Environmental toxins and stem cell epigenetic remodeling

环境毒素与干细胞表观遗传重塑

• 批准号: 8538392
• 负责人: Joyce Ellen Ohm
• 金额: $ 30.43万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538392
• 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 Methyltransferase; 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; Gene Expression Regulation; 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; epigenome; epigenomics; genetic regulatory protein; human disease; in utero; interest; metaplastic cell transformation; nerve stem cell; novel; oxidative damage; pluripotency; programs; promoter; protein complex; repaired; stem cell biology; stem cell population; theories; tissue regeneration; tool; 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）：流行病学研究长期以来一直表明，生命早期的有毒环境暴露与生命后期人类疾病的发展之间存在重要但知之甚少的联系。环境毒素在细胞中产生氧化应激，并且细胞中氧化应激和表观遗传变化之间的联系对多种人类疾病包括癌症、不育症和多种神经退行性疾病具有影响。虽然数据有限，但也有人认为环境毒素可能会破坏DNA甲基化模式和染色质结构，这不仅会导致基因表达的遗传变化，而且还会影响整体基因组稳定性。然而，环境毒素，氧化损伤和表观遗传变化之间的直接联系尚未建立，这是本提案的主要重点。有人提出，暴露于常见的环境污染物在发展过程中或在整个生命周期的敏感性（WOS）的关键窗口期间可能会诱导发育/分化细胞的异常表观遗传，恶变前的变化。预期该易感性窗口与发育或细胞修复/再生期间谱系定型所需的正常表观遗传重塑一致。具体目标1：确定环境毒素百草枯在分化干细胞中诱导DNA甲基化变化的体外WOS。据推测，干细胞是脆弱的错误表观遗传重塑时，他们收到的信号，积极重塑他们的染色质，即在发展和组织再生;具体目标2：调查是否百草枯暴露破坏的组成和/或功能招聘的干细胞转录抑制复合物肿瘤抑制基因启动子。据推测，在活性表观遗传重塑的窗口期间，DNA损伤剂的引入和细胞长期暴露于环境毒素可能导致多梳抑制复合物（PRC）、应激反应蛋白SIRT 1和/或DNA甲基转移酶的破坏和/或异常募集至具有异常DNA甲基化变化的基因启动子区域;以及具体目标3：确定低剂量、长期、子宫内百草枯暴露是否会诱导发育中的小鼠大脑DNA甲基化变化，破坏神经细胞可塑性，和/或增强F1代神经干细胞的恶性潜能。还假设胚胎发育期间表观遗传重塑的动态性质可能使细胞特别容易受到环境毒素的影响。长期暴露可能导致异常启动子相关DNA甲基化的积累，抑制神经元干细胞正确分化的能力，并可能诱导这些细胞中的恶性前变化，包括异常高的有丝分裂率、核分裂或局灶性坏死。