptionally effective modulators of the crosstalk between linear RNAs. In addition to their ceRNA function, it is possible that circRNAs may also bind and sequester RBPs, base pair with other RNAs or even produce proteins. (The multilayered complexity of circRNA crosstalk and competition)

2

Fig2. ciRS-7 functions as the sponge of miR-7 [4].

circRNAs and Diseases

Recent studies have focused increasing attention on the potential of circRNAs to contribute towards disease aetiology. For example, circular ANRIL (cANRIL) is the circular splice variants of ANRIL, a long non-coding RNA. Production of cANRIL in humans is associated with common single nucleotide polymorphisms (SNPs) predicted to affect ANRIL splicing and is correlated with the risk of human atherosclerosis. This study provides the strong evidence that circular RNAs might be involved in diseases as a novel class of biomarkers even with no biological function.

In addition, recent evidences have demonstrated that circular RNAs play a crucial role in fine tuning the level of miRNA mediated regulation of gene expression by sequestering the miRNAs. Their interaction with disease associated miRNAs indicates that circular RNAs are important for disease regulation. For example, the circular RNA ciRS-7 is highly abundant in human brain, and associated with a brain-specific microRNA (miR-7) in same tissues; ciRS-7 contains multiple, tandem miRNA-7 binding sites, thereby acting as an endogenous miRNA"sponge" to adsorb, and hence quench, normal miRNA-7 functions. Considering the widespread involvement of miR-7 as a key regulator of various cancer pathways and the suggested implications of miR-7 in Parkinson's disease by direct targeting of a-synuclein protein expression or in Alzheimer's disease by direct targeting of the ubiquitin protein ligaseA (UBE2A), ciRS-7 probably serves as a crucial factor significantly engaged in the functioning of neurons as well as a responsible candidate in neurological disorders and tumour development.

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