Conserved Fetal Epigenomic Signatures in a Primate Model of Maternal Obesity

描述（由申请人提供）：根据成人疾病的发展起源假说，妊娠早期出生后环境的扰动影响成人疾病的发展。来自我们实验室和其他实验室的数据共同表明，这是通过表观遗传改变“组蛋白密码”的基因表达重编程而发生的。什么构成了“组蛋白密码”？虽然几乎所有个体的细胞都具有几乎相同的基因组结构，但表型最终由基因表达谱决定。基因表达主要通过两种机制维持：(1)转录因子和转录后修饰因子；(2)表观遗传修饰，特别是DNA甲基化和核心组蛋白修饰。研究正在迅速证明表观遗传密码对人类正常发育的重要性，以及当表观遗传密码或机械故障时发生的疾病负担。然而，它仍然是表观基因组学研究领域的一个基本问题，胎儿表观基因组是否以及如何随着母亲表型和饮食改变而变化，以及它是否真的能预测以后的生活疾病状态（如肥胖和糖尿病）。我们的实验室致力于研究子宫内环境对胎儿表观遗传变化的影响。我们已经开发了一种非人类灵长类动物肥胖模型，现在已经是第九年了，用来研究胎儿组蛋白密码。我们已经证明，是母体的高脂肪饮食摄入（而不是母体肥胖本身）导致了下丘脑神经回路和外周神经带束的异常发育，而下丘脑神经回路和外周神经带束对胎儿葡萄糖和脂质稳态的调节是不可或缺的；这些改变伴随着染色质结构的表观遗传改变，导致胎儿基因表达的重编程。作为这项工作的结果，我们现在独特地准备应用伴随发展的高通量测序技术和先进的分析方法来破译灵长类动物表观基因组被修饰的分子手段。在本提案中，我们介绍了这些技术（ChIP-Seq， RNA-Seq和定制CpG阵列）在胎儿灵长类动物肝脏表观基因组全基因组表征中的应用。我们的研究与公共卫生相关，因为它们将阐明母体饮食如何影响灵长类动物婴儿的发育，以及这些变化是否会增加以后肥胖的风险。

DESCRIPTION (provided by applicant): According to the Developmental Origins of Adult Disease Hypothesis, perturbations in the gestational orearly postnatal environment influence the development of adult diseases. Data from our laboratory and others collectively suggest that this occurs with reprogramming of gene expression via epigenetic changes to the 'histone code'. What constitutes the 'histone code'? While almost all cells of an individual bear near identical genomic constitutions, phenotype is ultimately determined by the gene expression profile. Gene expression is maintained by two major mechanisms: (1) transcription factors and post-transcriptional modifiers, and (2) epigenetic modifications, in particular DNA methylation and core-histone modifications. Research is rapidly demonstrating the importance of the epigenetic code to normal human development as well as the burden of disease that occurs when the epigenetic code or machinery malfunctions. However, it remains a fundamental question in the field of epigenomics research if and how the fetal epigenome varies in response to maternal phenotype and diet modifications, and if it is truly predictive of later in life disease states (suh as obesity and diabetes). Our lab is dedicated to studying the effects of the in utero milieu on epigenetic changes in the fetus. We have developed a non-human primate model of obesity, now in its ninth year, to study the fetal histone code. We have shown that it is maternal high fat diet consumption (rather than maternal obesity per se) which results in abnormal development of both the hypothalamic neurocircuitry and peripheral entrainment integral to regulation of fetal glucose and lipid homeostasis; these alterations are accompanied by epigenetic changes in chromatin structure resulting in reprogramming of fetal gene expression. As a result of this work, we are now uniquely poised to apply concomitantly developed high throughput sequencing technologies with advanced analytical approaches to decipher the molecular means by which the primate epigenome is modified. In this proposal we present our application of these technologies (ChIP-Seq, RNA-Seq, and custom CpG arrays) in our genome wide characterization of the fetal primate hepatic epigenome. Our studies are relevant to public health since they will clarify how the maternal diet influences the developing primate infant, and whether these changes increase the risk of later in life obesity.