EPIGENETIC ALTERATIONS AS MARKERS OF THE INTRAUTERINE ENVIRONMENT

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在后基因组时代，我们对基因和环境之间相互作用的理解正在大大增强。有几个设置中的重要性，这种基因-环境接口是更深刻的比在子宫内发育，其中的“关键窗口”是狭窄的，在中断或修改可以影响胎儿的发展，以及导致整个生命过程中的健康规划。这种现象，现在被称为“胎儿编程”，是基因环境相互作用的模型，可以告知环境和发育的分子特征的协同效应的机制基础。胎儿编程和许多其他学科的研究现在集中在基因调控发生在DNA序列之外的范式上。表观遗传调控的关键作用，有丝分裂和减数分裂的基因表达的遗传控制不相关的DNA序列，在发展过程中是这个建议的主题。我们和其他人在癌症和发育方面的工作表明，表观遗传控制容易受到环境压力和侮辱的影响。这些表观遗传学改变的最佳特征是细胞DNA胞嘧啶甲基化的变化，特别是特定重复元件处基因组DNA的低甲基化，以及导致其功能失活的特定基因启动子的超甲基化。这些改变作为人类研究中的生物标志物特别重要，因为它们在功能上与基因表达的变化相关，但表现出相对持久性。对围产期发育中这些表观遗传改变的特定分子特征的研究还不太全面。胎盘在调节环境信号中起着至关重要的作用。关键的胎盘功能和胎盘基因表达对环境损伤作出反应并被其“标记”。我们假设，对宫内环境的不良影响导致异常的表观遗传学改变，可以在胎盘表观基因组中捕获。我们建议这些标记物可以作为生物标志物，定义一个“分子足迹”，这可能是推广到各种不利的子宫内条件。我们进一步假设，这些变化可以作为妊娠期间发生的事件的不良影响的标志。由于对其他病理学的潜在普遍性和对成人疾病的深远影响，我们将使用宫内生长受限（IUGR）作为我们的模型来检查胎盘表观基因组的改变作为宫内环境的标志物。我们的背景和强大的患者资源可用于COBRE围产期生物学使我们非常适合这项调查。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our understanding of the interplay between the genes and the environment is being greatly enhanced in the post-genome era. There are few settings where the importance of this gene-environment interface is more profound than during intrauterine development, where the "critical windows" are narrower and where disruption or modification can influence fetal development as well as lead to programming of health throughout the life course. This phenomenon, now known as "fetal programming", is a model of gene environment interaction and can inform the mechanistic basis of the synergistic effect(s) of the environment and the molecular character of development. Research in fetal programming and many other disciplines is now focusing on the paradigm that gene regulation occurs beyond the DNA sequence. The critical role of epigenetic regulation, the mitotically and meiotically heritable control of gene expression not related to DNA sequence, during development is the subject of this proposal. Our work and others' in cancer and development has demonstrated that epigenetic control is susceptible to stresses and insults from the environment. Among the best characterized of these epigenetic alterations are changes to cellular DNA cytosine methylation, particularly hypomethylation of genomic DNA at specific repetitive elements, and hypermethylation of specific gene promoters leading to their functional inactivation. These alterations are particularly important as biomarkers in human studies because they are functionally related to changes in gene expression, yet exhibit a relative permanence. Examination of the specific molecular character of these epigenetic alterations in perinatal development has been less comprehensive. The placenta plays a crucial role in modulating environmental signals. Crucial placental functions and placental gene expression respond to and are "marked" by environmental insults. We hypothesize that adverse effects on the intrauterine environment lead to aberrant epigenetic alterations which can be captured in the placental epigenome. We propose that these marks can serve as biomarkers defining a "molecular footprint" which may be generalizable to a variety of adverse intrauterine conditions. We further hypothesize that these alterations can be used as a marker of the adverse influence of events which occur during gestation. Due to the potential generalizability to other pathologies and the profound effects already demonstrated on adult disease, we will use intrauterine growth restriction (IUGR) as our model to examine alterations to the placental epigenome as markers of intrauterine environment. Our background and the robust patient resources available to the COBRE for Perinatal Biology make us uniquely suited for this investigation.