Environmental toxins and stem cell epigenetic remodeling

环境毒素与干细胞表观遗传重塑

• 批准号: 8850441
• 负责人: Joyce Ellen Ohm
• 金额: $ 31.05万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850441
• 关键词: Affect; Age; Area; Biological Assay; Brain; Cells; ChIP-seq; Chemical Exposure; Chromatin; Chromatin Structure; Chronic; Complex; Cytosine; DNA; DNA Damage; DNA Methylation; DNA Modification Methylases; Data; Development; Disease susceptibility; Dose; Embryo; Embryonic Development; Environmental Exposure; Environmental Pollution; Epidemiologic Studies; Epigenetic Process; Etiology; Event; Exposure to; Family; Functional disorder; Gene Expression; Gene Expression Profile; Generations; Genes; Genome Stability; Heavy Metals; Herbicides; Human; In Vitro; Incidence; Industrial fungicide; Infertility; Lead; Left; Life; Link; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Mitotic; Modeling; Modification; Molecular; Mus; Natural regeneration; Nature; Necrosis; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Nuclear Atypia; Oxidative Stress; Paraquat; Pattern; Pesticides; Play; Polycomb; Population; Predisposition; Premalignant; Promoter Regions; Proteins; RNA Sequences; Research; Research Personnel; Role; Signal Transduction; Stem cells; Stimulus; Stress; Testing; Therapeutic; Toxic Environmental Substances; Toxic effect; Toxin; Transcription Repressor/Corepressor; Tumor Biology; Tumor Suppressor Genes; biological adaptation to stress; chromatin remodeling; disorder risk; epigenetic regulation; epigenome; epigenomics; genetic regulatory protein; human disease; in utero; interest; metaplastic cell transformation; methylation pattern; nerve stem cell; novel; oxidative damage; pluripotency; programs; promoter; protein complex; repaired; stem cell biology; stem cell population; theories; tissue regeneration; tool; transcriptome sequencing; tumor; tumor initiation

DESCRIPTION (provided by applicant): Epidemiological studies have long suggested a critical, but poorly understood, link between toxic environmental exposures early in life and the development of human disease(s) later in life. Environmental toxins produce oxidative stress in cells, and a link between oxidative stress and epigenetic changes in a cell has implications for a variety of human diseases including cancer, infertility, and multiple neurodegenerative disorders. Though limited data exists, it has also been suggested that environmental toxins may disrupt both DNA methylation patterns and chromatin structure, which can confer not only heritable changes in gene expression, but also affect overall genomic stability. However, a direct link between environmental toxins, oxidative damage and epigenetic changes has not yet been established and is the primary focus of this proposal. It is proposed that exposure to common environmental contaminants during development or during key windows of susceptibility (WOS) throughout a lifetime may induce abnormal epigenetic, pre-malignant changes in developing/differentiating cells. It is expected that this window of susceptibility coincides with the normal epigenetic remodeling required for lineage commitment during development or periods of cellular repair/regeneration. To test this idea the following three specific aims are proposed: Specific Aim 1: Determine the in vitro WOS during which the environmental toxin paraquat induces DNA methylation changes in differentiating stem cells. It is hypothesized that stem cells are vulnerable to errors in epigenetic remodeling when they receive a signal to actively remodel their chromatin, i.e. during development and tissue regeneration; Specific Aim 2: Investigate whether paraquat exposure disrupts the composition and/or functional recruitment of stem cell transcriptional repressive complexes to tumor suppressor gene promoters. It is postulated that the introduction of DNA damaging agents and prolonged exposure of cells to environmental toxins during a window of active epigenetic remodeling may cause disruption and/or abnormal recruitment of polycomb repressive complexes (PRC), the stress response protein SIRT1, and/or DNA methyltransferases to gene promoter regions with abnormal DNA methylation changes; and Specific Aim 3: Determine whether low-dose, chronic, in utero paraquat exposure induces DNA methylation changes in the developing mouse brain, disrupts neural cell plasticity, and/or enhances the malignant potential of neural stem cells in the F1 generation. It is also hypothesized that the dynamic nature of epigenetic remodeling during embryonic development may leave cells particularly vulnerable to the effects of environmental toxins. Prolonged exposure may result in the accumulation of abnormal, promoter associated DNA methylation, inhibit the ability of neuronal stem cells to properly differentiate, and may induce pre-malignant changes including abnormally high mitotic rates, nuclear atypia, or focal necrosis in these cells.

描述（由申请人提供）：长期以来，流行病学研究表明，生命早期的有毒环境暴露与人类疾病的发展之间的联系至关重要但知之甚少。环境毒素在细胞中产生氧化应激，细胞中氧化应激与表观遗传变化之间的联系对多种人类疾病（包括癌症，不育和多种神经退行性疾病）具有影响。尽管存在有限的数据，但也有人提出，环境毒素可能会破坏DNA甲基化模式和染色质结构，这不仅可以赋予基因表达的可遗传变化，而且还会影响整体基因组稳定性。但是，尚未建立环境毒素，氧化损伤和表观遗传变化之间的直接联系，并且是该提案的主要重点。有人提出，在发育过程中或在一生中易感性（WOS）的关键窗户（WOS）期间暴露于常见的环境污染物，可能会引起异常的表观遗传学，前机构变化/分化细胞。预计这种敏感性窗口与在开发或细胞修复/再生期间所需的谱系承诺所需的正常表观遗传重塑相吻合。为了测试这一想法，提出了以下三个特定目的：具体目标1：确定环境毒素的体外WO会诱导分化干细胞中的DNA甲基化变化。假设干细胞在收到信号以积极重塑其染色质时，即在发育和组织再生过程中，很容易受到表观遗传重塑的错误。特定目标2：研究帕拉quat暴露是否会破坏干细胞转录抑制复合物对肿瘤抑制基因启动子的组成和/或功能募集。据推测，在主动表观遗传重塑的窗口中，引入DNA破坏剂和细胞长期暴露于环境毒素可能会导致多孔抑制复合物（PRC）的中断和/或异常募集，应力反应蛋白SIRT1，以及/或DNA甲基转移剂与基因促进剂促进剂DNA DNA DNA DNA耐药性DNA甲基化的区域和特定的目标3：确定子宫帕拉菌暴露中的低剂量，慢性，是否诱导发育中的小鼠脑中的DNA甲基化变化，破坏神经细胞的可塑性和/或增强F1生成中神经干细胞的恶性潜力。还可以假设，胚胎发育过程中表观遗传重塑的动态性质可能会使细胞特别容易受到环境毒素的影响。长时间暴露可能会导致异常，启动子相关的DNA甲基化的积累，抑制神经元干细胞正确分化的能力，并可能诱导恶性变化，包括异常高的有丝分裂速率，核预测，或这些细胞中局灶性坏死。