Placental H3K27me3 establishes female resilience to prenatal insults

Although sex biases in disease presentation are well documented, the mechanisms mediating vulnerability or resilience to diseases are unknown. In utero insults are more likely to produce detrimental health outcomes for males versus females. In our mouse model of prenatal stress, male offspring experience long-term dysregulation of body weight and hypothalamic pituitary adrenal stress axis dysfunction, endophenotypes of male-biased neurodevelopmental disorders. Placental function is critical for healthy fetal development, and we previously showed that sex differences in placental O-linked N-acetylglucosamine transferase (OGT) mediate the effects of prenatal stress on neurodevelopmental programming. Here we show that one mechanism whereby sex differences in OGT confer variation in vulnerability to prenatal insults is by establishing sex-specific trophoblast gene expression patterns and via regulation of the canonically repressive epigenetic modification, H3K27me3. We demonstrate that high...尽管疾病表现中的性别偏倚已有充分文献记载，但介导疾病易感性或抵抗性的具体机制仍不明朗。相较于雌性个体，子宫内损伤更易对雄性造成不良健康结局。在我们构建的产前应激小鼠模型中，雄性后代会出现体重长期失调与下丘脑-垂体-肾上腺应激轴功能异常，此类表型正是雄性偏向性神经发育障碍的内表型。胎盘功能对胎儿健康发育至关重要，我们前期研究已证实，胎盘组织中O-连接N-乙酰葡糖胺转移酶（O-linked N-acetylglucosamine transferase，OGT）的性别差异，可介导产前应激对神经发育编程的调控作用。本研究证实，OGT的性别差异介导产前损伤易感性差异的核心机制之一，在于构建性别特异性的滋养层细胞基因表达谱，并通过调控经典的抑制性表观遗传修饰——组蛋白H3赖氨酸27三甲基化（H3K27me3）来实现这一过程。我们证实，高……