Demethylase FTO-mediated m6A modification of SIK1 modulates placental cytotrophoblast syncytialization in type 2 diabetes mellitus

Summary: Type 2 diabetes mellitus (T2DM) represents a common complication during pregnancy that affects fetoplacental development. We demonstrated the existence of impaired trophoblast syncytialization under hyperglycemic conditions. However, the exact mechanism remains unknown. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism of mRNA and participates in various biological processes. We described the global m6A modification pattern in T2DM placenta by the combined analysis of methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq). Both the m6A modification and expression of SIK1, which is critical for syncytialization, were significantly decreased in trophoblast exposed to hyperglycemic conditions. In addition, the m6A demethylase fat mass and obesity-associated protein (FTO) affects the expression and mRNA stability of SIK1 by binding to its 3′-untranslated region (UTR) m6A site. This work reveals that the FTO-m6A-SIK1 axis plays critical roles in regulating syncytialization in the placenta.