The Environment and Epigenome: Interplay of Toxicants and Transposons in Mammals

描述(申请人提供)：转座子的数量是人类基因组中基因数量的50倍，通过环境和表观基因组的相互作用，它们可以成为基因调控的破坏性力量。自从表观遗传学领域开始以来，只有少数基因被确定为可通过环境暴露进行表观遗传修饰。这些基因座被称为“亚稳定表位基因”。大多数这些表观遗传不稳定的区域与重复元件的偶然插入有关，导致 例如，基因相同的Agti存活黄色(Avy)小鼠不同的毛皮颜色。早些时候 研究表明，暴露于常见的环境毒物双酚A(BPA)和铅(Pb)可通过改变哺乳动物重复元件的DNA甲基化来改变表观基因组。因此，这些毒物和重复元素上的表观基因组之间的相互作用可能会产生戏剧性和持久的影响。我们不知道亚稳能力背后的支配特征，也不知道毒物暴露如何影响转座子的甲基化不稳定性。候选人的研究策略旨在发现环境毒物在多大程度上扰乱了这些自私因素必要的沉默。有趣的是，候选人的初步证据表明，与小鼠亚稳态表位基因相关的两个脑池内A粒子(IAP)转座子彼此之间的序列相似性高于基因组中的任何其他转座子。因此，这项研究的总体目标是确定系统发育相似性是否可以预测转座子DNA甲基化的不稳定性，以及早期的环境侮辱是否会改变小鼠和人类的甲基化模式。这项拟议的工作提供了将重复元素基因组学与环境表观遗传学相结合的机会，并建立了良好的生物标记物来测试暴露在环境中的小鼠和人类种群。首先，候选人将测试遗传相似和不相似转座子DNA甲基化的可变性，以确定序列一致性是否是表观遗传不稳定性的控制因素(目标1)。这些被发现可变甲基化的转座子将在整个怀孕和早期生活中暴露于环境相关水平的双酚A或铅的小鼠身上得到验证。其次，利用已经接受下一代测序的BPA暴露分层的胎儿肝脏样本，候选者将开发一种公正的方法来识别人类潜在的亚稳定转座子(目标2)。最后，用这种方法确定的人类亚稳定基因候选将在一个特征良好的正在进行的流行病学出生队列中得到验证，即墨西哥早期生命暴露于环境毒物(ELENT)研究(目标3)。该项目的成功完成将导致对先前的环境暴露进行更准确的测试，并在小鼠和人类身上识别易受环境毒物修饰的亚稳定转座子。

DESCRIPTION (provided by applicant): There are fifty times as many transposons as there are genes in the human genome, and through interaction of the environment and the epigenome, they can become a disruptive force in gene regulation. Since the inception of the field of epigenetics, only a handful of genes have been definitively identified as epigenetically modifiable by environmental exposures. Such loci are termed "metastable epialleles". Most of these epigenetically labile regions are linked to chance insertions of repetitive elements, causing for example, the varying fur colors of genetically identical Agouti viable yellow (Avy) mice. Early exposure to the common environmental toxicants bisphenol A (BPA) and lead (Pb) has been shown to alter the epigenome through global changes in DNA methylation at repetitive elements in mammals. Consequently, the interaction between these toxicants and the epigenome at repetitive elements can have dramatic and long lasting effects. We do not know the governing features underlying the capacity for metastability, nor do we understand how toxicant exposure affects methylation instability in transposons. The candidate's research strategy is designed to discover the extent to which environmental toxicants disrupt the necessary silencing of these selfish elements. Intriguingly, the candidate's preliminary evidence shows that two intracisternal A particle (IAP) transposons associated with metastable epialleles in mice have a higher sequence similarity to each other than to any other transposon in the genome. Thus the overall objective in this study is to determine if phylogenetic similarity predicts the instability of DNA methylation at transposons and whether early environmental insults shift the methylation pattern in mice and humans. The proposed work presents opportunity to merge repetitive element genomics with environmental epigenetics and establish good biomarkers to test exposed populations of mice and humans. First the candidate will test variability in DNA methylation of genetically similar and dissimilar transposons to determine whether sequence identity is a controlling factor in epigenetic instability (Aim 1). Those transposons found to be variably methylated will be validated in mice exposed to environmentally relevant levels of BPA or Pb throughout gestation and early life. Second, using fetal liver samples stratified by BPA exposure that have undergone next-generation sequencing, the candidate will develop an unbiased methodology to identify potentially metastable transposons in humans (Aim 2). Finally, human metastable loci candidates identified with this approach will be validated in a well-characterized ongoing epidemiological birth cohort, the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study (Aim 3). The successful completion of this project will result in more accurate tests of prior environmental exposures and the identification of metastable transposons susceptible to modification by environmental toxicants in both mice and humans.