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Author Summary
Last year, we reported that circular RNA isoforms, previously thought to be very rare, are actually a pervasive feature of eukaryotic gene expression programs; indeed, the major RNA isoform from hundreds of human genes is a circle. Previous novel RNA species that initially appeared to be special cases, of dubious biological significa...
Citations
... Ablation of some core factors of the spliceosomal complex and treatment with a splicing inhibitor allows more back-splicing events to occur 73,76,77 . Despite the expected competition between forward and back-splicing, early genome-wide studies have shown that the levels of circular and linear isoforms are not fully correlated with each other 7,27,59,78,79 , although researchers have made further efforts to define the efficiency of back-splicing in terms of the circular-to-linear ratio (CLR). The CLR is the ratio of mapped sequencing reads that support back-splicing to those that support forward splicing 59 . ...
... The CLR is the ratio of mapped sequencing reads that support back-splicing to those that support forward splicing 59 . Although the CLR is known to be <1% for most human loci, some circRNAs are robustly expressed and sometimes accumulate to levels that exceed those of their corresponding linear forms 7,59,78 . However, the precise mechanism underlying the regulation of back splicing efficiency remains to be elucidated. ...
... For instance, in mice liver, 8,843 circRNAs were identified in the hepatocyte, while only 949 circRNAs derived from the endothelial cell of hepatic sinusoid [20]. Another study revealed that even the pattern of splice isoforms of circRNAs from each parental gene was cell-type specific [21]. These suggest that the different characteristics of circRNAs between cell and tissue, and previous circRNAs enrichment methods from cells may not be able to enrich circRNAs from all cell types within a tissue. ...
... These artefacts could generate reads that also map to the BSJ site and lead to false circRNAs identification. Moreover, circRNAs only account for up to 0.03% of total RNA molecules in eukaryote [21], while rRNAs account for more than 80% [30], followed by transfer RNA (tRNA) (~15%) and mRNA and other regulatory noncoding RNAs (~5%) [31]. Therefore, if these non-circRNAs molecules are not removed completely, reads generate from these highly expressed transcripts can weaken the signals of circRNAs BSJ site detection even with high sequencing depth. ...
Although circular RNAs (circRNAs) play important roles in regulating gene expression, the understanding of circRNAs in livestock animals is scarce due to the significant challenge to characterize them from a biological sample. In this study, we assessed the outcomes of bovine circRNA identification using six enrichment approaches with the combination of ribosomal RNAs removal (Ribo); linear RNAs degradation (R); linear RNAs and RNAs with structured 3′ ends degradation (RTP); ribosomal RNAs coupled with linear RNAs elimination (Ribo-R); ribosomal RNA, linear RNAs and RNAs with poly (A) tailing elimination (Ribo-RP); and ribosomal RNA, linear RNAs and RNAs with structured 3′ ends elimination (Ribo-RTP), respectively. RNA-sequencing analysis revealed that different approaches led to varied ratio of uniquely mapped reads, false-positive rate of identifying circRNAs, and the number of circRNAs per million clean reads (Padj <0.05). Out of 2,285 and 2,939 highly confident circRNAs identified in liver and rumen tissues, respectively, 308 and 260 were commonly identified from five methods, with Ribo-RTP method identified the highest number of circRNAs. Besides, 507 of 4,051 identified bovine highly confident circRNAs had shared splicing sites with human circRNAs. The findings from this work provide optimized methods to identify bovine circRNAs from cattle tissues for downstream research of their biological roles in cattle.
... CEACAM6 appears to play a large part in regulating anoikis via a Akt/c-src signaling pathway and may regulate gemcitabine resistance in IHCC and pancreatic cancer [28]. [51][52][53]. Specifically, circRNAs can act as sponges for microRNAs (miRNAs), thereby affecting gene expression at the post-transcriptional level [52,54]. In gastric cancer, it has been discovered that up-regulation of circ_0008035 can regulate the expression of CEACAM6 by sponging miR-1256 [55], thereby promoting the growth of gastric cancer. ...
Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is an immunoglobulin superfamily protein primarily expressed on epithelial surfaces and myeloid cells. It plays a significant role in cancer progression by inhibiting apoptosis, promoting drug resistance, and facilitating cancer cell invasion and metastasis. Overexpression of CEACAM6 has been observed in various cancers, including lung, breast, colorectal, and hepatocellular cancers, and is associated with poorer overall survival and disease-free survival. Its differential expression on tumor cell surfaces makes it a promising cancer marker. This review aims to provide a comprehensive summary of CEACAM6’s role in different cancer types, its involvement in signaling pathways, and recent advancements in CEACAM6-targeted treatments.
... Compared to traditional linear RNA, circRNAs form a covalently closed loop structure which lacks 3′ PolyA tails and 5′ caps, making them effectively resistant to degradation by the ribonuclease R (RNase R) [11]. Furthermore, circRNAs exhibit characteristics such as tissue specificity, conservation, and ubiquitous expression [12][13][14]42]. Due to these characteristics, circRNAs hold greater potential as a diagnostic biomarker for diseases [43][44][45][46]. ...
Background
Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to progressive joint damage. Circular RNA (circRNA) can regulate the inflammatory response of fibroblast-like synoviocytes (FLSs) in RA, influencing the disease progression. Paeoniflorin (PF) is the main active ingredient extracted from Paeonia lactiflora and is known for its anti-inflammatory effect. This study aims to explore the potential mechanisms by which hsa_circ_009012 and PF regulate the inflammatory response in RA.
Methods
RNA expression of hsa_circ_009012, has-microRNA-1286 (miR-1286), toll-like receptor 4 (TLR4), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) was assessed by real-time quantitative polymerase chain reaction (RT-qPCR) or western blotting (WB). Cell inflammation markers (TNF-α, IL-1β, IL-6) were assessed by RT-qPCR and immunofluorescence (IF). Counting Kit-8 (CCK-8) assay, flow cytometry, and transwell assay were utilized to test cell viability, cell cycle distribution, and migration.
Results
Hsa_circ_009012 was highly expressed in RA-FLS. Hsa_circ_009012 over-expression facilitated the inflammation in RA-FLS and was closely associated with the miR-1286/TLR4 axis. Paeoniflorin inhibited inflammation and the expression of hsa_circ_009012 and TLR4, while upregulating the expression of miR-1286 in RA-FLS. Moreover, the upregulation of hsa_circ_009012 reversed the repressive effect of paeoniflorin on RA-FLS progression.
Conclusion
Paeoniflorin inhibits the inflammation of RA-FLS via mediating the hsa_circ_009012/miR-1286/TLR4/NLRP3 axis.
... This article primarily expounds on the biogenesis, biological characteristics and identification methods of circRNA, providing a comprehensive summary of the circRNA-related biological functions and the methodologies used to elucidate their functions. The article published in 2013 in the journal PLoS Genetics titled "Cell-Type Specific Features of Circular RNA Expression" [32] ranks third in terms of citation frequency. The article used refined bioinformatics and statistical methods to identify circRNAs, revealing that the regulation of splicing sites during RNA circularization displays both gene-specific and cell-type-specific features. ...
Background and objective
Circular RNAs (circRNAs) have garnered considerable attention in the study of various human diseases due to their ubiquitous expression and potential biological functions. This study conducts a bibliometric and visualization-based analysis of circRNA-related research in diseases, aiming to reveal the current status, hotspots and emerging trends within the field.
Methods
Literature published between 2013 and 2022 and indexed in the Web of Science core databases was retrieved. Visualizations of publication volume, countries, authors, institutions, journals, references, and keywords were performed. Microsoft Excel (2021) was used to analyze and graph publication volume and growth trends. Additionally, CiteSpace (version 6.1.R6) and VOSviewer (version 1.6.18) were employed to visualize the bibliographic information.
Results
Between 2013 and 2022, a total of 4195 relevant articles on circRNA in the context of diseases were identified. These articles covered 56 countries, 2528 institutions, 19,842 authors and 698 journals, citing 85,541 references. The annual publication volume showed an exponential growth trend, with rapid development post-2017. China, the United States and Germany emerged as the top three contributors, demonstrating high publication volume and total citations. Notably, Nanjing Medical University exhibited the highest publication volume, boasting 291 articles. Burton B. Yang and Li Yang consistently ranked among the top 10 authors in terms of publication volume and citations, emerging as core contributors in this research field. The journal Bioengineered ranked first in terms of published articles (160), with an impact factor of 6.832, while Molecular Cancer garnered the highest impact factor (41.4), solidifying its position as a top journal in this field. Furthermore, high-frequency keywords included “expression” “proliferation” “biomarker” “microRNA” “cancer”, signifying the prevailing research hotspots and principal themes of this field over the past decade. As of 2022, “biomarker”, “prostate cancer”,“drug resistance”,“papillary thyroid carcinoma”, etc. continued as keywords during the outbreak period. At present, the value of circRNA application is mainly reflected in the two aspects of biomarkers and therapeutic targets, and the prediction of accurate diagnosis and precise treatment based on big data analysis, especially in cancer, will become a hot spot of research in the future.
Conclusion
The trajectory of circRNA research from its biological origins to its applications in diseases has been delineated from 2013 to 2022. However, the transition to disease-specific applications and exploration of biological functions warrants further attention in future research endeavors.
... Circular RNAs (circRNAs) are a subtype of non-coding RNAs that are generated from non-canonical backsplicing and covalent joining of RNA, including exons and introns of proteincoding genes. [7][8][9][10] They are the only type of RNA that has been found to be particularly enriched in the brain vs all other tissues and to be able to cross the BBB and to be readily-detectable in the blood. [7][8][9][11][12][13][14][15] Due to their unique structure, they are particularly resistant to exonuclease degradation, and are thus known to have robust inherent stability and much longer half lives compared to linear mRNA molecules. ...
... [7][8][9][10] They are the only type of RNA that has been found to be particularly enriched in the brain vs all other tissues and to be able to cross the BBB and to be readily-detectable in the blood. [7][8][9][11][12][13][14][15] Due to their unique structure, they are particularly resistant to exonuclease degradation, and are thus known to have robust inherent stability and much longer half lives compared to linear mRNA molecules. 14,15 CircRNAs are known to exert significant and diverse functional effects on gene expression by either sequestering microRNAs (miRNAs) and RNAbinding proteins (RBPs) or directly interacting with numerous RNA and protein partners to exert both transcriptional and post-transcriptional influence on a significant number of downstream gene targets. ...
Major Depressive Disorder (MDD) is a debilitating psychiatric disorder that currently affects more than 20% of the adult US population and is a leading cause of disability worldwide. Although treatment with antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRIs), has demonstrated clinical efficacy, the inherent complexity and heterogeneity of the disease and the “trial and error” approach in choosing the most effective antidepressant treatment for each patient, allows for only a subset of patients to achieve response to the first line of treatment. Circular RNAs (circRNAs), are highly stable and brain-enriched non-coding RNAs that are mainly derived from the backsplicing and covalent joining of exons and introns of protein-coding genes. They are known to be important for brain development and function, to cross the blood-brain-barrier, and to be highly sensitive to changes in neuronal activity or activation of various neuronal receptors. Here we present evidence of a brain-enriched circRNA that is regulated by Serotonin 5-HT2A and Brain-Derived Neurotrophic Factor (BDNF) receptor activity and whose expression in the blood can predict response to SSRI treatment. We present data using circRNA-specific PCR in baseline whole blood samples from the Establishing moderators and biosignatures of antidepressant response in clinical care (EMBARC) study, showing that before treatment this circRNA is differentially expressed between future responders and non-responders to sertraline. We further show that the expression of this circRNA is upregulated following sertraline treatment and that its trajectory of change post-treatment is associated with long-term remission. Furthermore, we show that the biomarker potential of this circRNA is specific to SSRIs, and not associated with prediction of response or remission after Placebo or Bupropion treatment. Lastly, we provide evidence in animal mechanistic and neuronal culture studies, suggesting that the same circRNA is enriched in the brain and is regulated by 5-HT2A and BDNF receptor signaling. Taken together, our data identify a brain-enriched circRNA associated with known mechanisms of antidepressant response that can serve as a blood biomarker for predicting response and remission with SSRI treatment.
... Circular RNAs (circRNAs), a novel member of noncoding RNAs (ncRNAs), are a distinct class of regulatory RNA, possessing a covalently closed loop structure without the 5′ and 3′ termini (Salzman et al., 2012;Kristensen et al., 2019). These are highly abundant in eukaryotes, and many are evolutionarily conserved (Memczak et al., 2013;Salzman et al., 2013). CircRNAs are thus considerably insusceptible to degradation by exonucleases and are more stable than their linear RNA molecules (Suzuki and Tsukahara, 2014;Li et al., 2018). ...
Prolonged or repeated exposure to stress elevates the risk of various psychological diseases, many of which are characterized by central nervous system dysfunction. Recent studies have demonstrated that circular RNAs (circRNAs) are highly abundant in the mammalian brain. Although their precise expression and function remain unknown, they have been hypothesized to regulate transcriptional and post-transcriptional gene expression. In this investigation, we comprehensively analyzed whether restraint stress for 2 days altered the circRNA expression profile in the amygdala of male rats. The impact of restraint stress on behavior was evaluated using an elevated plus maze and open field test. Serum corticosterone levels were measured using an enzyme-linked immunosorbent assay. A total of 10,670 circRNAs were identified using RNA sequencing. Ten circRNAs were validated by reverse transcription and quantitative polymerase chain reaction analysis. Gene ontology and Kyoto encyclopedia of genes and genomes pathway analyzes supported the notion that genes associated with differentially expressed circRNAs are primarily implicated in neuronal activity and neurotransmitter transport. Moreover, the three differentially expressed circRNAs showed high specificity in the amygdala. Overall, these findings indicate that differentially expressed circRNAs are highly enriched in the amygdala and offer a potential direction for further research on restraint stress.
... The augmentative effect of lovastatin on hsa_circRNA_102979 gene expression was further confirmed by other statins such as pravastatin and atorvastatin (Fig. 1B). Because hsa_circRNA_102979 is co-transcripted in chr20:398169-409233 with ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene 22 , we named hsa_circRNA_102979 as circRNA-RBCK1. ...
Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.
... Due to the lack of 5' or 3' ends and resistance to exonuclease-mediated degradation, circRNAs are presumably more stable than most linear RNA in cells, tissues, and body fluids (1)(2)(3)(4)(5). Their half-lives can be longer than 48 hours (1)(2)(3)(4)(5)18) and are easily detected using realtime PCR (19,20). Therefore, the identification of circRNAs provides a potential strategy for the development of novel diagnostic and prognostic biomarkers for human diseases. ...
Circular RNAs (circRNAs) are a class of transcripts that often are generated by back-splicing that covalently connects the 3′end of the exon to the 5′end. CircRNAs are more resistant to nuclease and more stable than their linear counterparts. One of the well-recognized roles of circRNAs is the miRNA sponging effects that potentially lead to the regulation of downstream proteins. Despite that circRNAs have been reported to be involved in a wide range of human diseases, including cancers, cardiovascular, and neurological diseases, they have not been studied in inflammatory lung responses. Here, we analyzed the circRNA profiles detected in extracellular vesicles (EVs) obtained from the broncho-alveolar lavage fluids (BALF) in response to LPS or acid instillation in mice. Next, we validated two specific circRNAs in the BALF-EVs and BALF cells in response to endotoxin by RT-qPCR, using specific primers targeting the circular form of RNAs rather than the linear host RNAs. The expression of these selected circRNAs in the BALF inflammatory cells, alveolar macrophages (AMs), neutrophils, and lung tissue were analyzed. We further predicted the potential miRNAs that interact with these circRNAs. Our study is the first report to show that circRNAs are detectable in BALF EVs obtained from mice. The EV-cargo circRNAs are significantly altered by the noxious stimuli. The circRNAs identified using microarrays may be validated by RT-qPCR using primers specific to the circular but not the linear form. Future studies to investigate circRNA expression and function including miRNA sponging in lung inflammation potentially uncover novel strategies to develop diagnostic/therapeutic targets.
... The advancement of sequencing technology and bioinformatics algorithms has enabled the identification of a class of potentially functional circular RNAs (cir-cRNAs) [9]. These circRNAs are linked together through the 5' and 3' ends of the parent gene to form a circular structure [10]. Studies have demonstrated that cir-cRNAs have important molecular functions for mammary gland development and lactation in mammals. ...
Background
Cow milk fat is an essential indicator for evaluating and measuring milk quality and cow performance. Growing research has identified the molecular functions of circular RNAs (circRNAs) necessary for mammary gland development and lactation in mammals.
Method
The present study analyzed circRNA expression profiling data in mammary epithelial cells (MECs) from cows with highly variable milk fat percentage (MFP) using differential expression analysis and weighted gene co-expression network analysis (WGCNA).
Results
A total of 309 differentially expressed circRNAs (DE-circRNAs) were identified in the high and low MFP groups. WGCNA analysis revealed that the pink module was significantly associated with MFP (r = − 0.85, P = 0.007). Parental genes of circRNAs in this module were enriched mainly in lipid metabolism-related signaling pathways, such as focal adhesion, ECM-receptor interaction, adherens junction and AMPK. Finally, six DE-circRNAs were screened from the pink module: circ_0010571, circ_0007797, circ_0002746, circ_0003052, circ_0004319, and circ_0012840. Among them, circ_0002746, circ_0003052, circ_0004319, and circ_0012840 had circular structures and were highly expressed in mammary tissues. Subcellular localization revealed that these four DE-circRNAs may play a regulatory role in the mammary glands of dairy cows, mainly as competitive endogenous RNAs (ceRNAs). Seven hub target genes (GNB1, GNG2, PLCB1, PLCG1, ATP6V0C, NDUFS4, and PIGH) were obtained by constructing the regulatory network of their ceRNAs and then analyzed by CytoHubba and MCODE plugins in Cytoscape. Functional enrichment analysis revealed that these genes are crucial and most probable ceRNA regulators in milk fat metabolism.
Conclusions
Our study identified several vital circRNAs and ceRNAs affecting milk fat synthesis, providing new research ideas and a theoretical basis for cow lactation, milk quality, and breed improvement.
