Circular RNA expression profiling of human granulosa cells during maternal aging reveals novel transcripts associated with assisted reproductive technology outcomes

Abstract

Circular RNAs (circRNAs) are a unique class of endogenous RNAs which could be used as potential diagnostic and prognostic biomarkers of many diseases. Our study aimed to investigate circRNA profiles in human granulosa cells (GCs) during maternal aging and to uncover age-related circRNA variations that potentially reflect decreased oocyte competence. CircRNAs in GCs from in vitro fertilization (IVF) patients with young age (YA, ≤ 30 years) and advanced age (AA, ≥ 38 years) were profiled by microarray, and validated in 20 paired samples. The correlation between circRNAs expression and clinical characteristics was analyzed in additional 80 samples. Chip-based analysis revealed 46 up-regulated and 11 down-regulated circRNAs in AA samples (fold change > 2.0). Specifically, circRNA_103829, circRNA_103827 and circRNA_104816 were validated to be up-regulated, while circRNA_101889 was down-regulated in AA samples. After adjustment for gonadotropin treatment, only circRNA_103827 and circRNA_104816 levels were positively associated with maternal age (partial r = 0.332, P = 0.045; partial r = 0.473, P = 0.003; respectively). Moreover, circRNA_103827 and circRNA_104816 expressions in GCs were negatively correlated with the number of top quality embryos (r = -0.235, P = 0.036; r = -0.221, P = 0.049; respectively). Receiver operating characteristic (ROC) curve analysis indicated that the performance of circRNA_103827 for live birth prediction reached 0.698 [0.570–0.825], with 77.2% sensitivity and 60.9% specificity (P = 0.006), and that of circRNA_104816 was 0.645 [0.507–0.783] (P = 0.043). Bioinformatics analysis revealed that both circRNAs were potentially involved in glucose metabolism, mitotic cell cycle, and ovarian steroidogenesis. Therefore, age-related up-regulation of circRNA_103827 and circRNA_104816 might be potential indicators of compromised follicular micro-environment which could be used to predict IVF prognosis, and improve female infertility management.

Identification and characterization of human ovary-derived circular RNAs and their potential roles in ovarian aging

“…For example, peripheral blood-derived circular RNA100783 could regulate phosphoprotein expression during CD28 related CD8(+) T cell aging, indicating its potential role as a novel biomarker for global immunosenescence [ 33 ]. Cheng et al [ 34 ] revealed that the elevated expression of circRNA_103827 and circRNA_104816 derived from human GCs from follicular fluid were closely associated with a declining ovarian reserve and adverse reproductive outcomes. Moreover, circRNA_103827 has predictive performance for pregnancy outcomes after assisted reproductive technique cycles, indicating its potential as a new biomarker for IVF outcomes.…”

The circular RNA aplacirc_13267 upregulates duck granulosa cell apoptosis by the apla‐miR‐1‐13/THBS1 signaling pathway

“…Recently, with the rapid development of bioinformatics techniques and deep sequencing, more functional circRNAs have been discovered in animal follicle development (Shen et al, 2019). Previous studies have shown that the circRNAs of follicles and GCs in goats, chicken, and humans were detected (J. Cheng et al, 2017; Shen et al, 2019; Tao et al, 2017). However, data associated with the function of circRNAs in ducks are still less reported, especially regarding follicle development.…”

“…Previous studies have shown that the circRNAs of follicles and GCs in goats, chicken, and humans were detected (J. Cheng et al, 2017;Tao et al, 2017). However, data associated with the function of circRNAs in ducks are still less reported, especially regarding follicle development.…”

Clinical significances of hsa_circ_0067582 and hsa_circ_0005758 in gastric cancer tissues

“…6 Many studies showed that circRNAs play important roles in human diseases, such as circ-Foxo3 in cardiac senescence, ciR-7 in Alzheimer's disease, and cir-ITCH in colorectal cancer. 7 CircRNAs exert distinct effects, both as tumor suppressors and oncogenes. 6 CircRNAs appear to be more often down-regulated in tumor tissues compared to normal tissues.…”