O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development
O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development
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DOI：
10.1073/pnas.1300065110
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发表时间：
2013-03-26
影响因子：
11.1
通讯作者：
Bale, Tracy L.
中科院分区：
文献类型：
--
作者：
Howerton, Christopher L.;Morgan, Christopher P.;Bale, Tracy L.
母亲压力是神经发育障碍的关键风险因素，包括精神分裂症和自闭症，这些疾病在表现率、发病年龄和症状严重程度上往往表现出性别偏见。胎盘是一种内分泌组织，在应对宫内环境的扰动中起着重要的中介作用，可用于诊断目的，可能提供预测疾病的生物标志物。因此，我们使用全基因组阵列方法筛选妊娠期间胎盘表达的候选基因，这些候选基因在小鼠中具有性别偏见和应激反应，并转化为人类组织。我们确定了O-linked-N-acetylglucosamine (O-GlcNAc) transferase (OGT)，这是一种X-linked基因，在调节参与染色质重塑的蛋白质中很重要，符合这些标准。男性的OGT及其生化标记o - glcn酰化水平均显著降低，并因产前应激而进一步降低。对人类胎盘组织的检查发现了与X染色体剂量有关的类似模式。为了证明胎盘OGT在神经发育中的重要性，我们发现胎盘特异性半合子OGT小鼠的新生儿大脑中下丘脑基因表达和广泛的表观遗传microrna环境发生了实质性改变。这些研究发现，OGT是一种有希望的胎盘生物标志物，可能与神经发育中的性别偏向结果有关。
Maternal stress is a key risk factor for neurodevelopmental disorders, including schizophrenia and autism, which often exhibit a sex bias in rates of presentation, age of onset, and symptom severity. The placenta is an endocrine tissue that functions as an important mediator in responding to perturbations in the intrauterine environment and is accessible for diagnostic purposes, potentially providing biomarkers predictive of disease. Therefore, we have used a genome-wide array approach to screen placental expression across pregnancy for gene candidates that are sex-biased and stress-responsive in mice and translate to human tissue. We identifed O-linked-N-acetylglucosamine (O-GlcNAc) transferase (OGT), an X-linked gene important in regulating proteins involved in chromatin remodeling, as fitting these criteria. Levels of both OGT and its biochemical mark, O-GlcNAcylation, were significantly lower in males and further reduced by prenatal stress. Examination of human placental tissue found similar patterns related to X chromosome dosage. As a demonstration of the importance of placental OGT in neurodevelopment, we found that hypothalamic gene expression and the broad epigeneticmicroRNA environment in the neonatal brain of placental-specific hemizygous OGT mice was substantially altered. These studies identified OGT as a promising placental biomarker of maternal stress exposure that may relate to sex-biased outcomes in neurodevelopment.