Abstract
The N6-methyladenosine (m6A) RNA modification regulates the expression of genes associated with various biological and pathological processes, including spontaneous abortion (SA). The aim of this study was to determine the role of the m6A demethylase fat mass and obesity (FTO)- associated protein in SA. The FTO,IGF2BP1 and IGF2BP2 mRNA levels were significantly lower in the chorionic villi obtained from spontaneously aborted pregnancies compared to that of normal pregnancies, while the expression levels of METTL3 and WTAP were significantly elevated. However, ALKBH5, YTHDF2, and IGF2BP3 were elevated with no statistical significance between groups. In addition, MDA was elevated and SOD levels were decreased in the villi tissues of the SA group compared to the normal group, which was indicative of placental oxidative stress in the former. Furthermore, the expression of FTO and HLA-G were significantly decreased in the trophoblasts of the SA patients compared to that of normal pregnant women, while that of m6A was markedly higher in the former. In addition, the HLA-G and VEGFR mRNA levels were downregulated in the SA versus the control group, and that of MMP2, MMP7, MMP9 and VEGFA were upregulated. Finally, The RIP assay showed significantly decreased levels of FTO-bound HLA-G, VEGFR and MMP9 RNA in SA patients (P < 0.05), which corresponded to an increase in transcripts enriched with the m6A antibody (P < 0.05). However, compared with normal pregnant women, the levels of HLA-G, VEGFA, VEGFR, and MMP2 mRNA bound by YTHDF2 were significantly decreased in SA patients. Compared to the normal pregnant women, both FTO- and m6A-bound MMP7 were significantly increased in SA patients (P < 0.05), but YTHDF2 almost unbound to MMP7 mRNA. In summary, the downregulation of FTO in the chorionic villi disrupts immune tolerance and angiogenesis at the maternal-fetal interface, resulting in aberrant methylation and oxidative stress that eventually leads to SA.
Highlights
Spontaneous abortion (SA) is the most common complication during the first trimester of pregnancy with an incidence rate of 10–15% (Sahin et al, 2001)
To explore whether mRNA m6A methylation is involved in the pathogenesis of spontaneous abortion (SA), we screened samples with differential fat mass and obesity (FTO) expression according to the FTO levels at enrolment and analyzed the expression of m6A “writers,” “erasers,” and “readers” in the villi tissues in the above SA patients (n = 8) and normal (n = 8) using qRT-PCR and Western blot (Figures 3H)
We found that the RNA demethylase FTO was downregulated in the chorionic villi of women that underwent SA, and correlated with oxidative stress and aberrant m6A accumulation at the maternal-fetal interface
Summary
Spontaneous abortion (SA) is the most common complication during the first trimester of pregnancy with an incidence rate of 10–15% (Sahin et al, 2001). A dysfunctional maternal-fetal interface induces oxidative stress in the placenta and the subsequent loss of placental synthetic trophoblast cells, which contributes to the pathogenesis of abortion and eclampsia (Jauniaux et al, 2003). Women with lower HLA-G expression have a higher risk of recurrent spontaneous abortion (RSA) and preeclampsia (PE) (Cecati et al, 2011), which can be attributed to increased infiltration of maternal immune cells. The placenta at the maternal-fetal interface is formed by cytotrophoblast cells (CTB), which invade the uterine tissue and migrate to the uterine spiral artery, wherein they further differentiate into endovascular trophoblast cells (Sultana et al, 2018). Trophoblast invasion and migration mediate immunotolerance and remodeling of the uterine spiral artery at the maternalfetal interface during embryo implantation (Ren et al, 2020). The post-transcriptional regulation of the above genes in the context of trophoblast function and SA have not been studied in detail
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