Particulate matter-induced changes in DNA methylome and transcriptome

颗粒物诱导的 DNA 甲基化组和转录组变化

• 批准号: 9273532
• 负责人: Gokhan M. Mutlu
• 金额: $ 62.15万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273532
• 关键词: Abate; Acute; Adolescent; Adult; Affect; Age; Age-Months; Air Pollution; Alveolar; Alveolar Macrophages; Aorta; Biological; Blood Cells; Breathing; C57BL/6 Mouse; Cardiac Myocytes; Cardiopulmonary; Cells; Cessation of life; Chronic; DNA; DNA Methylation; DNA Modification Process; Data; Development; Disease; Early identification; Endothelial Cells; Environmental Health; Epigenetic Process; Epithelial Cells; Epithelium; Event; Exposure to; Female; Gene Expression; Genes; Genetic; Genetic Transcription; Harvest; Heart; Human; Inbred BALB C Mice; Individual; Leukocytes; Life; Longevity; Lung; Mono-S; Morbidity - disease rate; Mouse Strains; Mus; Nasal Epithelium; Nose; Nuclear; Particulate Matter; Pattern; Peripheral Blood Mononuclear Cell; Play; Pulmonary Heart Disease; Repetitive Sequence; Risk; Role; Switch Genes; Testing; Time; Tissues; age effect; aged; air filter; base; burden of illness; clinically relevant; differential expression; experimental study; genome-wide; global environment; in vivo; macrophage; male; methylation pattern; methylome; monocyte; mortality; mouse model; peripheral blood; pregnant; premature; prenatal exposure; public health relevance; response; seal; sex; transcriptome; transcriptome sequencing; whole genome

 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.

 描述（由适用提供）：颗粒物（PM）空气污染是一个全球环境健康问题，每年导致370万例死亡，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增加。尽管减轻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。需要尽早确定有PM引起的心肺疾病风险的个体，以进一步减少疾病的燃烧。暴露于PM与DNA的表观遗传修饰有关，例如DNA甲基化（5MC）和调节基因转录的羟甲基（5HMC）。对这些表观遗传变化的评估可能有助于确定有PM诱导的心肺疾病风险的个体。越来越多的研究表明，PM诱导表观遗传变化，但是这些发现的含义受到限制，因为这些研究集中在重复元素的甲基化模式上，而没有对整个基因组进行详细分析。此外，研究是在替代细胞中进行的，例如血清细胞和鼻皮细胞，而目标时间没有任何相关性。在初步研究中，尚不清楚在外周血单核细胞中DNA甲基化或羟甲基化的变化，我们发现PM治疗引起的上皮变化，其特征是5MC的降低，鼻腔和肺上皮细胞和肺泡细胞和肺泡巨噬细胞的降低和5HMC的增加。除了表观遗传变化外，PM还引起了某些基因的相似表达，而在原发性人类鼻和肺上皮细胞中的其他基因表达则是体内的，以及在体内PM暴露的鼠模型中。 PM诱导的基因表达和DNA甲基化在原发性鼻鼻上皮细胞中以及男性和女性之间的不同，这表明与宿主相关因素（例如遗传学，年龄和性别影响PM诱导的反应）的重要作用。根据我们的初步数据，我们假设替代细胞中DNA甲基化和羟甲基化的变化以及基因表达（RNA-SEQ）（鼻皮上上皮细胞和外周血单核细胞）可用于预测目标时间中的这些变化（肺上皮细胞，肺部和巨噬细胞，心脏和心脏，心脏和依然酸）。在AIM 1中，使用临床相关的PM暴露鼠模型，我们将确定PM诱导的DNA甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基和转录组的变化如何在替代物（鼻上皮细胞和外周血单细胞）和靶细胞（肺泡上皮细胞，元素上皮细胞，乳腺癌，心脏，心脏和ATRORTA）中如何不同。在AIM 2中，我们将确定与宿主相关的因素（应变，性别和年龄）会影响PM诱导的替代物和靶细胞中DNA甲基甲基和转录组的变化，并且在AIM 3中，我们将确定PM诱导的DNA甲基甲基组和替代物中替代物和靶细胞中的转录组的变化是否在整个生命周期内持续存在。