Particulate matter-induced changes in DNA methylome and transcriptome

 描述（由申请人提供）：颗粒物（PM）空气污染是一个全球性的环境健康问题，每年导致370万人过早死亡，占全球所有死亡人数的6.7%。这些死亡主要是由于急性心肺疾病的增加。尽管降低PM水平的努力导致PM引起的发病率和死亡率降低，但PM与心肺疾病之间的关联仍然存在。有必要早期识别个人谁是在PM诱导的心肺疾病的风险，以进一步减少疾病的负担。暴露于PM与DNA的表观遗传修饰有关，如DNA甲基化（5 mC）和羟甲基化（5 hmC），这些修饰调节基因转录。这些表观遗传变化的评估可能有助于识别个人的风险发展PM诱导的心肺疾病。越来越多的研究表明，PM诱导表观遗传变化，但这些发现的影响是有限的，因为这些研究集中在重复元件的甲基化模式，而没有详细的分析整个基因组。此外，这些研究是在替代细胞如血液白细胞和鼻上皮细胞中进行的，与靶组织没有任何相关性。目前尚不清楚外周血单核细胞中DNA甲基化或羟甲基化的变化是否也可以在靶组织或细胞如肺上皮细胞、肺泡巨噬细胞或主动脉内皮细胞中发现。在初步研究中，我们发现PM治疗引起了表观遗传变化，其特征在于鼻和肺上皮细胞和肺泡巨噬细胞中5 mC减少和5 hmC增加。除了表观遗传学的变化，PM诱导的一些基因的表达相似和其他人的差异表达在原代人鼻和肺上皮细胞离体和PM暴露在体内的小鼠模型。PM诱导的原代人鼻上皮细胞基因表达和DNA甲基化的变化在个体之间以及男性和女性之间是不同的，这表明宿主相关因素如遗传、年龄和性别在影响PM诱导的反应中起重要作用。基于我们的初步数据，我们假设替代细胞（鼻上皮细胞和外周血单核细胞）中DNA甲基化和羟甲基化以及基因表达（RNA-seq）的变化可用于预测靶组织（肺上皮细胞和巨噬细胞，心脏和主动脉）中的这些变化。在目标1中，使用通过吸入PM暴露的临床相关小鼠模型，我们将确定PM诱导的DNA甲基化组和转录组的变化在替代物（鼻上皮和外周血单核细胞）和靶细胞（肺泡上皮细胞、巨噬细胞、心脏和主动脉）中如何不同。在目标2中，我们将确定宿主相关因素（品系、性别和年龄）是否影响PM诱导的替代细胞和靶细胞中DNA甲基化组和转录组的变化，在目标3中，我们将确定PM诱导的替代细胞和靶细胞中DNA甲基化组和转录组的变化是否在整个寿命期内持续存在。

 DESCRIPTION (provided by applicant): Particulate matter (PM) air pollution is a global environmental health problem that causes 3.7 million premature deaths annually, representing 6.7% of all deaths worldwide. These deaths are largely due to increased acute cardiopulmonary disease. Although efforts to abate PM levels led to reduction in PM-induced morbidity and mortality, the association between PM and cardiopulmonary disease still persists. There is need for early identification of individuals who are at risk for PM-induced cardiopulmonary disease to reduce the burden of disease further. Exposure to PM is associated with epigenetic modifications of DNA such as DNA methylation (5mC) and hydroxymethylation (5hmC) that regulate gene transcription. Assessment of these epigenetic changes may help with the identification of individuals at risk for development of PM-induced cardiopulmonary diseases. Increasing number of studies demonstrate that PM induces epigenetic changes but the implications of these findings are limited because these studies focused on the methylation patterns of the repetitive elements without detailed analysis of the whole genome. Furthermore, the studies were done in surrogate cells such as blood leukocytes and nasal epithelial cells without any correlation in target tissues. It is not known whether changes in DNA methylation or hydroxymethylation in peripheral blood monocytes can also be found in the target tissue or cell such as lung epithelial cells, alveolar macrophages or aortic endothelial cells. In preliminary studies, we found that PM treatment caused epigenetic changes characterized by reduction in 5mC and increased 5hmC in nasal and lung epithelial cells and alveolar macrophages. In addition to epigenetic changes, PM induced similar expression of some genes and differential expression of others in primary human nasal and lung epithelial cells ex vivo and in a murine model of PM exposure in vivo. PM-induced changes in gene expression and DNA methylation in primary human nasal epithelial cells were different among individuals as well as between males and females suggesting an important role for host-related factors such as genetics, age and sex in influencing the PM-induced responses. Based on our preliminary data, we hypothesized that changes in DNA methylation and hydroxymethylation and the gene expression (RNA-seq) in surrogate cells (nasal epithelial cells and peripheral blood mononuclear cells) can be used to predict those changes in target tissues (lung epithelial cells, and macrophages, heart and aorta). Using a clinically relevant murine model of PM exposure via inhalation, in Aim 1, we will determine the how PM-induced changes in DNA methylome and transcriptome differ in surrogate (nasal epithelium, and peripheral blood monocytes) and target cells (alveolar epithelial cells, macrophages, heart and aorta). In Aim 2, we will determine whether the host related factors (strain, sex and age) affect PM-induced changes in DNA methylome and transcriptome in surrogate and target cells and in Aim 3, we will determine whether the PM-induced changes in DNA methylome and transcriptome in surrogate and target cells persist throughout the lifespan.