Epigenetic marks of in utero exposure to gestational diabetes

描述（由申请人提供）：在美国，肥胖影响着五分之一的儿童，妊娠期糖尿病（GDM）在所有种族和民族群体中都在增加，了解生命早期甚至出生前发生的事件如何改变个体的肥胖轨迹变得越来越重要。胎儿营养过剩假说认为，糖尿病和肥胖孕妇的宫内环境可能通过发育程序永久性地改变后代患肥胖和代谢性疾病的长期风险。这种风险被假设是通过靶基因表达变化引起的细胞和组织结构和功能的永久性变化而发生的。表观遗传修饰是环境对基因表达影响的媒介，可能是参与这些过程的关键机制。EPOCH （explore Perinatal Outcomes in Relationship CHildren）研究是一项历史前瞻性队列研究，纳入了平均年龄10.5岁的儿童（首次EPOCH访问T1时采集母体和后代外周血），这些儿童在宫内生活期间暴露于或未暴露于母体GDM。EPOCH的后代现在正在进入青春期，并将再进行5年的随访（EPOCH更新最近资助；2R01 DK068001-6），第二次EPOCH随访（T2）平均在16.5岁时进行，并计划收集外周血DNA和RNA用于表观遗传和转录研究。鉴于表观遗传学在介导暴露对基因表达的影响中所起的既定作用，该提议的总体假设是，母体在子宫内暴露于GDM将与后代关键基因/途径的DNA甲基化模式的变化有关，这些表观遗传变化将介导子宫内暴露与儿童/青少年肥胖相关结果之间的关联。我们将通过图1中列出的三个具体目标对85名暴露儿童和255名未暴露儿童进行测试。简而言之，我们打算确定与子宫内GDM暴露相关的DNA甲基化变化（目标1），随后确定因果和介导肥胖相关结果的表观遗传标记（目标2），并确定持续到青春期的DNA甲基化标记（以及相关基因表达变化）（目标3）。

DESCRIPTION (provided by applicant): With obesity now affecting one in five children in the U.S. and gestational diabetes mellitus (GDM) increasing among all racial and ethnic groups, it is becoming increasingly important to understand how events that happen early in life, even before birth, can alter the obesity trajectory of individuals. The fetal over-nutrition hypothesis posits hat intrauterine environment of diabetic and obese pregnancies may permanently alter the offspring's long- term risk for obesity and metabolic diseases, through developmental programming. This risk is hypothesized to operate through permanent changes in cell and tissue structure and function induced by changes in expression of target genes. Epigenetic modifications are mediators of the effect of the environment on gene expression and are likely to be a crucial mechanism involved in these processes. The EPOCH (Exploring Perinatal Outcomes in Relationship CHildren) study is a historical prospective cohort that enrolled children aged 10.5 on average (first EPOCH visit T1 when maternal and offspring peripheral blood was collected) who were exposed or not exposed to maternal GDM during the intrauterine life. EPOCH offspring are now transitioning through puberty and will be followed for another five years (EPOCH renewal recently funded; 2R01 DK068001-6) with a second EPOCH visit (T2) occurring on average at 16.5 years and a planned collection of peripheral blood DNA and RNA for epigenetic and transcriptional studies. Given the established role of epigenetics in mediating the effects of exposure on gene expression, the overarching hypothesis of this proposal is that exposure to maternal GDM in utero will be associated with changes in DNA methylation patterns of key genes/pathways in the offspring and that these epigenetic changes will mediate the association between in utero exposure and childhood/adolescence adiposity-related outcomes. We will test this hypothesis through the three specific aims outlined in Figure 1 in 85 exposed and 255 unexposed children. Briefly, we intend to identify DNA methylation changes that are associated with in utero GDM exposure (Aim 1), followed by identification of epigenetic marks that are causal and mediate adiposity-related outcomes (Aim 2), and to identify DNA methylation marks (and associated gene expression changes) that persist into adolescence (Aim 3).