TET1 modulates trophoblast function by regulation of ODC1 in preeclampsia

Preeclampsia (PE) is a pregnancy-specific disease that seriously endangers the health of the pregnant woman and the fetus. DNA hydroxymethylation, an epigenetic modification, plays crucial roles in the development of PE. However, the molecular mechanism remains to be elucidated. TET1 is a DNA demethylase that regulates placental trophoblast function. Herein, we investigated the role of TET1 in PE occurrence. Firstly, we confirmed that the 5-methylcytosine (5-mC) levels were reduced in placental tissues from human PE patients and a mouse PE model, while TET1 expression was upregulated. In an oxidative stress model of HTR8/SVneo cells, knockdown of TET1 partially restored the impaired cell invasion and migration caused by H₂O₂. To elucidate the mechanism, bioinformatics analysis of TET1-knockdown RNA Sequencing and ChIP-seq data identified ornithine decarboxylase (ODC1), a rate-limiting enzyme in the polyamine biosynthesis, as a potential target. Similarly, knockdown of ODC1 alleviated the H₂O₂-induced dysfunction in HTR8/SVneo cells. Moreover, the CUT&RUN and dual-luciferase assays revealed that TET1 regulates the expression of ODC1 by affecting the methylation level of its promoter. Collectively, these results demonstrate that TET1-mediated DNA hydroxymethylation is associated with the occurrence of PE. This is partially attributed to the regulation of ODC1 through altered promoter methylation, which leads to trophoblast dysfunction and contributes to the development of PE.

DNA hydroxymethylation; ODC1; Preeclampsia; TET1; Trophoblast.