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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

基本信息

批准号：
10515635
负责人：
Max Costa
金额：
$ 41.39万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10515635
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 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 Predisposition Prevention Process Property Proteins Pulmonary Edema Pulmonary Fibrosis Regulation Risk Role Source Stainless Steel Structure System Testing Toxic Environmental Substances Transcription Alteration Up-Regulation Zinc Fingers 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

项目摘要

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.

项目总结