RNA Demethylase FTO Mediated RNA m6A Modification Is Involved in Maintaining Maternal-Fetal Interface in Spontaneous Abortion

Weiyu Qiu; Yuexi Zhou; Haiwang Wu; Xiaoli Lv; Lilin Yang; Zhenxing Ren; He Tian; Qingying Yu; Jing Li; Weixian Lin; Ling Zhao; Songping Luo; Jie Gao

doi:10.3389/fcell.2021.617172

RNA Demethylase FTO Mediated RNA m⁶A Modification Is Involved in Maintaining Maternal-Fetal Interface in Spontaneous Abortion

Front Cell Dev Biol. 2021 Jul 19:9:617172. doi: 10.3389/fcell.2021.617172. eCollection 2021.

Authors

Weiyu Qiu¹, Yuexi Zhou², Haiwang Wu¹, Xiaoli Lv², Lilin Yang¹, Zhenxing Ren³, He Tian², Qingying Yu², Jing Li², Weixian Lin², Ling Zhao⁴, Songping Luo¹, Jie Gao¹

Affiliations

¹ Department of Gynecology, The Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
² Guangzhou University of Chinese Medicine, Guangzhou, China.
³ Shanghai Key Laboratory of Diabetes Mellitus, Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
⁴ Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

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.

Keywords: FTO; RNA methylation; m6A; spontaneous abortion; villous.