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。自表观遗传学领域成立以来，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。这样的基因座被称为“亚稳定表观等位基因”。大多数表观遗传不稳定区域与重复元件的偶然插入有关， 例如，遗传上相同的Agglutinalviable yellow（Avy）小鼠的不同皮毛颜色。早期 暴露于常见的环境毒物双酚A（BPA）和铅（Pb）已显示通过哺乳动物中重复元件处DNA甲基化的整体变化来改变表观基因组。因此，这些毒物与表观基因组在重复元件处的相互作用可能具有显著和持久的影响。我们不知道亚稳态能力的基本特征，也不了解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破坏这些自私元素的必要沉默的程度。有趣的是，候选人的初步证据表明，与小鼠中的亚稳态表观等位基因相关的两个脑池内A颗粒（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，本研究的总体目标是确定系统发育相似性是否预测转座子处DNA甲基化的不稳定性，以及早期环境损伤是否改变小鼠和人类的甲基化模式。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志物来测试暴露的小鼠和人类种群。首先，候选人将测试遗传相似和不相似转座子的DNA甲基化的变异性，以确定序列同一性是否是表观遗传不稳定性的控制因素（目标1）。将在整个妊娠期和生命早期暴露于环境相关水平的BPA或Pb的小鼠中验证那些被发现甲基化的转座子。其次，使用经过下一代测序的BPA暴露分层的胎肝样本，候选人将开发一种无偏倚的方法来识别人类中潜在的亚稳态转座子（目标2）。最后，将在一个特征良好的正在进行的流行病学出生队列中验证用这种方法确定的人类亚稳态基因座候选者，即墨西哥环境毒物早期暴露（ELEMENT）研究（目标3）。该项目的成功完成将导致对先前环境暴露的更准确的测试，以及对小鼠和人类中易受环境毒物修饰的亚稳态转座子的鉴定。

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.