The role of DNA hydroxymethylation and TET enzymes in placental development and pregnancy outcome

Abstract

The placenta is a temporary organ that is essential for supporting mammalian embryo and fetal development. Understanding the molecular mechanisms underlying trophoblast differentiation and placental function may contribute to improving the diagnosis and treatment of obstetric complications. Epigenetics plays a significant role in the regulation of gene expression, particularly at imprinted genes, which are fundamental in the control of placental development. The Ten-Eleven-Translocation enzymes are part of the epigenetic machinery, converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). DNA hydroxymethylation is thought to act as an intermediate in the DNA demethylation mechanism and potentially be a stable and functionally relevant epigenetic mark on its own. The role of DNA hydroxymethylation during differentiation and development of the placenta is not fully understood but increasing knowledge in this field will help to evaluate its potential role in pregnancy complications. This review focuses on DNA hydroxymethylation and its epigenetic regulators in human and mouse placental development and function. Additionally, we address 5hmC in the context of genomic imprinting mechanism and in pregnancy complications, such as intrauterine growth restriction, preeclampsia and pregnancy loss. The cumulative findings show that DNA hydroxymethylation might be important for the control of gene expression in the placenta and suggest a dynamic role in the differentiation of trophoblast cell types during gestation.

Sex differences in DNA methylation across gestation: a large scale, cross-cohort, multi-tissue analysis

“…In addition, we here only focused on DNAm assessed on EPIC arrays. Sex could also have an impact on placental function through other epigenetic characteristics, e.g., hydroxymethylation [ 81 ], i.e. the replacement of the hydrogen atom at the C5 position in the cytosine with a hydroxymethyl-group, or histone modifications, e.g.…”

Syncytiotrophoblast Markers Are Downregulated in Placentas from Idiopathic Stillbirths

“…The STB communicates with maternal blood in the intervillous space, while the villous core is formed by extraembryonic mesenchymal cells and the foetal vasculature. As pregnancy progresses, syncytial knots form through the accumulation and budding off of syncytial nuclei in the STB [9,10], appearing transcriptionally inactive and exhibiting evidence of oxidative damage [11]. Dysregulated STB formation can compromise the integrity of the placental exchange surface and negatively impact the foetal development [12].…”