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Identification and Characterization of Circular RNA as a Novel Regulator and Biomarker in Preterm Birth.

ABSTRACT: Preterm birth (PTB), as the leading cause of neonatal death, is a severe threat to maternal-fetal health. The diagnosis and treatment of PTB are difficult as its underlying mechanism still unknown. Circular RNA (circRNA) is an emerging molecule that plays an essential role in the pathological processes of various diseases. However, it is still unclear whether circRNAs are abnormal or involves in the PTB pathology. In this study, we analyzed RNA-seq data of peripheral blood from preterm and term pregnant women and verified with microarray data. There were 211 circRNA expression disorders in PTB, of which 68 increased and 143 decreased. Bioinformatics analysis revealed that the top 20 circRNAs competitively bind 68 miRNAs, thereby regulating 622 mRNAs mainly related to immunity, inflammation, and nerve activity, which may ultimately contribute to the occurrence of PTB. Moreover, 6 regulatory pairs, including hsa-MORC3_0001-hsa-miR-1248-CHRM2 were the core parts of this mechanism network, which might be therapeutic targets for PTB. Besides, ROC analysis indicated that hsa-ANKFY1_0025, hsa-FAM13B_0019, and hsa-NUSAP1_0010 (AUC = 0.7138, 0.9589, 1.000) have an excellent discrimination ability for PTB. Taken together, we explored for the first time the circRNA expression profile of PTB, and preliminarily analyzed its regulatory mechanism and predictive value for PTB, thus bringing new light to the diagnosis and treatment of PTB.

SUBMITTER: Ran Y

PROVIDER: S-EPMC7775733 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Identification and Characterization of Circular RNA as a Novel Regulator and Biomarker in Preterm Birth.

Ran Yuxin Y Yin Nanlin N Huang Dongni D Zhao Yangyu Y Yang Jing J Zhang Hanwen H Qi Hongbo H

Frontiers in bioengineering and biotechnology 20201202

Preterm birth (PTB), as the leading cause of neonatal death, is a severe threat to maternal-fetal health. The diagnosis and treatment of PTB are difficult as its underlying mechanism still unknown. Circular RNA (circRNA) is an emerging molecule that plays an essential role in the pathological processes of various diseases. However, it is still unclear whether circRNAs are abnormal or involves in the PTB pathology. In this study, we analyzed RNA-seq data of peripheral blood from preterm and term ...[more]

PMID: 33392159

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Project description:BackgroundPreterm birth (PTB) is a multifactorial syndrome that seriously threatens the health of pregnant women and babies worldwide. Recently, circular RNAs (circRNAs) have been understood as important regulators of various physiological and pathological processes. However, the expression pattern and potential roles of circRNAs in PTB are largely unclear.MethodsIn this study, we extracted and analyzed the circRNA expression profiles in maternal and fetal samples of preterm and term pregnancies, including maternal plasma, maternal monocytes, myometrium, chorion, placenta, and cord blood. We identified the circRNAs which is associated with PTB in different tissues and explored their relationships from the perspective of the overall maternal-fetal system. Furthermore, co-expression analysis of circRNAs and mRNAs, target microRNAs (miRNAs), and RNA-binding proteins (RBPs), provided new clues about possible mechanisms of circRNA function in PTB. In the end, we investigated the potential special biofunctions of circRNAs in different tissues and their common features and communication in PTB.ResultsSignificant differences in circRNA types and expression levels between preterm and term groups have been proved, as well as between tissues. Nevertheless, there were still some PTB-related differentially expressed circRNAs (DECs) shared by these tissues. The functional enrichment analysis showed that the DECs putatively have important tissue-specific biofunctions through their target miRNA and co-expressed mRNAs, which contribute to the signature pathologic changes of each tissue within the maternal-fetal system in PTB (e.g., the contraction of the myometrium). Moreover, DECs in different tissues might have some common biological activities, which are mainly the activation of immune-inflammatory processes (e.g., interleukin1/6/8/17, chemokine, TLRs, and complement).ConclusionsIn summary, our data provide a preliminary blueprint for the expression and possible roles of circRNAs in PTB, which lays the foundation for future research on the mechanisms of circRNAs in PTB.

Project description:Background: The morbidity and mortality of gastric cancer (GC) remain high worldwide. With the advent of the Human Genome Sequencing Project, circular RNAs (circRNAs) have attracted widespread attention in cancer research due to their stable ring structure. Our aim was to identify differentially expressed circRNAs in GC and explore their potential roles in GC diagnosis, treatment, and prognostic prediction. Methods: Large-scale gene screening was performed in three pairs of GC tissues and adjacent noncancerous tissues using high-throughput sequencing. The expression of hsa_circ_0001821 was detected in 80 pairs of tissue samples by quantitative real-time PCR (qRT-PCR). Stability of the ring structure of hsa_circ_0001821 RNA was verified by exonuclease digestion assay, and its diagnostic value was evaluated by receiver operating characteristic (ROC) analysis. In addition, the location of hsa_circ_0001821 in GC cells was detected by nucleoplasm separation assay. Results: A total of 25,303 circRNAs were identified, among which 2,007 circRNAs were differentially expressed (fold change > 2.0, P < 0.05). Further validation disclosed that hsa_circ_0001821 was significantly downregulated in the 80 pairs of GC tissues and 30 whole-blood specimens obtained from the GC patients. The specificity of hsa_circ_0001821 in GC was higher than that in other solid tumors. In addition, hsa_circ_0001821 was relatively stable after RNA exonuclease digestion. Clinicopathological parameter analysis showed that hsa_circ_0001821 was negatively correlated with tumor depth (r = -0.255, P = 0.022) and lymph node metastasis (r = -0.235, P = 0.036). Area under the curve (AUC) analysis showed that the diagnostic efficiency of circulating hsa_circ_0001821 in distinguishing GC patients was higher than that in GC tissues (0.872, 95%CI: 0.767-0.977 vs. 0.792, 95%CI: 0.723-0.861). Combined use of circulating hsa_circ_0001821 with the existing tumor markers yielded the largest AUC of 0.933. Finally, hsa_circ_0001821 was demonstrated to mainly locate in the cytoplasm, implying that it played a potential regulatory role in GC at the posttranscriptional level. Conclusion: Hsa_circ_0001821 may prove to be a new and promising potential biomarker for GC diagnosis.

Project description:Preterm birth (PTB) is defined as childbirth occurring at less than 37 completed weeks or 259 days of gestation. Premature babies have higher rates of cerebral palsy, sensory deficits, learning disabilities and respiratory illnesses that extend into adulthood. This lifelong morbidity results in high economic and social costs to families and communities. PTB is a syndrome initiated by multiple mechanisms, including infection or inflammation, uteroplacental ischaemia or haemorrhage, uterine overdistension, stress, and other immunologically mediated processes. Identifying and monitoring molecular signals in easily accessible body fluids that can diagnose or predict the risk of preterm labor in pregnant women will reduce or prevent PTBs. A number of studies reported the identification of putative biomarkers for PTB including protein, miRNA and hormone from different body fluids such as serum/plasma, cervical vaginal fluid, saliva and amniotic fluids. These putative biomarkers identified can largely be grouped into three main functional categories: inflammatory related molecules, placenta or fetal derived molecules and stress related molecules. In the past few years next generation sequencing (NGS) has become the major platform for miRNA analysis especially with body fluids. However, studies have shown significant sequence bias among different small RNA library preparation protocols. We have modified the small RNA library construction protocol which greatly reduces the sequence bias and increase miRNA coverage in sample. We also adapted a newly developed size exclusion chromatography (SEC) based EV purification protocol which can provide cleaner EVs compared to other methods. We are using these improved approaches to gain more reliable profile of circulating RNA in body fluid as well as its associated EVs. With these new approaches, we explore the possibility of using specific circulating miRNAs, specifically those encapsulated in EVs, as a noninvasive biomarker for PTB by comparing the miRNA profiles in maternal plasma, EV and EV-depleted plasma between individuals who had a spontaneous preterm birth and uncomplicated pregnancies.

Project description:BACKGROUND: Spontaneous preterm birth (SPB, before 37 gestational weeks) is a major cause of perinatal mortality and morbidity, but its pathogenesis remains unclear. Studies on SPB have been hampered by the limited availability of markers for SPB in predelivery clinical samples that can be easily compared with gestational age-matched normal controls. We hypothesize that SPB involves aberrant placental RNA expression, and that such RNA transcripts can be detected in predelivery maternal plasma samples, which can be compared with gestational age-matched controls. PRINCIPAL FINDINGS: Using gene expression microarray to profile essentially all human genes, we observed that 426 probe signals were changed by >2.9-fold in the SPB placentas, compared with the spontaneous term birth (STB) placentas. Among the genes represented by those probes, we observed an over-representation of functions in RNA stabilization, extracellular matrix binding, and acute inflammatory response. Using RT-quantitative PCR, we observed differences in the RNA concentrations of certain genes only between the SPB and STB placentas, but not between the STB and term elective cesarean delivery placentas. Notably, 36 RNA transcripts were observed at placental microarray signals higher than a threshold, which indicated the possibility of their detection in maternal plasma. Among them, the IL1RL1 mRNA was tested in plasma samples taken from 37 women. It was detected in 6 of 10 (60%) plasma samples collected during the presentation of preterm labor (?32.9 weeks) in women eventually giving SPB, but was detected in only 1 of 27 (4%) samples collected during matched gestational weeks from women with no preterm labor (Fisher exact test, p?=?0.00056). CONCLUSION: We have identified 36 SPB-associated RNA transcripts, which are possibly detectable in maternal plasma. We have illustrated that the IL1RL1 mRNA was more frequently detected in predelivery maternal plasma samples collected from women resulting in SPB than the gestational-age matched controls.

Project description:BackgroundEndometriosis is a challenging disease with symptoms such as dysmenorrhea and infertility. However, its etiology is still vague and there is still no effective markers or treatment. This study aimed to profile the circular RNAs (circRNAs) expressed in eutopic endometrium from patients with ovarian endometriosis and explore potential clues to the pathogenesis of endometriosis, providing an evidence for clinical diagnosis and treatment.MethodsA total of 63 clinical samples, including control endometrium (n = 22) and eutopic endometrium (n = 41), were collected from Peking Union Medical College Hospital between May 1, 2016, and December 31, 2016. Of them, four samples in each group were used for circRNA microarray. Then, four upregulated circRNAs were screened out for quantitative real-time polymerase chain reaction (qRT-PCR) validation. After that, bioinformatics analysis was performed to predict miRNAs targeted by validated circRNAs and investigate the circRNA-miRNA-mRNA interactions.ResultsAmong 88 differentially expressed circRNAs, 11 were upregulated and 77 were downregulated in eutopic endometrium of patients with endometriosis. qRT-PCR validation results for two upregulated circRNAs (circ_0004712 and circ_0002198) matched the microarray results. The area under the receiver operating characteristic curve of circ_0002198 for distinguishing ovarian endometriosis was 0.846 (95% confidence interval [CI]: 0.752-0.939; P < 0.001) while that of circ_0004712 was 0.704 (95% CI: 0.571-0.837; P = 0.008). On the basis of target prediction, we depicted the molecular interactions between the identified circRNAs and their dominant target miRNAs, as well as constructed a circRNA-miRNA-mRNA network.ConclusionsThis study provides evidence that circRNAs are differentially expressed between eutopic and normal endometrium, which suggests that circRNAs are candidate factors in the activation of endometriosis. circ_0002198 and circ_0004712 may be potential novel biomarkers for the diagnosis of ovarian endometriosis.

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Identification and Characterization of Circular RNA as a Novel Regulator and Biomarker in Preterm Birth.

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Identification and Characterization of Circular RNA as a Novel Regulator and Biomarker in Preterm Birth.

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