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:9899647
- 负责人:
- 金额:$ 45.4万
- 依托单位:
- 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:
- 关键词:AgarAllergic Contact DermatitisAsthmaAtmosphereAtopic DermatitisBindingBinding SitesBronchitisCRISPR/Cas technologyCell-Cell AdhesionCellsCharacteristicsChromatinChromatin StructureConsumptionCoupledDNA BindingDevelopmentDiseaseEnvironmentEpigenetic ProcessEpithelialEpithelial CellsEpitheliumEtiologyExposure toFibrosisFossil FuelsGene ActivationGene ExpressionGene Expression AlterationGene SilencingGenerationsGenesGenetic TranscriptionGoalsGrantHealthHealth HazardsHistonesHumanIndustrializationLong-Term EffectsLungMalignant NeoplasmsMapsMediatingMedical DeviceMesenchymalMethyltransferaseMolecularMusNeoplasm MetastasisNeoplastic Cell TransformationNickelNoseNude MiceOutcomePathogenicityPhenotypePhysical condensationPredisposing FactorPreventionProcessPropertyProteinsPulmonary EdemaPulmonary FibrosisRegulationRiskRoleSourceStainless SteelStructureSystemTestingToxic Environmental SubstancesTranscription AlterationTransitional EpitheliumUp-RegulationZinc Fingersbasebronchial epitheliumdifferential expressionepidemiology studyepigenomefunctional outcomesgenome-widehistone modificationhuman diseaseinsightknock-downmedical implantnoveloverexpressionpreventpromotertranscription factortranscriptometumor
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Max Costa的其他文献
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{{ truncateString('Max Costa', 18)}}的其他基金
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:
10077549 - 财政年份:2020
- 资助金额:
$ 45.4万 - 项目类别:
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:
10515635 - 财政年份:2020
- 资助金额:
$ 45.4万 - 项目类别:
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:
10294236 - 财政年份:2020
- 资助金额:
$ 45.4万 - 项目类别:
Arsenic and Nickel Carcinogenesis in Human Lung Cells
砷和镍对人肺细胞的致癌作用
- 批准号:
10470848 - 财政年份:2019
- 资助金额:
$ 45.4万 - 项目类别:
Arsenic carcinogenesis and disruption of histone variant H3.3 assembly
砷致癌和组蛋白变体 H3.3 组装的破坏
- 批准号:
10407027 - 财政年份:2019
- 资助金额:
$ 45.4万 - 项目类别:
MEG3 deletion drives lung tumorigenesis due to environmental nickel exposure
由于环境镍暴露,MEG3 缺失导致肺部肿瘤发生
- 批准号:
9852426 - 财政年份:2019
- 资助金额:
$ 45.4万 - 项目类别:
Arsenic and Nickel Carcinogenesis in Human Lung Cells
砷和镍对人肺细胞的致癌作用
- 批准号:
10004646 - 财政年份:2019
- 资助金额:
$ 45.4万 - 项目类别:
Arsenic carcinogenesis and disruption of histone variant H3.3 assembly
砷致癌和组蛋白变体 H3.3 组装的破坏
- 批准号:
10631227 - 财政年份:2019
- 资助金额:
$ 45.4万 - 项目类别:
Arsenic and Nickel Carcinogenesis in Human Lung Cells
砷和镍对人肺细胞的致癌作用
- 批准号:
10681242 - 财政年份:2019
- 资助金额:
$ 45.4万 - 项目类别:
Arsenic and Nickel Carcinogenesis in Human Lung Cells
砷和镍对人肺细胞的致癌作用
- 批准号:
10245059 - 财政年份:2019
- 资助金额:
$ 45.4万 - 项目类别:
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