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.

The landscape of circular RNA in preterm birth

“…In samples from maternal circulation (plasma and monocytes), we found that the PTB-related DECs might contribute to the pathological process of PTB by involving the immune-inflammatory response, which is in agreement with our previous finding in peripheral whole blood ( 5 ). In maternal plasma, 33 DECs were identical to those previously identified in peripheral whole blood, and 18 of them showed the same change pattern in both previous and current studies.…”

“…Unfortunately, the overall molecular changes and underlying mechanisms of PTB have not been well elucidated, which poses challenges for the prediction and treatment of PTB. Recently, the research progress of non-coding RNA (ncRNA) molecules (e.g., circRNA) has provided new ideas for the study of the mechanisms of PTB ( 5 ).…”

“…Besides, integrated analysis of circRNA expression in multiple tumor tissues provided the macroscopic circRNA landscape in cancer, which contributes to subsequent in-depth exploration of circRNAs as diagnostic or therapeutic targets across cancer types ( 14 ). In 2020, our team took the lead in exploring the circRNAs expression profile of maternal peripheral blood in PTB and demonstrated that the PTB-related circRNAs participate in its core immune-inflammatory mechanisms ( 5 ).…”

Plasma miRNA Profile in High Risk of Preterm Birth during Early and Mid-Pregnancy

“…In recent years, ncRNAs have proven to be promising biomarkers or targets for treatment of various diseases, including pregnancy complications [ 9 ]. There are few studies on preterm birth and long non-coding RNAs (lncRNAs) [ 10 , 11 , 12 , 13 ] or circular RNAs (circRNAs) [ 14 , 15 ], but the most studied ncRNAs in preterm birth are microribonucleic acids (miRNAs). There are a large number of independent studies searching for the association between miRNAs and common gestational disorders [ 16 , 17 ].…”

Identification of the correlations between interleukin-27 (IL-27) and immune-inflammatory imbalance in preterm birth

“…In addition, 153 miRNAs in maternal peripheral blood were found to be dynamically associated with the gestational week of PTB pregnancies, and bioinformatic analysis further suggested that they were enriched in pathways regulating the immune process [32]. Recently, transcriptomic analysis has shown that circRNAs act as novel biomarkers of PTB and regulate the immune-inflammatory imbalance in PTB [33]. Thus, high-throughput data-based bioinformatics strategies are efficient and comprehensive research methods that have effectuated new perspectives and remarkable breakthroughs in resolving disease perplexities [34][35][36].…”