Topic review

Circular RNAs

Subjects: Genetics View times: 108
Submitted by: Priscilla Prestes

Abstract

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in adults in developed countries. CVD encompass many diseased states including hypertension, coronary artery disease and atherosclerosis. Studies in animal models and human studies have elucidated the contribution of many genetic factors, including non-coding RNAs. Non-coding RNAs are RNAs not translated into protein, involved in gene expression regulation post-transcriptionally and implicated in CVD. These include long non-coding RNAs. Of these, circular RNAs (circRNAs) and micro RNAs. CircRNAs are created by the back-splicing of pre-messenger RNA and have been underexplored as contributors to CVD. These circRNAs may also act as biomarkers of human disease as they can be extracted from whole blood, plasma, saliva and seminal fluid. CircRNAs have recently been implicated in various disease processes, including hypertension and other cardiovascular disease. This review article will explore the promising and emerging roles of circRNAs as potential biomarkers and therapeutic targets in CVD, in particular hypertension.

CircRNAs are abundant, underexplored ncRNAs. Recent studies revealed that large numbers of circRNAs are endogenous, highly conserved and stable in mammalian cells and prevalent in disease states (Figure 2) [7]. Although mRNA and circRNAs both originate from precursor-mRNAs, they are formed differently, giving them unique characteristics. mRNAs are formed by RNA splicing where introns are removed, and certain exons are included or excluded to create alternative coding mature mRNAs. This process creates linear mRNAs with exposed poly(A) tails. This characteristic leaves them prone to degradation by RNases [55]. Meanwhile, circRNAs are formed by back-splicing, promoting the circularization process where exons and/or introns converge onto each other, potentially protecting them from degradation and conferring a half-life of approximately 48 h, around five times more stable than linear mRNAs (Figure 1) [56].

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Figure 1. Biogenesis of mature messenger RNA (mRNA) and circular RNA (circRNA) from precursor mRNA (pre-mRNA). Pre-mRNA undergoes RNA splicing to form a mature mRNA or back-splicing to form circRNAs.

The definitive function of circRNAs still remains unclear. It has been proposed that circRNAs regulate the expression of linear mRNA transcripts both directly, via the competition with the splicing machinery [57]; and indirectly, acting as sponges to miRNAs due to the presence of multiple binding sites, allowing them to interact with and sequester cellular miRNAs preventing the performance of their roles on post-transcriptional regulation (Figure 2) [58,59].

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Figure 2. Circular RNA (circRNA) functions. (A) The upregulation of circRNAs leads to a decrease in microRNA (miRNA) availability, messenger RNA (mRNA) degradation or inhibition, resulting in an increase of protein translation. (B) Conversely, the downregulation of circRNAs leads to more miRNA available and higher levels of mRNA degradation or inhibition, leading to a downregulation in protein translation.

Importantly, circRNAs make up 1% of total RNA being expressed widely in various cell types and may have a regulatory function in human disease, with a pivotal role in the initiation and progression of various types of biological processes [58], potentially acting as a biomarker for the discovery and investigation on the progression of disease. However promising, research to identify and characterize circRNAs has mostly been performed using bioinformatics and in silico approaches and a limited number of studies have investigated their function in situ or in vivo to establish their involvement in disease.

The properties described above and promising research in the field of cancer genomics using circRNAs as biomarkers is encouraging and should be explored and translated into cardiovascular genomics research. This is extremely relevant, as conventional methods for controlling risk factors and initiating early treatment in CVD intervention have often led to poor prognosis. Current biomarkers usually detect the disease at later stages of development, increasing the need for the discovery of new biomarkers for prevention or at early onset of disease. This further highlights the benefits of using circRNAs as potential biomarkers in CVD (Table 1).

Emerging evidence of circular RNAs in cardiovascular disorders has demonstrated differential expression in both healthy and diseased hearts [60–63]. However, the relevance of circular RNAs to the cardiovascular system remains poorly characterised, and an improvement in understanding of circRNA involvement in CVD will form a basis for the development of these RNAs as biomarkers for discovery, prediction and therapeutic agents. Importantly, the combination of genetic sequencing and bioinformatics discovery has enabled the identification of many novel circRNAs.

Table 1. Summary of circRNAs implicated in cardiovascular diseases, including species and sample types studied and differential expression direction.

Disease

Circular RNA

Species

Sample

Expression

References

Hypertension

hsa_circ_0005870

Human

Blood

Down

[64]

hsa_circ_0037909

Human

Blood

Up

[65]

hsa_circ_0037911

Human

Blood

Up

[66]

hsa_circ_0126991

Human

Blood

Up

[67]

hsa_circ_0014243

Human

Blood

Up

[68]

Myocardial infarction

mmu_circ_0001878

Mouse

Cardiomyocytes

Up

[69]

circTtc3

Rats

Cardiomyocytes

Up

[70]

MICRA

Human

Blood

Down

[71]

circNfix

Mouse

Cardiomyocytes

Up

[72]

circFndc3b

Mouse

Human

Cardiomyocytes

Down

[73]

Atherosclerosis

circRNA-0044073

Human

Blood

Up

[74]

ocu-ciR-novel-18038

Rabbit

Blood

Down

[75]

ocu-ciR-novel-18298

Rabbit

Blood

Up

ocu-ciR-novel-15993

Rabbit

Blood

Up

ocu-ciR-novel-17934

Rabbit

Blood

Down

ocu-ciR-novel-17879

Rabbit

Blood

Up

ocu-ciR-novel-18036

Rabbit

Blood

Up

ocu-ciR-novel-14389

Rabbit

Blood

Up

circANRIL

Human

Blood

Up

[76]

circCHFR

Human

VSMC

Up

[77]

circRNA-0003575

Mouse

Endothelial cells

Up

[78]

Coronary artery disease

hsa_circ_0001879

Human

Blood

Up

[79]

hsa_circ_0004104

Human

Blood

Up

hsa_circ_0124644

Human

Blood

Up

[80]

hsa_circ_0098964

Human

Blood

Up

hsa_circ_0030769

Human

Blood

Up

[81]

hsa_circ_0079828

Human

Blood

Up

hsa_circ_15486-161

Human

Blood

Up

hsa_circ_0122274

Human

Blood

Up

hsa_circ_16316-13

Human

Blood

Up

hsa_circ_0140538

Human

Blood

Up

Cardiomyopathy

mmu_circ_0000254

Mouse

Cardiomyocytes

Down

[82]

hsa_circ_0076631

Human

Cardiomyocytes and Serum

Up

[83]

circRNA_000203

Mouse

Ventricular

Cardiomyocytes

Up

[84]

circSlc8a1

Mouse

Cardiomyocytes

Up

[85]

Legend: ciR, circular; circ, circular; circANRIL, circular antisense non-coding RNA in the INK4 locus; circCHFR, circular checkpoint with fork-head associated and ring finger; circFndc3b, circular fibronectin type III domain containing 3B; circNfix, circular nuclear factor I X; circSlc8a1, circular solute carrier family 8 member a1; circTtc3, circular tetratricopeptide repeat domain 3; hsa, Homo sapiens; MICRA, myocardial infarction-associated circular RNA; mmu, Mus musculus; ocu, Oryctolagus cuniculus; VSMC, vascular smooth muscle cells.

The entry is from 10.3390/ijms21103666

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