Data from: 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 levels of H3K27me3 in the female placenta create
resilience to the altered hypothalamic programming associated with
prenatal stress exposure.

尽管疾病表现中的性别偏向已得到充分记载，但介导疾病易感性或抵抗力的机制仍不明确。宫内损伤对男性后代产生有害健康结果的可能性高于女性。在我们的产前应激小鼠模型中，雄性后代表现出体重长期失调及下丘脑-垂体-肾上腺应激轴功能障碍——这些是男性偏向性神经发育障碍的内表型。胎盘功能对健康胎儿发育至关重要，我们此前的研究表明，胎盘O-连接N-乙酰葡萄糖胺转移酶（OGT）的性别差异介导了产前应激对神经发育编程的影响。本研究表明，OGT性别差异导致产前损伤易感性差异的机制之一，是通过建立性别特异性滋养层基因表达模式，以及调控经典的抑制性表观遗传修饰H3K27me3。我们证实，雌性胎盘内高水平的H3K27me3可增强其对产前应激暴露相关下丘脑编程改变的抵抗力。