Environmental toxins and stem cell epigenetic remodeling

环境毒素与干细胞表观遗传重塑

• 批准号: 9326729
• 负责人: Joyce Ellen Ohm
• 金额: $ 39.17万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326729
• 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; 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）：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甲基化酶转移到具有异常DNA甲基化变化的基因启动子区域；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。

项目成果

Exploiting Replication Stress as a Novel Therapeutic Intervention.

• DOI: 10.1158/1541-7786.mcr-20-0651
• 发表时间: 2021-03
• 期刊: Molecular cancer research : MCR
• 作者: Martin JC;Hoegel TJ;Lynch ML;Woloszynska A;Melendy T;Ohm JE
• 通讯作者: Ohm JE

Environmental Exposures, the Epigenome, and African American Women's Health.

环境暴露、表观基因组和非裔美国妇女的健康。

• DOI: 10.1007/s11524-018-00332-2
• 发表时间: 2019
• 期刊: Journal of urban health : bulletin of the New York Academy of Medicine
• 作者: Ohm,JoyceE

Establishing a role for environmental toxicant exposure induced epigenetic remodeling in malignant transformation.

确定环境毒物暴露在恶性转化中诱导表观遗传重塑的作用。

• DOI: 10.1016/j.semcancer.2018.11.002
• 发表时间: 2019
• 期刊: Seminars in cancer biology
• 影响因子: 14.5
• 作者: Humphrey,KristenM;Pandey,Sumali;Martin,Jeffery;Hagoel,Tamara;Grand'Maison,Anne;Ohm,JoyceE
• 通讯作者: Ohm,JoyceE