Identification of human imprint regulatory regions associated with obesity in children

摘要/摘要 过去30年来肥胖患病率的迅速增加导致了表观遗传学的假设 机制介导环境线索和肥胖结果之间的关联。然而，表观遗传 改变肥胖风险的区域仍然是未知的。我们缺乏一个全面衡量的筛选工具， 表观遗传修饰，并且在任何感兴趣的疾病或暴露中进行这种筛查的能力将是非常重要的。 对广泛的人类健康研究具有很大的实用性。对人类表观遗传学数据的解释 使用基因组规模的方法受到三个主要障碍的阻碍。首先，现有数据主要基于 关于一生中不同年龄段通过横断面获得的DNA中测量的甲基化差异 当然，DNA甲基化标记随年龄而变化。第二，在外周细胞类型中进行的测量 从其他健康个体获得的细胞类型并不总是与那些有助于 肥胖症，因为已知甲基化因细胞和组织类型而异。第三，表观遗传标记的改变可以是 肥胖引起的，这种暴露和结果之间的时间模糊性使因果推理复杂化。 据估计，表观遗传调控的印迹基因占人类基因组的1-2%（200-400个基因）。 基因组，并在早期胚胎的发育至关重要。印迹基因的单等位基因表达是 由先前建立的印记控制区（ICR）的起源特异性DNA甲基化的亲本调控 胚层规格和维持在体细胞组织在整个生命。因此，甲基化标记 调节这些基因的表达是功能相关的，并且是相似的，不管细胞类型如何， 个人，年龄。ICR的这些独特特征为疾病的表观遗传学研究提供了很好的机会。 为了克服目前此类研究的障碍，我们将全面鉴定调控DNA 甲基化印记基因，创造了“印记组”的第一稿。综合识别 ICRs是必要的，因为虽然多达400个基因已被预测为印记，只有~30 ICRs 已知有70-80个基因。我们的首要目标是使用全基因组方法系统地 使用各种各样的样品鉴定所有ICR，包括来自 年龄跨度大。以这种方式，鉴定可以仅限于差异甲基化， 在细胞类型、性别和年龄上都是一致的--这是ICR的标志。压印机面板随后将 评估与肥胖的关系，以将脐带血中的甲基化与随后的肥胖发作相关联， 童年.完全识别改变的印记规则将为预期风险提供标记 评估，确定导致肥胖发展的机制，并为未来的工作提供信息， 影响肥胖的环境暴露。该测定也将适用于任何疾病或病症。 暴露，为了解这些条件创造新的机会。

Summary/Abstract The rapid increase in the prevalence of obesity in the last 30 years has led to the hypothesis that epigenetic mechanisms mediate associations between environmental cues and obesity outcomes. However, epigenetic regions that alter obesity risk are still unknown. We lack a screening tool for comprehensive measurement of epigenetic modifications, and the ability for such a screen in any disease or exposure of interest would be of great utility for a broad range of human health studies. The interpretation of human epigenetic data generated using genome-scale approaches is hampered by three main obstacles. First, available data are largely based on methylation differences measured in DNA obtained cross-sectionally at different ages throughout the life course, yet DNA methylation marks vary by age. Second, measurements made in the peripheral cell types accessible from otherwise healthy individuals do not always correlate with those of cell types that contribute to obesity, as methylation is known to vary by cell and tissue types. Third, alteration to epigenetic marks can be caused by obesity, and this temporal ambiguity between exposure and outcome complicates causal inference. Epigenetically regulated imprinted genes are estimated to comprise 1-2% (200-400 genes) of the human genome, and are critical in the development of the early embryo. Monoallelic expression of imprinted genes is regulated by parent of origin specific DNA methylation at imprint control regions (ICRs) that is established prior to germ-layer specification and maintained in somatic tissues throughout life. Therefore, methylation marks regulating the expression of these genes are functionally relevant, and are similar, regardless of cell type, individual, and age. These unique features of ICRs provide a great opportunity for epigenetic studies of disease. To overcome the current obstacles to such studies, we will comprehensively identify regulatory DNA methylation for imprinted genes, creating the first draft of the “imprintome”. The comprehensive identification ICRs is necessary, because while as many as 400 genes have been predicted to be imprinted, only ~30 ICRs regulating 70-80 genes are known. Our overarching goal is to use genome-wide approaches to systematically identify all ICRs using a wide variety of samples, including multiple cell types from males and females from a wide age range. In this way, identification can be restricted to only that differential methylation which is consistent across cell type, sex, and age – the hallmark of an ICR. The imprintome panel will then be evaluated in relation to obesity, to correlate methylation in umbilical cord blood to the onset of obesity later in childhood. Complete identification of altered imprint regulation will provide markers for prospective risk assessment, identify mechanisms contributing to obesity development, and inform future work into environmental exposures affecting obesity. This assay would also then be applicable to any disease or exposure, creating new opportunities for understanding these conditions.