N6-methyladenosine dynamics in placental development and trophoblast functions, and its potential role in placental diseases

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2024-10, Vol.1870 (7), p.167290, Article 167290
• Main Authors: Wu, Suwen, Liu, Ketong, Cui, Yutong, Zhou, Bingyan, Zhao, Huanqiang, Xiao, Xirong, Zhou, Qiongjie, Ma, Duan, Li, Xiaotian
• Format: Article
• Language: English
• Subjects: Epigenetic modifications; N6-methyladenosine; Placental development; Trophoblast function; WTAP
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167290

N6-methyladenosine (m6A) is the most abundant modification controlling RNA metabolism and cellular functions, but its roles in placental development are still poorly understood. Here, we characterized the synchronization of m6A modifications and placental functions by mapping the m6A methylome in human placentas (n = 3, each trimester), revealing that the dynamic patterns of m6A were associated with gene expression homeostasis and different biological pathways in placental development. Then, we generated trophoblast-specific knockout mice of Wtap, a critical component of methyltransferase complex, and demonstrated that Wtap was essential for trophoblast proliferation, placentation and perinatal growth. Further in vitro experiments which includes cell viability assays and series molecular binding assays demonstrated that WTAP-m6A-IGF2BP3 axis regulated the RNA stability and translation of Anillin (ANLN) and VEGFA, promoting trophoblast proliferation and secretion. Dysregulation of this regulatory axis was observed in placentas from pregnancies with fetal growth restriction (FGR) or preeclampsia, revealing the pathogenic effects of imbalanced m6A modifications. Therefore, our findings provide novel insights into the functions and regulatory mechanisms of m6A modifications in placental development and placental-related gestational diseases. •This study aims to characterize the synchronization of m6A modifications and placental functions across normal pregnancy.•We depict a temporally dynamic profile of RNA m6A in placentation.•Trophoblast-specific knockout mice of Wtap exhibited deficiencies in placental development.•Dysregulation of m6A-regulatory axis was observed in placental dysfunctions.