Environmental toxins and stem cell epigenetic remodeling

环境毒素与干细胞表观遗传重塑

• 批准号: 8390167
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8390167
• 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; 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. PUBLIC HEALTH RELEVANCE: A role for environmental toxins in tumor initiation has long been suggested and continues to be an area of particular interest for cancer researchers, as populations with increased exposure to pesticides, herbicides, fungicides, and heavy metals have been shown to have increased cancer incidence. Chemical exposures in utero are of particular concern, as development is dependent on a tightly orchestrated epigenetic remodeling program. This proposal seeks to directly assay the role of exposure to environmental toxins in the induction of abnormal epigenetic drift and disruption of stem cell pluripotency, and investigates a potential role for these toxins in tumor etiology. This proposal will investigate the mechanisms by which oxidative damage may be mechanistically linked to these epigenetic changes and mediate pre- malignant changes at a molecular level in this vulnerable stem cell population. We will also identify novel relationships between the stem cell and developmental proteins that may be involved (including the strongly implicated Polycomb family of transcriptional repressors) and both known and unknown epigenetic regulatory protein complexes. This study has significant potential for increasing our understanding the role of environmental epigenomics in tumor-initiating events in humans, and seeks to identify key mechanisms responsible for these changes. This study is also expected to identify embryonic factors and epigenetic modifications that play a role in tumor initiation and may be exploited for therapeutic purposes.

描述（由申请人提供）：流行病学研究长期以来一直表明，生命早期接触有毒环境与晚年人类疾病的发展之间存在着重要的联系，但人们对此知之甚少。环境毒素会在细胞中产生氧化应激，氧化应激与细胞表观遗传变化之间的联系对多种人类疾病（包括癌症、不孕症和多种神经退行性疾病）有影响。尽管数据有限，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，这不仅会导致基因表达发生遗传性变化，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确定，这是该提案的主要焦点。有人提出，在整个一生的发育过程中或关键易感窗口（WOS）期间接触常见的环境污染物可能会导致发育/分化细胞发生异常的表观遗传、癌前变化。预计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。为了检验这一想法，提出了以下三个具体目标： 具体目标 1：确定体外 WOS，在此期间环境毒素百草枯诱导分化干细胞中的 DNA 甲基化变化。据推测，当干细胞收到积极重塑其染色质的信号时，即在发育和组织再生过程中，它们很容易在表观遗传重塑中出错；具体目标 2：调查百草枯暴露是否会破坏干细胞转录抑制复合物向肿瘤抑制基因启动子的组成和/或功能募集。据推测，在活跃的表观遗传重塑窗口期间，DNA损伤剂的引入和细胞长时间暴露于环境毒素可能会导致多梳抑制复合物（PRC）、应激反应蛋白SIRT1和/或DNA甲基转移酶对具有异常DNA甲基化变化的基因启动子区域的破坏和/或异常募集；具体目标 3：确定低剂量、长期的子宫内百草枯暴露是否会诱导发育中小鼠大脑中的 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。还假设胚胎发育过程中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。长时间暴露可能导致异常的启动子相关DNA甲基化的积累，抑制神经元干细胞正常分化的能力，并可能诱发癌前变化，包括异常高的有丝分裂率、核异型性或这些细胞的局灶性坏死。 公共卫生相关性：长期以来，人们一直认为环境毒素在肿瘤发生中的作用，并且仍然是癌症研究人员特别感兴趣的领域，因为事实证明，接触杀虫剂、除草剂、杀菌剂和重金属的人群会增加癌症发病率。子宫内的化学物质暴露尤其值得关注，因为发育依赖于严格精心策划的表观遗传重塑程序。该提案旨在直接分析暴露于环境毒素在诱导异常表观遗传漂移和干细胞多能性破坏中的作用，并研究这些毒素在肿瘤病因学中的潜在作用。该提案将研究氧化损伤与这些表观遗传变化之间的机制，并在分子水平上介导这一脆弱干细胞群的癌前变化。我们还将确定干细胞和可能涉及的发育蛋白（包括密切相关的转录抑制蛋白 Polycomb 家族）以及已知和未知的表观遗传调节蛋白复合物之间的新关系。这项研究对于增进我们对环境表观基因组学在人类肿瘤引发事件中的作用的理解具有巨大的潜力，并试图确定导致这些变化的关键机制。这项研究还有望确定在肿瘤发生中发挥作用并可用于治疗目的的胚胎因素和表观遗传修饰。