Genome-wide DNA Methylation Profiles Associated with Abnormal Intrauterine Growth

描述(申请人提供)：2型糖尿病(T2 DM)是一种与年龄相关的主要疾病，在过去20年中成年人的发病率急剧上升(1)。事实上，年轻人令人震惊的增长速度可能会保持这种陡峭的轨迹。以胎儿生长极端(宫内生长受限(IUGR)和胎龄过大(LGA))为标志的宫内环境扰动，可能对确定长期疾病易感性产生重大影响，特别是在T2 DM和心血管疾病方面(2)。尽管这一机制仍不精确，但基因表达的永久性变化涉及表观遗传调节，这可能是对胎儿状况的生物记忆，进而可能传播给后代，从而产生跨代放大。与IUGR和LGA相关的诱导成虫表型性状因个体而异，但都有代谢途径、体内平衡控制过程和组织结构和功能的变化。对慢性病的易感性和涉及多个器官系统的共性类似于随着年龄的增长而出现的对疾病抵抗力的正常下降，并表明这一过程的推进。在子宫中诱发表观遗传学改变可能预示着一个人的“年龄”，因此，对年龄相关疾病的易感性，T2 DM就是一个具体的例子。我们提出了一个新的假设，即胎儿发育期间的条件改变了非胚胎干细胞中DNA甲基化的表观遗传模式，这可能是T2 DM和其他年龄相关疾病的易感性的标志或促成因素。比较两种截然相反的宫内‘应激’(IUGR和LGA)引起的DNA甲基化情况，可能会更好地了解早期生活事件的根本影响，这些事件创造了更容易发生成人疾病的成人表型。除了潜在地阐明在其他组织中发生的变化外，在这个可访问的、至关重要的多能祖细胞群体中诱导的表观遗传修饰可能会阻碍对疾病抵抗力的下降，从而延缓与正常衰老相关的慢性病易感性的增加。我们的第一个具体目标是使用我们研究所开发的高分辨率全基因组DNA甲基化图谱分析，全面表征并提供从IUGR、LGA和适当生长的对照组新生儿脐带血中分离的单个人类造血(CD34)干细胞中胞嘧啶甲基化的全球表观遗传学模式。我们的第二个具体目标是使用我们团队设计的分析管道对基因座进行初步分析和优先排序，以公正的方式识别一组具有高度重要性和生物学相关性的基因座，用于评估功能意义并与其他细胞类型(来自脐带和孕妇外周血的淋巴细胞和白细胞以及脐静脉内皮细胞)进行比较。爱因斯坦表观基因组学中心是高通量分子技术和分析海量数据集所需的计算表观基因组信息学的资源。该中心由其中一名PI(Gally博士)领导，是一个拥有不同专业知识的个人的集中地，致力于领导表观基因组研究及其在人类疾病中的应用的发现的进展。了解发育对疾病易感性的影响的表观遗传学基础可能有助于发现早期生命标记物，这些标记物可以识别年龄相关疾病的风险个体，如T2 DM，并导致针对特定脆弱人群的更有效的预防策略。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM) is an example of a major age-related disease that has risen dramatically in adults in the last two decades(1). Indeed, the alarming rate of increase in young people is likely to maintain this steep trajectory. Perturbations of the intrauterine environment, marked by the extremes of fetal growth (intrauterine growth restriction (IUGR) and large for gestational age (LGA)), can have major effects in determining long-term disease susceptibility, particularly in regards to T2DM and cardiovascular disease(2). Although the mechanism for this remains imprecise, permanent alterations in gene expression implicate epigenetic regulation, which may serve as the biological memory of fetal conditions and may, in turn, be propagated to subsequent generations creating a transgenerational amplification. The induced adult phenotypic traits associated with IUGR and LGA vary among individuals, but share altered activity of metabolic pathways, homeostatic control processes and tissue structure and function. The commonality of susceptibility to chronic disease and involvement of multiple organ systems is analogous to the normal decline of resistance to disease that occurs with aging and suggests the advancement of this process. The induction of epigenetic alterations in utero may presage the 'age' of an individual, and therefore, susceptibility to age-related diseases, with T2DM being a specific example. We offer a novel hypothesis that conditions during fetal development alter epigenetic patterns of DNA methylation in non-embryonic stem cells, which may be a marker for, or contribute to, susceptibility to T2DM and other age-related diseases. The comparison of DNA methylation profiles induced by exposure to two diametrically opposed intrauterine 'stresses' (IUGR and LGA) may lead to greater insight into the fundamental impact of early life events that create an adult phenotype, which is more susceptible to adult-onset diseases. In addition to being potentially elucidative of the changes that occur in other tissues, the induced epigenetic modifications in this accessible, vitally important population of mulitpotent progenitors may encumber the decline in resistance to disease, thus deferring the increase in susceptibility of chronic disease associated with normal aging. Our first specific aim is to use a high-resolution genome-wide DNA methylation profiling assay, developed at our institution, to comprehensively characterize and make available the global epigenetic patterns of cytosine methylation in a single population of human hematopoietic (CD34+) stem cells isolated from umbilical cord blood of neonates with IUGR, LGA and appropriately grown controls. Our second specific aim is to use the analytic pipelines designed by our group for primary analysis and prioritization of loci, to identify in an unbiased fashion, a set of highly significant and biologically relevant loci for evaluation of functional significance and comparison in other cell types (lymphocytes and leukocytes from umbilical cord and maternal peripheral blood and umbilical vein endothelial cells). The Einstein Center for Epigenomics is a resource for high-throughput molecular technology and the computational epigenomic informatics necessary to analyze massive datasets. The Center, led by one of the PIs (Dr. Greally), is a concentration of individuals with diverse expertise that is committed to leading the advancement of discoveries for epigenomic research and its application to human disease. Understanding the epigenetic underpinning of the developmental contributions to disease susceptibility may aid in the discovery of early life markers that identify individuals at risk for age-related diseases, such as T2DM and result in more effective preventative strategies directed at a specific vulnerable population.