circRNA N6-methyladenosine methylation in preeclampsia and the potential role of N6-methyladenosine-modified circPAPPA2 in trophoblast invasion

Abstract

Here, we performed N6-methyladenosine (m6A) RNA sequencing to determine the circRNA m6A methylation changes in the placentas during the pathogenesis of preeclampsia (PE). We verified the expression of the circRNA circPAPPA2 using quantitative reverse transcription-PCR. An invasion assay was carried out to identify the role of circPAPPA2 in the development of PE. Mechanistically, we investigated the cause of the altered m6A modification of circPAPPA2 through overexpression and knockdown cell experiments, RNA immunoprecipitation, fluorescence in situ hybridization and RNA stability experiments. We found that increases in m6A-modified circRNAs are prevalent in PE placentas and that the main changes in methylation occur in the 3’UTR and near the start codon, implicating the involvement of these changes in PE development. We also found that the levels of circPAPPA2 are decreased but that m6A modification is augmented. Furthermore, we discovered that methyltransferase‑like 14 (METTL14) increases the level of circPAPPA2 m6A methylation and that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) maintains circPAPPA2 stability. Decreases in IGF2BP3 levels lead to declines in circPAPPA2 levels. In summary, we provide a new vision and strategy for the study of PE pathology and report that placental circRNA m6A modification appears to be an important regulatory mechanism.

IGF2BP2 enhances LincRNA01116 stability via m6A: A potential biomarker and therapeutic target for patients with pre‐eclampsia

“…Previous studies have shown that m 6 A alterations affect mRNA or miRNA targeting and could be associated with the progression of various diseases 31,32 . Several previous studies support that m 6 A RNA methylation in the placental trophoblast of PE provides a novel posttranscriptional mechanism for aberrant m 6 A modification in PE, which may contribute to preeclamptic trophoblast dysfunction 16,18 .…”

Methyltransferase-like 3 aggravates endoplasmic reticulum stress in preeclampsia by targeting TMBIM6 in YTHDF2-dependent manner

“…Up to now, PE has been an intractable complication associated with pregnancy and brought about increasing mortality in both pregnant women and fetuses (Mol et al 2016). Previous studies indicated that PE was always accompanied by trophoblast dysfunction due to ER stress, increased ROS production, and apoptosis rate (Capatina et al 2021), and m 6 A modification could play an important role in this dysfunction (Taniguchi et al 2020;Zhang et al 2021b). While aberrant m 6 A modification for trophoblast dysfunction during PE has been observed (Wang et al 2020;Gu et al 2021;Guo et al 2022), there are no reports on the relationship between the ER stress state in trophoblasts and m 6 A modification in PE.…”

N6-methyladenosine modifications in maternal-fetal crosstalk and gestational diseases

“…This rapid development makes the prenatal period particularly vulnerable because of the complicated trajectory of cells and environmental perturbations. To maintain placental homeostasis, several epigenetic mechanisms have been highlighted to drive short- and long-term gene expression changes ( Nelissen et al, 2011 ), including DNA methylation ( Koukoura et al, 2012 ; Lorincz and Schubeler, 2017 ), histone modifications ( Meister et al, 2021 ), non-coding RNAs ( Du et al, 2021 ; Zhang et al, 2021 ; Zarkovic et al, 2022 ), and also RNA methylation ( Mu et al, 2022 ). As one of the most prevalent internal modifications in RNAs, N6-methyladenosine (m 6 A) extensively regulate RNA metabolism ( Jia et al, 2022 ).…”