Genome-wide DNA Methylation Profiles Associated with Abnormal Intrauterine Growth

描述（由申请人提供）：2型糖尿病（T2DM）是一种主要的年龄相关疾病，在过去二十年中在成年人中急剧上升(1)。事实上，年轻人惊人的增长速度很可能会保持这种陡峭的轨迹。宫内环境的扰动，以胎儿生长的极端（宫内生长受限（IUGR）和胎龄大（LGA））为标志，可以在决定长期疾病易感性方面产生重大影响，特别是在T2DM和心血管疾病方面(2)。尽管其机制尚不明确，但基因表达的永久改变暗示了表观遗传调控，这可能作为胎儿条件的生物记忆，并可能反过来传播给后代，从而产生跨代扩增。与IUGR和LGA相关的诱导成体表型性状因个体而异，但代谢途径、稳态控制过程和组织结构和功能的活性都发生了改变。慢性疾病易感性和多器官系统受累的共性类似于随着年龄增长而发生的对疾病抵抗力的正常下降，并表明这一过程的推进。子宫内表观遗传改变的诱导可能预示着个体的“年龄”，因此，对年龄相关疾病的易感性，T2DM就是一个具体的例子。我们提出了一个新的假设，即胎儿发育过程中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2型糖尿病和其他年龄相关疾病易感性的标志或促成因素。暴露于两种截然相反的宫内“压力”（IUGR和LGA）诱导的DNA甲基化谱的比较，可能会让我们更深入地了解早期生活事件的基本影响，这些事件会产生成人表型，更容易受到成人发病疾病的影响。除了潜在地阐明发生在其他组织中的变化之外，在这个可接近的、至关重要的多能祖细胞群体中诱导的表观遗传修饰可能阻碍疾病抵抗力的下降，从而推迟与正常衰老相关的慢性疾病易感性的增加。我们的第一个具体目标是使用我们机构开发的高分辨率全基因组DNA甲基化分析方法，全面表征并提供从IUGR， LGA和适当生长对照的新生儿脐带血中分离的单个人类造血（CD34+）干细胞群体中胞嘧啶甲基化的整体表观遗传模式。我们的第二个具体目标是使用我们团队设计的分析管道进行基因座的初步分析和优先排序，以无偏倚的方式识别一组高度显著和生物相关的基因座，用于评估其他细胞类型（来自脐带和母体外周血的淋巴细胞和白细胞以及脐静脉内皮细胞）的功能意义和比较。爱因斯坦表观基因组学中心是高通量分子技术和计算表观基因组信息学的资源，分析大量数据集是必要的。该中心由一位pi （Greally博士）领导，汇集了具有不同专业知识的个人，致力于引领表观基因组研究的发现及其在人类疾病中的应用。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活标记物，识别有年龄相关疾病风险的个体，如2型糖尿病，并导致针对特定易感人群的更有效的预防策略。公共卫生相关性：出生时体重极端（即最小和最大）的婴儿成年后更容易患2型糖尿病和其他与年龄相关的疾病(1)。了解子宫内状况对慢性成人疾病的影响可能会导致发现可用于识别高危个体的标志物，并可能有助于预防慢性疾病和过早死亡。

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. Public Health Relevance: Infants born at the extremes of birth weight (i.e. the smallest and largest) are more likely to development type 2 diabetes and other age-related diseases as adults(1). Understanding the contribution of intrauterine conditions to chronic adult disease may lead to the discovery of markers that can be used to identify individuals at risk and may help to prevent chronic disease and premature death.