The Role of circRNA‐SETD2/miR‐519a/PTEN Axis in Fetal Birth Weight through Regulating Trophoblast Proliferation

Abstract

Abnormal birth weight is the one of the major causes of adulthood diseases such as obesity, metabolic syndrome, cardiovascular disease, type 2 diabetes, and hypertension. Accumulating evidence has suggested that the placental trophoblast is one of the most important reasons that influence birth weight. Our previous study showed that miR-519a are correlated with low fetal birth weight through regulating trophoblast proliferation. To further clarify the detailed mechanisms on how it is regulated, we screened the placental-specific circular RNAs (circRNAs) via microarray assay. The result identified that circ-SETD2 was highly expressed in the placenta of the patients with fetal macrosomia compared with healthy donors. Furthermore, bioinformatic analyses and the luciferase reporter assay revealed that miR-519a possessing the binding sites for both circ-SETD2 and phosphate and tensin homolog was deleted on chromosome 10 (PTEN). Interestingly, upregulation of circ-SETD2 enhanced the proliferation and invasion of the human trophoblast-like cell line HTR8/SVneo cell. A parallel study performed by Western blotting showed that overexpression of circ-SETD2 reduced miR-519a levels and increased PTEN levels in HTR8/SVneo cells. Importantly, the enhancement of HTR8/SVneo cell activity by circ-SETD2 overexpression was nullified when the cells were cotransfected by circ-SETD2 and miR-519a, suggesting the involvement of the circ-SETD2/miR-519a/PTEN axis in trophoblast activity. Taken together, we illustrate the role of circ-SETD2, as an upstream signaling of miR-519a/PTEN, in placenta development via regulating trophoblast proliferation and invasion. These findings improve our understanding of the mechanisms of progression of fetal macrosomia and will guide future development of therapeutic strategies against the disease by targeting the circ-SETD2/miR-519a/PTEN axis.

Emerging roles of circular RNAs in osteoporosis

“…19 , 33 , 34 , 35 , 36 Increasing studies showed that circRNAs involved in the development of many diseases including cancers, neurological diseases, congenital diseases, intervertebral disc degeneration and endocrine diseases. 37 , 38 , 39 , 40 , 41 , 42 , 43 Recently, studies indicated that circRNAs also play important roles in osteoporosis. 44 …”

Non-coding RNAs: The link between maternal malnutrition and offspring metabolism

“…However, circRNAs are mainly considered as miRNA inhibitors (or “sponges”) ( 164 ), and then regulate gene expression at post-transcriptional levels. So they explored the downstream target of circRNA-SETD2 in cell experiment, verified that the circRNA-SETD2/miR-519a/PTEN axis ( 163 ). And miR-519a has been mentioned previously to be involved in regulating birth weight.…”

“…Of note, in 2020, instead of investigating the LBW groups, Wang et al ( 163 ) studied miRNAs in the placenta of macrosomia, finding that circRNA-SETD2 (hsa-circRNA-103345) is upregulated. Compared with miRNAs, the mechanism of circRNAs is not fully understood and there are some controversies.…”

Functional Role of circRNAs in the Regulation of Fetal Development, Muscle Development, and Lactation in Livestock

“…Most circRNAs can perform specific dynamic regulation during embryonic development and are mainly involved in the regulation of material metabolic pathways in early embryonic development [15]. 3 BioMed Research International detect the expression of circRNAs [14]. They found that the sow's quantity and complexity of circRNAs expression were most obvious in the cortex at the 60th day of pregnancy of the 13,854 expressed genes detected; 2,195 genes expressed 4,634 unique circRNAs; In addition, Hirotsu et al found that the expression of circRIMS2 in the embryonic pig cortex reached a peak during development, suggesting that cir-cRNAs are one of the major factors regulating mammalian embryonic brain development [51].…”

“…In addition, studies have shown that circRNAs can regulate fetal development, and their expression is the most abundant and complex in the cerebral cortex on the 60th day of pregnancy [14][15][16]. Studies have shown that there are 10,032 circRNAs in human ocytes and embryos, a small portion of which are maternally expressed, and most of the circRNAs have been shown to be related to animal embryo development [17].…”