Placental CpG methylation of infants born extremely preterm predicts cognitive impairment later in life

Background
The placenta is the central regulator of maternal and fetal interactions. Perturbations of placental structure and function have been associated with adverse neurodevelopmental outcomes later in life. Placental CpG methylation represents an epigenetic modification with the potential to impact placental function, fetal development and child health later in life.
Study design
Genome-wide placental CpG methylation levels were compared between spontaneous versus indicated deliveries from extremely preterm births (EPTBs) (n = 84). The association between the identified differentially methylated CpG sites and neurocognitive outcome at ten years of age was then evaluated.
Results
Spontaneous EPTB was associated with differential CpG methylation levels in 250 CpG sites (217 unique genes) with the majority displaying hypermethylation. The identified genes are known to play a role in neurodevelopment and are enriched for basic helix-loop-helix transcription factor binding sites. The placental CpG methylation levels for 17 of these sites predicted cognitive function at ten years of age.
Conclusion
A hypermethylation signature is present in DNA from placentas in infants with spontaneous EPTB. CpG methylation levels of critical neurodevelopment genes in the placenta predicted later life cognitive function, supporting the developmental origins of health and disease hypothesis (DOHaD).

研究背景
胎盘是介导母体与胎儿交互作用的核心调控因子。胎盘结构与功能异常与子代日后的不良神经发育结局密切相关。胎盘CpG甲基化（CpG methylation）是一种表观遗传修饰，可影响胎盘功能、胎儿发育以及子代日后的健康状况。

研究设计
本研究纳入84例极早早产儿（extremely preterm births, EPTB），比较了其自然临产分娩与医源性指征分娩的胎盘全基因组CpG甲基化水平；随后评估了所鉴定的差异甲基化CpG位点与受试者10岁时的神经认知结局之间的关联。

研究结果
极早早产儿自然临产分娩组在250个CpG位点（对应217个独特基因）中出现了CpG甲基化水平差异，其中绝大多数表现为高甲基化。所鉴定的基因均已知参与神经发育过程，且显著富集碱性螺旋-环-螺旋（basic helix-loop-helix）转录因子结合位点。其中17个位点的胎盘CpG甲基化水平可预测受试者10岁时的认知功能。

研究结论
极早早产儿自然临产分娩组的胎盘DNA中存在高甲基化特征。胎盘中关键神经发育基因的CpG甲基化水平可预测子代日后的认知功能，这一结果支持了健康与疾病的发育起源（developmental origins of health and disease, DOHaD）假说。