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。儿童(从婴儿到年轻人)的肥胖率正在不成比例地上升。这种快速增长不太可能仅仅是环境或遗传因素造成的。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，可能通过染色质结构的表观遗传改变(一种改变的“组蛋白密码”)重新编程基因表达而发生。有趣的是，我们在宫内生长受限(IUGR)的啮齿动物跨代模型中观察到，补充必要的 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有关。然而，尽管在啮齿动物身上建立的这种模型表明，组蛋白密码中的胎儿变化与出生后改变的表型的持续和传递有关，但关于母体饮食和由此导致的肥胖对灵长类胎儿生物学的影响知之甚少。我们假设，非人类灵长类动物的高脂肪饮食会导致肝脏染色质结构的变化，导致对儿童和成人肥胖的发展至关重要的胎儿基因的表达发生变化。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 技术(比较表观基因组学和代谢组学)，以破译肥胖母亲环境中的灵长类表观基因组和代谢组，然后衡量补充剂对差异变化的表观基因组和由此产生的疾病的影响。这部小说的创新和意义在于它的潜力 提供(1)扩大对母体高脂肪饮食改变灵长类基因表达的机制的理解，以及(2)在当前肥胖流行和缺乏有效治疗的情况下，具有巨大潜在影响的简单干预(既不饮食也不改变行为的基本营养补充)。

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.