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

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

  • Biochim Biophys Acta Mol Basis Dis. 2024 Jun 11;1870(7):167290. doi: 10.1016/j.bbadis.2024.167290.
Suwen Wu 1,  Ketong Liu 2,  Yutong Cui 2,  Bingyan Zhou 3,  Huanqiang Zhao 4,  Xirong Xiao 2,  Qiongjie Zhou 5,  Duan Ma 6,  Xiaotian Li 7
Affiliations

Affiliations

  • 1 Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
  • 2 Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
  • 3 Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, China.
  • 4 Shenzhen Maternity and Children Health Care Hospital, Shenzhen, China.
  • 5 Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. Electronic address: zhouqiongjie1732@fckyy.org.cn.
  • 6 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: duanma@fudan.edu.cn.
  • 7 Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China; Shenzhen Maternity and Children Health Care Hospital, Shenzhen, China. Electronic address: xiaotianli555@163.com.
PMID: 38866113 DOI: 10.1016/j.bbadis.2024.167290
Abstract

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.

Keywords

Epigenetic modifications; N6-methyladenosine; Placental development; Trophoblast function; WTAP.

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