Placental ischemia disrupts DNA methylation patterns in distal regulatory regions in rats

Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality worldwide. However, the impact of PE on the organization of the functional architecture of the placental methylome remains largely unknown. We performed whole-genome bisulfite sequencing of placental DNA and applied a Hidden Markov Model to investigate epigenome-wide alterations in functional structures, including partially methylated domains (PMDs), low-methylated regions (LMRs), and unmethylated regions (UMRs), in a reduced uterine perfusion pressure (RUPP) rat model of PE. The remarkable similarity we observed between the rat and human placental DNA methylomes suggests that the RUPP rat model is appropriate to elucidate the epigenetic mechanisms underlying human PE. The notable changes in PMDs indicate RUPP-induced perturbation of the stressed placental methylome. This was probably regulated via modulation of the epigenetic modifier expression, including significant downregulation of Dnmt1 and Dnmt3a and upregulation of Tet2. More importantly, changes in RUPP-induced DNA methylation occurred predominately in LMRs (80 %), which represent active enhancers, rather than in canonical UMRs (3 %), which represent promoters, suggesting that placental ischemia disrupts enhancer DNA methylation. Our findings emphasize the role of enhancer methylation in response to PE, corroborating discoveries in human PE studies. We suggest paying more attention to enhancer regions in future studies on PE.