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Developmentally Delayed Epigenetic Reprogramming Underlying the Pathogenesis of Preeclampsia

By Wei A He, Yuan Wei, Xiaoli Gong, Luyuan Chang, Wan Jin, Ke Liu, Xinghuan Wang, Yu Xiao, Wenjing Zhang, Qiong Chen, Kai Wu, Lili Liang, Jia Liu, Yawen Chen, Huanhuan Guo, Wenhao Chen, Jiexia Yang, Yiming Qi, Wei Dong, Meng Fu, Xiaojuan Li, Jiusi Liu, Yi Zhang, Aihua Yin

Posted 10 May 2020
bioRxiv DOI: 10.1101/2020.05.08.085290

Preeclampsia, a life-threatening pregnancy complication characterized by hypertension and multiorgan damage, affects 2-5% of pregnancies and causes 76,000 deaths per year. Most preeclampsia associated syndromes immediately dispel after removal of placenta, indicating a casual role of placenta in the pathogenesis. Failed transformation of spiral artery due to insufficient invasion and excessive apoptosis of trophoblast suggested developmental defects in preeclampsia placenta. However, the underlying molecular mechanisms that affected placenta development in preeclampsia remained elusive. Here we show that, in preeclampsia placenta, the epigenetic landscape formed during extraembryonic tissue differentiation was disrupted: dramatic chromatin accessibility shift affected known and novel genes implicated in preeclampsia. DNA methylation defects in preeclampsia affected lineage-defining PcG-controlled loci in trophectoderm. LTR12 retrotransposons associated with VCT/SCT-specific genes were hypermethylated. Meanwhile, hundreds of PcG-regulated EVT-specific gene promoters, which otherwise undergone post-ZGA extraembryonic-tissue-specific de novo methylation, were hypomethylated and hyper-activated. Together, these epigenetic defects resulted in placenta developmental delay in preeclampsia. The defective methylation pattern could be detected in serum cfDNA, and could be used to accurately predict preeclampsia at early pregnancy weeks in independent validation cohorts. Our data suggests that the preeclampsia placenta represents a stalled state of epigenetic reprogramming en route of development from trophectoderm to normal placenta. ### Competing Interest Statement Provisional patents were filed for the single-stranded NGS library preparation method Tequila 7N (WO 2020/073748) and the method for using cell-free DNA methylation pattern to predict placenta development status and pregnancy outcome (202010084924.X).

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