Characterization of the Fetal Primate Epigenome and Metabolome Under In Utero

项目摘要。肥胖会造成巨大的社会、经济和健康负担。肥胖率是 在儿童(婴儿到年轻人)中不成比例地升级。这种快速增长不太可能是由于 单独的环境或遗传因素。我们实验室和其他机构积累的证据表明，成年人 代谢性疾病起源于子宫，很可能通过基因表达的重新编程而发生 染色质结构的表观遗传变化(一种改变的“组蛋白密码”)。有趣的是，我们在一个 宫内生长受限(IUGR)啮齿类动物跨代模型的建立 营养素，但其热量含量没有改变，可以预防成人代谢性疾病，并与 取消重新编程的基因表达。然而，尽管在啮齿动物中建立的这种模型 证明组蛋白密码中的胎儿改变参与了组蛋白的持久性和运输 改变了出生后的表型，关于母体饮食和由此导致的肥胖对灵长类动物的影响知之甚少 胎儿生物学。我们假设非人类灵长类动物的高脂肪饮食会引起肝脏的变化。 染色质结构导致对儿童和儿童发育至关重要的胎儿基因表达改变 成人肥胖。根据我们的初步数据，这项建议的重点是应用开发的高吞吐量 破译灵长类表观基因组和代谢组的技术(比较表观基因组学和代谢组学) 然后在肥胖的母体环境中测量补充剂的差异性影响 表观基因组改变和由此导致的疾病。这部小说的创新和意义在于它的潜力 提供(1)对母体高脂肪饮食重新编程的机制的扩展理解 灵长类基因表达和(2)简单干预(既不节食也不补充基本营养 行为调整)，具有巨大的潜在影响，因为目前的肥胖流行和缺乏 有效的疗法。

Project Summary. Obesity causes substantial social, economic and health burdens. The rate of obesity is escalating disproportionately in children (infants to young adults). This rapid increase is unlikely to be due to environment or genetics alone. Accumulating evidence from our laboratory and others suggests that adult metabolic diseases originate in utero, and likely occur through the reprogramming of gene expression via epigenetic changes in chromatin structure (an altered "histone code"). Of interest, we have observed in a rodent transgenerational model of intrauterine growth restriction (IUGR) that a diet supplemented with essential nutrients, yet unaltered in its caloric content, prevents adult metabolic disease and is associated with abrogation of reprogrammed gene expression. However, although such established models in rodents demonstrate that fetal alterations in the histone code are involved in the persistence and conveyance of the altered postnatal phenotype, little is known about the effects of maternal diet and resultant obesity on primate fetal biology. We hypothesized that a high fat diet in non-human primates would induce changes in hepatic chromatin structure resulting in altered expression of fetal genes critical to the development of childhood and adult obesity. Based on our preliminary data, the focus of this proposal is to apply developed high throughput technology (comparative epigenomics and metabolomics) to decipher the primate epigenome and metabolome in the obese maternal environment and then measure the impact of supplementation on the differentially altered epigenome and resultant disease. The novel innovation and significance resides within its potential to provide (1) an expanded understanding of the mechanism through which a maternal high fat diet reprograms primate gene expression and (2) a simple intervention (essential nutrient supplementation with neither diet nor behavioral modification) with tremendous potential impact given the current obesity epidemic and the lack of efficacious therapeutics.