PON Epigenetics and Neurodevelopment in Children

描述（申请人提供）：儿童的神经行为和认知受到遗传、环境和社会因素的影响，但其分子机制尚不清楚，这促使人们对表观遗传失调的潜在作用进行研究。表观遗传机制在不改变DNA序列的情况下控制基因表达，DNA甲基化和非编码rna是两种重要的表观遗传修饰。最近的研究表明，多功能抗氧化酶对氧磷酶（PON1）与儿童神经发育不良和不良健康结局之间存在关联。我们之前在CHAMACOS研究中对墨西哥裔美国儿童及其母亲的PON1功能基因组学进行了表征，发现PON1酶活性的范围超过100倍，部分由年龄和基因型决定。尽管遗传影响了25%的PON1表达，但PON1变异性的很大一部分仍未得到解释，这表明其他因素如表观遗传的作用。事实上，一些研究表明，表观遗传失调可以影响神经发育和认知过程，如学习、记忆和神经发生。在CHAMACOS儿童中，PON1基因型和酶水平与2岁时行为和学习的变化以及7岁时较低的智商分数（认知能力的测量）有关。虽然没有关于PON1表观遗传学在基因表达和认知障碍中的作用的研究报道，但我们的初步数据显示，PON1的DNA甲基化与PON1酶水平密切相关。我们假设表观遗传机制在很大程度上导致了PON1酶水平的广泛变异和儿童神经发育不良。拟议的研究将利用通过CHAMACOS研究已经积累的PON1遗传学特征数据，丰富的生物样本收集和神经行为数据。我们的具体目标是：(1)确定怀孕期间母亲PON1 DNA甲基化谱与孩子出生和7岁时的甲基化谱之间的关系；(2)表征结合PON1的mirna的表达；(3)研究表观遗传标记与PON1表达的关系；(4)建立PON1表观遗传学对7岁儿童注意、运动功能和认知的影响。总样本量为315对母子，包括完整的神经发育评估、PON1基因和酶水平数据，以及所有拟议分析的生物样本。这项工作将作为候选易感基因研究的模型，并将解决环境分子流行病学的几个关键知识空白。了解表观遗传机制如何影响孕妇和儿童的神经发育和PON1变异，将有助于确定易感亚群。环境暴露可导致表观遗传改变，因此表征表观遗传学与疾病之间的关系将为研究表观遗传学介导基因环境相互作用奠定必要的基础。

DESCRIPTION (provided by applicant): Neurobehavior and cognition in children are affected by hereditary, environmental and social factors, but the molecular mechanisms remain largely unknown, prompting the study of the potential role of epigenetic dysregulation. Epigenetic mechanisms control gene expression without changes in DNA sequence, and DNA methylation and non-coding RNAs are two important types of epigenetic modifications. Recent studies have demonstrated associations between the multifunctional antioxidant enzyme paraoxonase (PON1) and poor neurodevelopment and adverse health outcomes in children. We previously characterized PON1 functional genomics in Mexican-American children and their mothers from the CHAMACOS study, and found a greater than 100-fold range of PON1 enzyme activities defined in part by age and genotype. Although genetics influence 25% of PON1 expression, a large portion of PON1 variability remains unexplained suggesting a role for other factors such as epigenetics. In fact, some studies have shown that epigenetic dysregulation can affect neurodevelopment and cognitive processes such as learning, memory, and neurogenesis. Among CHAMACOS children, PON1 genotype and enzyme levels were associated with changes in behavior and learning at age 2 and lower IQ scores (measure of cognitive abilities) at age 7. While no studies on the role of PON1 epigenetics on gene expression and poor cognition have been reported, our preliminary data show that DNA methylation in PON1 is strongly associated with PON1 enzyme levels. We hypothesize that epigenetic mechanisms significantly contribute to the broad variability in PON1 enzyme levels and poor neurodevelopment in children. The proposed study will take advantage of the well characterized data on PON1 genetics, rich collection of biological samples and neurobehavioral data already amassed through the CHAMACOS study. Our specific aims are to (1) determine the relationship between maternal PON1 DNA methylation profiles during pregnancy with those of their children at birth and age 7; (2) characterize expression of miRNAs that bind to PON1; (3) examine the relationship between epigenetic marks and PON1 expression; and (4) establish the effect of PON1 epigenetics on attention, motor function, and cognition in 7 year olds. The total sample size will be 315 mother-child pairs with complete neurodevelopment assessment, PON1 genetic and enzyme level data, and biological samples for all proposed analyses. This work will serve as model for studies of candidate susceptibility genes and will address several key knowledge gaps in environmental molecular epidemiology. Understanding how epigenetic mechanisms affect child neurodevelopment and PON1 variability in pregnant women and children will help to identify vulnerable sub populations. Environmental exposures can result in epigenetic alterations, thus characterization of the relationship between epigenetics and disease will establish the foundation necessary for examining mediation of gene environment interactions by epigenetics.