Zheng Xiaoguo, Lian Yahan, Zhou Jing, Zhou Qian, Zhu Yu, Tang Chunhua, Zhang Ping, Zhao Xinzhi
International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai, China.
Department of Laboratory Animal Science, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
Life Sci. 2023 May 15;321:121623. doi: 10.1016/j.lfs.2023.121623. Epub 2023 Mar 29.
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.
子痫前期（PE）是全球孕产妇和胎儿发病及死亡的主要原因。然而，PE对胎盘甲基化组功能结构组织的影响在很大程度上仍不清楚。我们对胎盘DNA进行了全基因组亚硫酸氢盐测序，并应用隐马尔可夫模型研究了子痫前期子宫灌注压降低（RUPP）大鼠模型中功能结构的全表观基因组改变，包括部分甲基化结构域（PMD）、低甲基化区域（LMR）和未甲基化区域（UMR）。我们在大鼠和人类胎盘DNA甲基化组之间观察到的显著相似性表明，RUPP大鼠模型适合阐明人类PE潜在的表观遗传机制。PMD的显著变化表明RUPP诱导了应激胎盘甲基化组的扰动。这可能是通过表观遗传修饰因子表达的调节来实现的，包括Dnmt1和Dnmt3a的显著下调以及Tet2的上调。更重要的是，RUPP诱导的DNA甲基化变化主要发生在代表活性增强子的LMR（80%）中，而不是代表启动子的典型UMR（3%）中，这表明胎盘缺血会破坏增强子DNA甲基化。我们的研究结果强调了增强子甲基化在子痫前期反应中的作用，证实了人类子痫前期研究中的发现。我们建议在未来子痫前期的研究中更多地关注增强子区域。
