Persistent transcriptional changes induced by nickel through epigenetic alterations

镍通过表观遗传改变诱导持续转录变化

• 批准号: 9899647
• 负责人: Max Costa
• 金额: $ 45.4万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899647
• 关键词: Agar; Allergic Contact Dermatitis; Asthma; Atmosphere; Atopic Dermatitis; Binding; Binding Sites; Bronchitis; CRISPR/Cas technology; Cell-Cell Adhesion; Cells; Characteristics; Chromatin; Chromatin Structure; Consumption; Coupled; DNA Binding; Development; Disease; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Etiology; Exposure to; Fibrosis; Fossil Fuels; Gene Activation; Gene Expression; Gene Expression Alteration; Gene Silencing; Generations; Genes; Genetic Transcription; Goals; Grant; Health; Health Hazards; Histones; Human; Industrialization; Long-Term Effects; Lung; Malignant Neoplasms; Maps; Mediating; Medical Device; Mesenchymal; Methyltransferase; Molecular; Mus; Neoplasm Metastasis; Neoplastic Cell Transformation; Nickel; Nose; Nude Mice; Outcome; Pathogenicity; Phenotype; Physical condensation; Predisposing Factor; Prevention; Process; Property; Proteins; Pulmonary Edema; Pulmonary Fibrosis; Regulation; Risk; Role; Source; Stainless Steel; Structure; System; Testing; Toxic Environmental Substances; Transcription Alteration; Transitional Epithelium; Up-Regulation; Zinc Fingers; base; bronchial epithelium; differential expression; epidemiology study; epigenome; functional outcomes; genome-wide; histone modification; human disease; insight; knock-down; medical implant; novel; overexpression; prevent; promoter; transcription factor; transcriptome; tumor

Project Summary Nickel (Ni) compounds are environmental toxicants, prevalent in the atmosphere due to their use in several industrial processes, as well as extensive consumption of Ni containing products such as stainless steel, batteries, medical devices and medical implants. In addition, combustion of fossil fuels is a major source of Ni contamination in the atmosphere. Exposure to Ni is a major human health hazard, associated with a multitude of health risks including allergic contact dermatitis, bronchitis, pulmonary fibrosis, and pulmonary edema. Moreover, epidemiological studies indicate cancer development as a major outcome of Ni exposure. However, the molecular basis of Ni-induced diseases remains poorly understood. To better understand the molecular mechanisms underlying Ni-induced diseases, we investigated the effects of Ni-exposure on human epithelial cells. Our studies show that Ni-exposure-induced gene expression changes persist long after the cessation of exposure. This resulted in the cells undergoing epithelial-mesenchymal transition (EMT), and the EMT phenotype continued long after the termination of exposure. EMT is the process in which polarized epithelial cells lose cell-cell adhesion and acquire invasive and migratory mesenchymal properties. EMT is implicated in a number of diseases associated with Ni-exposure including asthma, fibrosis, cancer and metastasis. Therefore, our results suggest that persistent transcriptional changes caused by Ni exposure are likely important in the etiology of Ni-exposure associated diseases. The overarching goal of this grant is to understand the mechanisms that drive long-term transcriptional changes caused by Ni exposure. Our preliminary results suggest that Ni-exposure disrupts chromatin regulation mediated by the histone modification, H3K27me3 and the zinc finger protein, CTCF. Based on our preliminary results, we hypothesize that Ni-exposure increases chromatin accessibility through H3K27me3 loss, causing gene upregulation. CTCF binds the newly accessible chromatin and prevents H3K27me3 re-establishment after termination of Ni-exposure, thereby persistently altering gene expression. In Aim 1, we will investigate the role of H3K27me3-loss in Ni- induced persistent gene expression alterations in human lung epithelial cells. In Aim 2, we will investigate the mechanisms underlying Ni-induced persistent chromatin alterations by knocking-down CTCF and by disrupting CTCF binding sites using CRISPR/Cas9 system to examine if loss of CTCF binding could reverse Ni-induced persistent transcriptional changes. In Aim 3, we will examine the functional outcome of Ni-induced persistent transcriptional changes by investigating the tumor generating potential of Ni-exposed cells in in mice. The overall impact of our study will be the identification of the mechanisms underlying long-term transcriptional changes caused by nickel exposure, which will reveal the molecular basis of its pathogenicity, and will have major human health implications.

项目摘要 镍化合物是一种环境毒物，由于它们在几种环境中的使用而在大气中普遍存在 工业过程，以及不锈钢等含镍产品的广泛消费， 电池、医疗设备和医疗植入物。此外，化石燃料的燃烧是镍的主要来源。 大气中的污染。接触镍是一种主要的人类健康危害，与 包括过敏性接触性皮炎、支气管炎、肺纤维化和肺水肿在内的健康风险。 此外，流行病学研究表明，癌症的发展是镍接触的主要结果。然而， 镍诱发疾病的分子基础仍然知之甚少。为了更好地理解分子 镍诱发疾病的机制，我们研究了镍暴露对人上皮细胞的影响 细胞。我们的研究表明，镍暴露引起的基因表达变化在停止接触后持续很长时间 曝光。这导致细胞经历上皮-间充质转化(EMT)，并且EMT 在停止接触后很长一段时间内，表型仍在继续。EMT是极化上皮细胞 细胞失去细胞间黏附，获得侵袭性和迁移性间充质特性。EMT牵涉到一起 许多与镍接触有关的疾病，包括哮喘、纤维化、癌症和转移。因此， 我们的结果表明，镍暴露引起的持续转录变化可能在 镍接触相关疾病的病原学研究。这笔赠款的首要目标是理解 驱动镍暴露引起的长期转录变化的机制。我们的初步结果表明 镍暴露扰乱了组蛋白修饰、H3K27me3和锌介导的染色质调节 手指蛋白，CTCF.根据我们的初步结果，我们假设接触镍会增加 染色质可通过H3K27me3丢失，导致基因上调。CTCF绑定了新的 可获得染色质，并防止H3K27me3在终止镍暴露后重新建立， 从而持续地改变基因表达。在目标1中，我们将研究H3K27me3-Lost在Ni- 诱导人肺上皮细胞持续性基因表达改变。在目标2中，我们将调查 镍诱导持续染色质改变的机制：击倒CTCF和干扰 用CRISPR/Cas9系统检测CTCF结合位点的丢失是否能逆转镍诱导的CTCF结合 持续的转录变化。在目标3中，我们将检查镍诱导的持续性的功能结局 通过研究镍暴露细胞在小鼠体内的致瘤能力来研究转录的变化。整体而言 我们研究的影响将是确定长期转录变化的机制 由镍引起，这将揭示其致病的分子基础，并将对人类产生重大影响 对健康的影响。